2. Antibacterial Activity
Natural products represent an important potential source of new antibacterial drugs [
27], particularly those that prevent biofouling by barnacles, tubeworms, mussels, and other “smothering” marine organisms [
28,
29].
Many gorgonian soft coral metabolites are biofilm inhibitors. For example, the South China Sea gorgonian
Dichotella gemmacea has yielded several antibacterial briarane diterpenoids
1–
12, several of which contain chlorine, as summarized in
Figure 1 [
30,
31].
Figure 1.
Structures of gemmacolide briarane diterpenoids from
Dichotella gemmacea [
30,
31].
Figure 1.
Structures of gemmacolide briarane diterpenoids from
Dichotella gemmacea [
30,
31].
Of these gemmacolides, N (
1), O (
2), and Q (
4) show antibacterial activity against the Gram-negative bacterium
E. coli in the agar diffusion assay, with the chlorinated gemmacolide O being the most active [
30]. Antitumor and antifungal activities are discussed in the appropriate sections to follow.
The prolific gorgonian
Dichotella gemmacea is also the source of numerous new briarane diterpenoids, the dichotellides, many of which contain chlorine or iodine or both [
32,
33,
34]. In particular, of the 16 novel briarane diterpenoids, dichotellides F–U, found in
Dichotella gemmacea, H (
13), I (
14), K (
15), L (
16), M (
17), N (
18), O (
19), P (
20), and U (
21) exhibit potent antifouling activities (
Figure 2;
Table 1) [
34].
Figure 2.
Structures of selected dichotellide briarane diterpenoids from
Dichotella gemmacea [
34].
Figure 2.
Structures of selected dichotellide briarane diterpenoids from
Dichotella gemmacea [
34].
Table 1.
Biofouling activity of dichotellides (
13–
21) against the larval settlement of the barnacle
Balanus amphitrite [
34].
Table 1.
Biofouling activity of dichotellides (13–21) against the larval settlement of the barnacle Balanus amphitrite [34].
Compound | EC50 (μg/mL) a | LC50/EC50 b |
---|
H (13) | 4.1 | >24 |
I (14) | 1.82 | >54.9 |
K (15) | 6.3 | >16 |
L (16) | 7.6 | >13 |
M (17) | 4.6 | >11 |
N (18) | 1.2 | >88 |
O (19) | 5.6 | >18 |
P (20) | 0.79 | >126.6 |
U (21) | 2.0 | >48 |
The South China Sea gorgonian
Junceella fragilis has also yielded 12 new briarane diterpenoids, fragilisinins A–L (
22–
33) (
Figure 3), several of which have potent antifouling activity, but are not superior to the previously known junceelloide A and junceellonoid D (
Table 2) [
35].
Figure 3.
Structures of fragilisinins A–L briarane diterpenoids from
Junceella fragilis [
35].
Figure 3.
Structures of fragilisinins A–L briarane diterpenoids from
Junceella fragilis [
35].
Table 2.
Biofouling activity of fragilisinins against the larval settlement of the barnacle
Balanus amphitrite [
35].
Table 2.
Biofouling activity of fragilisinins against the larval settlement of the barnacle Balanus amphitrite [35].
Compound | EC50 (μM) | LC50/EC50 |
---|
fragilisinin E (30) | 14.0 | >13 |
fragilisinin F (32) | 12.6 | >14.5 |
fragilisinin J (25) | 11.9 | >11.5 |
junceellolide A (34) | 5.6 | >33.3 |
junceellonoid D (35) | 10.0 | >20 |
positive control a | 2.5 | – |
An examination of the Chinese soft coral
Sinularia rigida has yielded 19 new cembrane diterpenoids, the sinulariols, of which J (
36) and P (
37) display antifouling activity against
B. amphitrite (5.65 μg/mL) and
B. neritina (14.03 µg/mL), respectively (
Figure 4). The one chlorine-containing example, sinulariol E (
38) is less active [
36].
Figure 4.
Structures of selected sinulariol cembrane diterpenoids from
Sinularia rigida [
36].
Figure 4.
Structures of selected sinulariol cembrane diterpenoids from
Sinularia rigida [
36].
Potent antifouling activity is observed in some newly isolated resorcylic acid lactones found in the fungus
Cochlionbolus lunatus derived from the gorgonian
Dichotella gemmacea. Thus obtained were cochliomycins A–C (
39–
41) (
Figure 5) [
37,
38]. Only cochliomycin A (
39) shows potent activity against
Balanus amphitrite (EC
50 1.2 μg/mL; LC
50/EC
50 > 16.7), which was superior to the known analogues zeaenol, LL-Z1640-1, and LL-Z1640-2. Insufficient material of cochliomycins B and C was available for testing.
Figure 5.
Structures of cochliomycins A–C (
39–
41) from
Cochliobolus lunatus [
37,
38].
Figure 5.
Structures of cochliomycins A–C (
39–
41) from
Cochliobolus lunatus [
37,
38].
Another soft-coral derived fungus,
Pestalotiopsis sp. from the South China Sea
Sarcophyton sp., contains the novel (±)-pestalachloride D (
42) and the known analogue (±)-pestalachloride C (
43) (
Figure 6) [
39,
40]. Both compounds are active against the bacteria
E. coli,
Vibrio anguillarum, and
Vibrio parahaemolyticus with MIC values of 5.0, 10.0, and 20.0 µM, respectively [
39].
Figure 6.
Structures of (±)-pestalachlorides D (
42) and C (
43) from
Pestalotiopsis sp. [
39,
40].
Figure 6.
Structures of (±)-pestalachlorides D (
42) and C (
43) from
Pestalotiopsis sp. [
39,
40].
The Antarctic soft coral
Alcyonium roseum has yielded the two new illudalanes, alcyopterosins
44 and
45 (
Figure 7) [
41]. Although insufficient material was available for antibacterial testing, the authors believe that these metabolites may be feeding deterrents for the predatory sea star
Odontaster validus and have antifouling activity, based on similar properties of related alcyopterosins. The soft-coral associated actinomycetes strain,
Streptomyces sp. OUCMDZ-1703 has yielded the novel strepchloritides A (
46) and B (
47), which exhibit modest activity against
E. coli,
Pseudomonas aeruginosa, and
S. aureus (
Figure 7).
Figure 7.
Structures of alcyopterosins
44 and
45 from
Alcyonium roseum [
41], and strepchloritides A (
46) and B (
47) from
Streptomyces sp. OUCMDZ-1703 [
42].
Figure 7.
Structures of alcyopterosins
44 and
45 from
Alcyonium roseum [
41], and strepchloritides A (
46) and B (
47) from
Streptomyces sp. OUCMDZ-1703 [
42].
The Mediterranean gorgonian
Paramuricea clavata is reported to contain three new brominated metabolites, 2-bromo-
N-methyltryptamine (
48), 3-bromo-
N-methyltyramine (
49), and 6-bromo-
N-methyltryptamine (
50) (
Figure 8) in addition to several known analogues [
43]. Compound
50 was previously known from synthesis. Of the ten compounds tested,
48 shows the highest activity in preventing adhesion of three bacterial strains (
Pseudoalteromonas sp. D41 and TC8, and
Paracoccus sp. 4M6). However, insufficient material was available for toxicity screening.
The marine sponge
Pseudoceratina sp. has yielded numerous brominated alkaloids with biological activity [
2,
3,
4], including the four new pseudoceramines A–D (
51–
54) collected from this sponge in the Great Barrier Reef, Queensland, Australia (
Figure 9) [
44]. Pseudoceramine B (
52) inhibits bacterial growth with IC
50 40 µM.
Figure 8.
Brominated compounds
48–
50 from
Paramuricea clavata [
43].
Figure 8.
Brominated compounds
48–
50 from
Paramuricea clavata [
43].
Figure 9.
Structures of pseudoceramines A–D (
51–
54) from the sponge
Pseudoceratina sp. [
44].
Figure 9.
Structures of pseudoceramines A–D (
51–
54) from the sponge
Pseudoceratina sp. [
44].
Of the 12 bromotyrosines isolated from the southern Australian sponge
Pseudoceratina sp., four were new metabolites: aplysamine-7 (
55), (–)-purealin B (
56), purealin C (
57), and purealin D (
58) (
Figure 10) [
45]. Purealin C shows a broad spectrum of activity against two strains each of the Gram-positive
S. aureus (IC
50 2.6 and 6.2 µM) and
B. subtilis (IC
50 2.6 and 2.8 µM), while (–)-purealin B is only active against
B. subtilis (IC
50 3.4 and 3.8 µM).
Figure 10.
Structures of bromotyrosines
55–
58 from the sponge
Pseudoceratina sp. [
45].
Figure 10.
Structures of bromotyrosines
55–
58 from the sponge
Pseudoceratina sp. [
45].
A collection of the sponge
Iotrochota purpurea from Hainan Island, China, has yielded the ten new halogenated purpuroines A–J (
59–
68), five of which contain iodine (
Figure 11) [
46]. In addition to antifungal activity to be discussed in the next section, purpuroine I (
67) shows selective inhibition of the human pathogen
Streptococcus pneumonia (IC
50 18.06 ± 0.76 µg/mL; ampicillin, IC
50 0.38 ± 0.029 µg/mL).
Figure 11.
Structures of purpuroines A–J (
59–
68) from the sponge
Iotrochota purpurea [
46].
Figure 11.
Structures of purpuroines A–J (
59–
68) from the sponge
Iotrochota purpurea [
46].
The deep-sea Great Australian Bight sponge,
Axinella sp., contains the three new brominated imidazoles, 14-
O-sulfate massadine (
69), 14-
O-methyl massadine (
70), and 3-
O-methyl massadine chloride (
71) (
Figure 12) [
47]. The latter chlorine-containing metabolite (
71) exhibits antibacterial activity against the Gram-positive bacteria
Staphylococcus aureus (ATCC 9144 and 25923; IC
50 3.7 and 4.2 µM, respectively) and
B. subtilis (ATCC 6051 and 6633; IC
50 2.6 and 2.2 µM, respectively), and the Gram-negative bacteria
E. coli (ATCC 11775; IC
50 4.4 µM) and
P. aeruginosa (ATCC 10145; IC
50 4.9 µM). The effect of the chlorine atom is noteworthy.
Figure 12.
Structures of massadines
69–
71 from the sponge
Axinella sp. [
47].
Figure 12.
Structures of massadines
69–
71 from the sponge
Axinella sp. [
47].
A deep-water
Asteropus sponge from the Bahamas contains the novel indolo[3,2-
a]carbazoles
72 and
73 (
Figure 13);
72 shows some activity against methicillin-resistant
S. aureus (MRSA; minimum inhibitory concentration (MIC) of 50 µg/mL [
48].
Figure 13.
Structures of indolo[3,2-
a]carbazoles
72 and
73 from the sponge
Asteropus sp. [
48].
Figure 13.
Structures of indolo[3,2-
a]carbazoles
72 and
73 from the sponge
Asteropus sp. [
48].
Examination of the southern Australian sponge
Ianthella sp. has revealed the presence of dictyodendrins F–J (
74–
78) (
Figure 14) [
49]. Antibacterial activity is limited to the Gram-positive
B. subtilis (ATCC 6051 and 6633):
74 (IC
50 2.7 and 2.3 µM),
76 (IC
50 1.2 and 3.1 µM), and
77 (IC
50 2.5 and 2.8 µM).
Figure 14.
Structures of dictyodendrins F–J (
74–
78) from the sponge
Ianthella sp. [
49].
Figure 14.
Structures of dictyodendrins F–J (
74–
78) from the sponge
Ianthella sp. [
49].
A series of structurally novel indole alkaloids was isolated from the Okinawan sponge
Suberites sp., including nakijinamines A (
79), B (
80), F (
81), G (
82), H (
83), I (
84), and 6-bromoconicamin (
85) (
Figure 15) [
50]. An earlier study by this same research team identified the related nakijinamines C–E (not shown) [
51]. Of these alkaloids, only nakijinamine A (
79) is active against
S. aureus (MIC 16 µg/mL),
B. subtilis (MIC 16 µg/mL), and
Micrococcus luteus (MIC 2 µg/mL). Nakijinamine I (
84) is the first aaptamine-type alkaloid to have a 1,4-dioxane unit.
Figure 15.
Structures of nakijinamines
79–
84 and 6-bromoconicamin (
85) from the sponge
Suberites sp. [
50].
Figure 15.
Structures of nakijinamines
79–
84 and 6-bromoconicamin (
85) from the sponge
Suberites sp. [
50].
The Okinawan sponge
Agelas sp. is a rich source of brominated pyrrole alkaloids and several recent studies have added to this collection. The agelasines O–U (
86–
92) from
Agelas sp. (NSS-19) are novel diterpene alkaloids tethered to a 9-
N-methyladenine unit (
Figure 16) [
52]. Of these alkaloids, only agelasines O–R (
86–
89) and T (
91) show activity against
S. aureus and
B. subtilis (MIC 8.0–32.0 µg/mL), but not against
E. coli (MIC ≥ 32.0 µg/mL). For both strains the activity decreases: Q (
88) ~ R (
89) > O (
86) ~ T (
91) > P (
87).
Figure 16.
Structures of agelasines O–U (
86–
92) from the sponge
Agelas sp. [
52].
Figure 16.
Structures of agelasines O–U (
86–
92) from the sponge
Agelas sp. [
52].
Another examination of the sponge
Agelas sp. (SS-162) from the Kerama Islands, Okinawa, has led to the isolation of the new bromopyrrole alkaloids, 2-bromokeramadine (
93), 2-bromo-9,10-dihydrokeramadine (
94), tauroacidins C (
95) and D (
96), and mukanadin G (
97) (
Figure 17) [
53]. Of these bromopyrroles, only 2-bromokeramadine (
93) shows (weak) activity against
E. coli, although mukanadin G (
97) has moderate antifungal activity (next section). The highly complex agelamadins A (
98) and B (
99) were also characterized in the Okinawan sponge
Agelas sp. (SS-162) (
Figure 18) [
54]. Both bromopyrroles are active against
B. subtilis (MIC, 16 µg/mL each) and
Micrococcus luteus (MIC, 4.0 and 8.0 µg/mL, respectively). The related agelamadins C–E exhibit only antifungal activity as shown in the next section.
The South China Sea sponge
Acanthella cavernosa contains eight new chlorinated diterpenoids, kalihinols M–T (
100–
107) (
Figure 18). In addition, seven previously isolated analogues were isolated [
55]. Kalihinols O (
102), P (
103), Q (
104), R (
105), S (
106), and T (
107) exhibit significant antifouling activity against
Balanus amphitrite larvae: EC
50 1.43, 0.72, 1.48, 1.16, 0.53, and 0.74 µM, respectively.
Figure 17.
Structures of bromopyrroles
93–
99 from the sponge
Agelas sp. (SS-162) [
53,
54].
Figure 17.
Structures of bromopyrroles
93–
99 from the sponge
Agelas sp. (SS-162) [
53,
54].
Figure 18.
Structures of kalihinols M–T (
100–
107) from the sponge
Acanthella caverenosa [
55].
Figure 18.
Structures of kalihinols M–T (
100–
107) from the sponge
Acanthella caverenosa [
55].
While no new marinopyrroles were reported in the time frame for this review, it is important to cite an excellent survey of these antibacterial marine halogenated pyrroles [
56] and an equally excellent report on their activity against methicillin-resistant
S. aureus, including synthetic marinopyrrole analogues [
57].
Like gorgonians and marine sponges, algae employ a chemical arsenal to prevent bacterial smothering (biofouling), and several examples of halogenated antibacterial compounds have been isolated from algae.
Figure 19.
Structures of red algae metabolites
108–
114 [
58,
59,
60].
Figure 19.
Structures of red algae metabolites
108–
114 [
58,
59,
60].
The prodigious organohalogen-producing red alga
Asparagopsis taxiformis “limu kohu,” which is the favorate edible seaweed of native Hawaiians, and the source of more than 100 organohalogens [
2,
3], contains the unusual mahorone (
108) and 5-bromomahorone (
109) (
Figure 19) [
58]. Both compounds are highly toxic to the marine bacterium
Vibrio fisheri (EC
50 0.16 µM for both), and both are most active against the Gram-negative bacterium
Acinebacter baumanni and lesser activity towards
E. coli and
S. aureus. The red alga
Plocamiun angustum metabolite plocamenone (
110) inhibits the growth of
B. subtilis comparable to that of chloramphenicol (inhibition zone of 10 mm
vs. 12 mm, respectively). Species of
Laurencia red algae continue to reveal novel halogenated natural products. A Chinese collection of
Laurencia okamurae yielded the three new laurokamins A–C (
112–
114) (
Figure 19) [
60], but only laurokamins B (
113) and C (
114) show (weak) activity against
E. coli (6 mm inhibition diameter).
Three omaezallenes (
115–
117) were isolated and characterized from a collection of
Laurencia sp. from Omaezaki, Japan (
Figure 20) [
61]. Of the three metabolites, omaezallene (
115) was the most active in an antifouling assay against the larvae of the barnacle
Amphibalanus amphitrite (EC
50 0.22 µg/mL), but only weakly toxic to the larvae (LC
50 4.8 µg/mL). The other metabolites have:
116, EC
50 0.30 µg/mL, and
117, EC
50 1.5 µg/mL.
Figure 20.
Structures of omaezallenes
115–
117 from the red alga
Laurencia sp. [
61].
Figure 20.
Structures of omaezallenes
115–
117 from the red alga
Laurencia sp. [
61].
A collection of Formosan
Laurencia brongniarii afforded the new polybrominated indole, 4,5,6-tribromo-2-methylsulfinylindole (
118) in addition to 11 known brominated indoles (
Figure 21) [
62]. Although
118 is inactive, of the known indoles,
119–
121 show significant antibacterial activity against
Enterobacter aerogenes (ATCC 13048),
Salmonella enteritidis (ATCC 13076), and
Serratia marcescens (ATCC 25419). Several bromoditerpenes were characterized from the red alga,
Sphaerococcus coronopifolius, living in the Berlenga Nature Reserve, Peniche, Portugal. These include the new sphaerodactylomelol (
122) and the previous known sphaeranes
123–
126 (
Figure 21) [
63]. Although no activity against
E. coli (ATCC 25922) and
Pseudomonas aeruginosa (ATCC 27853) is observed for
122–
126, sphaerodactylomelol (
122),
123, and
125 are active against
S. aureus (IC
50 96.30, 22.42, and 6.35 µM, respectively).
Figure 21.
Structures of bromoindoles
118–
121 and bromosphaerols
122–
126 [
62,
63].
Figure 21.
Structures of bromoindoles
118–
121 and bromosphaerols
122–
126 [
62,
63].
The Fijian red alga
Callophycus sp. has yielded five new bromophycoic acids A–E (
127–
131) (
Figure 22) [
64]. These new examples of diterpene-benzoate marine natural products possess a range of biological activities, including antibacterial. For example, all five compounds are active against methicillin-resistant
S. aureus (MIC 1.6–6.3 µg/mL) with bromophycoic acid A (
127) being comparable to vancomycin (1.6
vs. 2 µg/mL). Likewise, bromophycoic acids A and E are active against vancomycin-resistant
Enterococcus facium (MIC 6.3 and 1.6 µg/mL, respectively).
The ascidian
Synoicum sp. collected from Korean waters was found to contain eudistomins Y
2–Y
7 (
132–
137) (
Figure 23) [
65]. These known β-carbolines display a range of activity against both Gram-positive and Gram-negative bacteria (
Table 3). This study also included the synthesis of several hydroxyl analogues via sodium borohydride reduction of the carbonyl group, but no improvement in antibacterial activity is observed. Although
132–
137 were previously described, antibacterial activity was not reported [
66].
Another examination of this ascidian from Korea has revealed the presence of nine new brominated furanones, cadiolides
138–
142 and synoilides
143–
146 (
Figure 24) [
67]. Cadiolides H and synoilides A and B are interconverting
Z and
E isomers. Simultaneously with this study, another group isolated cadiolide E (
138) along with the related cadiolides C (
147), D (
148), and F (
149) from the ascidian
Pseudodistoma antinboja (
Figure 24) [
68]. Like the eudistomins (
Table 3), the cadiolides display significant antibacterial activity against both Gram-positive and Gram-negative bacteria (
Table 4). The synoilides (
143–
146) show much weaker or no activity against these bacteria. Cadiolide F (
149) and rubrolides P (
150) and Q (
151) also exist as interconverting
Z and
E isomers.
Figure 22.
Structures of bromophycoic acids A–E (
127–
131) from the red alga
Callophycus sp. [
64].
Figure 22.
Structures of bromophycoic acids A–E (
127–
131) from the red alga
Callophycus sp. [
64].
Figure 23.
Structures of eudistomins Y
2–Y
7 (
132–
137) from the ascidian
Synoicum sp. [
65].
Figure 23.
Structures of eudistomins Y
2–Y
7 (
132–
137) from the ascidian
Synoicum sp. [
65].
Table 3.
Antibacterial activity of eudistomins Y
2–Y
7 (
132–
137) (MIC µg/mL) [
65].
Table 3.
Antibacterial activity of eudistomins Y2–Y7 (132–137) (MIC µg/mL) [65].
Bacterium | Y2 (132) | Y3 (133) | Y4 (134) | Y5 (135) | Y6 (136) | Y7 (137) |
---|
Staphylococcus aureus (ATCC 6538p) | 50 | 12.5 | 3.125 | 6.25 | 1.56 | 3.125 |
Bacillus subtilis (ATCC 6633) | 25 | 12.5 | 0.78 | 3.125 | 1.56 | 0.78 |
Micrococcus luteus (IFO 12708) | 25 | 12.5 | 1.56 | 3.125 | 1.56 | 1.56 |
Salmonella typhimurium (ATCC 14028) | 50 | 6.25 | 0.39 | 0.78 | 0.39 | 0.78 |
Proteus vulgaris (ATCC 3851) | 25 | 6.25 | 0.39 | 1.56 | 0.78 | 0.78 |
Escherichia coli (ATCC 35270) | >100 | >100 | 50 | 100 | 50 | 50 |
Similar to the cadiolides are the rubrolides and, in addition to rubrolides P (
150) and Q (
151), four new examples were found in a South African
Synoicum globosum ascidian, 3″-bromorubrolide F (
152), 3′-bromorubrolide E (
153), 3′-bromorubrolide F (
154), and 3′,3″-dibromorubrolide E (
155) (
Figure 25) [
69]. The previously known non-brominated rubrolides E (
156) and F (
157) were also isolated from this animal, and all six rubrolides display varying degrees of antibacterial activity (
Table 5). It is noted that 3′-bromorubrolide F (
154) is identical to rubrolide Q (
151).
Figure 24.
Structures of the cadiolides, synoilides, and rubrolides (
138–
151) from the ascidians
Synoicum and
Pseudodistoma antinboja [
67,
68].
Figure 24.
Structures of the cadiolides, synoilides, and rubrolides (
138–
151) from the ascidians
Synoicum and
Pseudodistoma antinboja [
67,
68].
Table 4.
Antibacterial activity of cadiolides E, G, H, and I (
138–
142,
147–
149) and rubrolides P and Q (
150,
151) (MIC µg/mL) [
67,
68].
Table 4.
Antibacterial activity of cadiolides E, G, H, and I (138–142, 147–149) and rubrolides P and Q (150, 151) (MIC µg/mL) [67,68].
Bacterium | 138 | 139 | 140/141 | 142 | 147 | 148 | 149 | 150 | 151 |
---|
Staphylococcus aureus | 3.1 | 3.1 | 6.3 | 0.8 | 0.4 | 6.3 | 12.5 | 50 | 50 |
Bacillus subtilis | 1.6 | 12.5 | 1.6 | 0.8 | 3.1 | 6.3 | 12.5 | 50 | 50 |
Kocuria rhizophilia | 0.8 | 3.1 | 3.1 | 0.8 | – | – | – | – | – |
Salmonella enterica | 1.6 | 0.8 | 3.1 | 1.6 | – | – | – | – | – |
Proteus hauseri | 3.1 | 3.1 | 3.1 | 6.3 | – | – | – | – | – |
Escherichia coli | >100 | >100 | >100 | >100 | – | – | – | – | – |
Staphylococcus epidermidis | – | – | | | 0.4 | 0.8 | 6.3 | 50 | 25 |
Kocuria rhizophila | – | – | | | 0.2 | 1.6 | 3.1 | 6.3 | 3.1 |
Figure 25.
Structures of rubrolides
152–
157 from the ascidian
Synoicum globosum [
69].
Figure 25.
Structures of rubrolides
152–
157 from the ascidian
Synoicum globosum [
69].
Table 5.
Antibacterial activity of rubrolides
152–
157 from the ascidian
Synoicum globosum (IC
50 µM) [
69].
Table 5.
Antibacterial activity of rubrolides 152–157 from the ascidian Synoicum globosum (IC50 µM) [69].
Bacterium | 152 | 153 | 154 | 155 | 156 | 157 |
---|
MRSA a (ATCC BAA-1720) | 256 | 82 | 360 | 89 | 105 | 1006 |
Staphylococcus epidermidis (ATCC 35984) | 98 | 38 | 42 | 28 | 21 | 79 |
Enterococcus faecalis (ATCC 700802) b | 43 | 16 | 2 | 2 | 89 | 47 |
Escherichia coli (0157:H7) b | 22 | 0 | 14 | 25 | 16 | 15 |
The ascidian
Synoicum pulmonaria from the Norwegian coast contains synoxazolidinones A (
158) and C (
159), and pulmonarins A (
160) and B (
161) (
Figure 26) [
70]. The two synoxazolidinones display broad activity against fouling marine species and
159 is comparable to the most active commercial antifouling product, Sea-Nine-211. In contrast, the pulmonarins prevent bacterial growth but have lower activity against microalgae and no activity towards barnacles (
Table 6). In addition, several analogues were synthesized, but are generally less active than their natural counterparts.
Figure 26.
Structures of synoxazolidinones A (
158) and C (
159), and pulmonarians A (
160) and B (
161) from the ascidian
Synoicum pulmonaria [
70].
Figure 26.
Structures of synoxazolidinones A (
158) and C (
159), and pulmonarians A (
160) and B (
161) from the ascidian
Synoicum pulmonaria [
70].
Table 6.
Adhesion growth inhibition of synoxazolidiones A (
158) and C (
159), and pulmonarin A (
160) from the ascidian
Synoicum pulmonaria [
70]
a.
Table 6.
Adhesion growth inhibition of synoxazolidiones A (158) and C (159), and pulmonarin A (160) from the ascidian Synoicum pulmonaria [70] a.
| 156 | 159 | 160 | 161 |
---|
| Ad b | Gr c | Ad | Gr | Ad | Gr | Ad | Gr |
---|
Marine Bacteria |
Halomonas aquamarina | 20 | – | – | 2 | 3 | – | – | – |
Polaribacter irgensii | – | 20 | 20 | 2 | – | 0.2 | – | – |
Pseudoalteromonas elyakovii | – | 0.02 | – | 20 | – | 0.2 | – | – |
Roseobacter litoralis | – | 0.02 | 2 | 0.2 | 0.03 | – | 20 | – |
Shewanella putrefaciens | – | 0.2 | – | 20 | – | – | – | – |
Vibrio aestuarians | – | 0.02 | 2 | 0.2 | 0.03 | – | 20 | – |
Vibrio carchariae | – | 2 | 20 | 2 | 3 | – | 20 | – |
Vibrio harveyi | – | – | 2 | 0.02 | – | – | – | – |
Vibrio natriegens | – | 0.02 | 20 | 2 | 0.03 | – | 20 | – |
Vibrio proteolylicus | – | 0.02 | 2 | 0.02 | – | – | – | – |
Microalgae |
Cylindrotheca closterium | 20 | 20 | 2 | 0.2 | – | – | – | – |
Exanthemachrysis gayraliae | 20 | 20 | 2 | 0.2 | – | – | – | – |
Halamphora coffeaeformis | 20 | 20 | 2 | 2 | 30 | – | – | – |
Pleurochrysis roscoffensis | 20 | 20 | 2 | 2 | – | – | – | – |
Porphyridium purpureum | – | 20 | 0.2 | 0.02 | – | 0.2 | – | – |
Crustacean Settlement |
Balanus improvisus (IC50) | 15 | | 2 | | – | | – | |
Several novel antibacterial organohalogen marine fungal metabolites have been discovered in recent years. The fungus
Bartalinia robillardoides (strain LF550), which was isolated from the Mediterranean sponge
Tethya aurantium, produces three novel chloroazaphilones, helicusin E (
162), isochromophilone X (
163), and isochromophilone XI (
164) (
Figure 27) [
71]. Only isochromophilone XI (
164) shows antibacterial activity against
B. subtilis (IC
50 55.6 µM) and
Staphylococcus lentus (IC
50 78.4 µM), which is slightly less active than the previously known deacetylsclerotiorin, also isolated from this fungus.
Figure 27.
Structures of fungal metabolites
162–
164 from the fungus
Bartalinia robillardoides strain LF550 [
71].
Figure 27.
Structures of fungal metabolites
162–
164 from the fungus
Bartalinia robillardoides strain LF550 [
71].
The deep-sea derived
Spiromastix sp. fungus (collected at 2869 meters) has furnished 15 new spiromastixones A–O (
165–
179) (
Figure 28) [
72]. These novel chlorodepsidones display impressive antibacterial activity against the Gram-positive bacteria
S. aureus (ATCC 29213),
Bacillus thuringensis (SCS10 BT01), and
B. subtilis (SCS10 BT01), but not against the Gram-negative
E. coli (ATCC 25922). For example, spiromastixone J (
175) has 0.125, 0.25, and 0.125 µg/mL, respectively, against the three Gram-positive bacteria. Moreover,
175 is strongly inhibitory towards MRSA, methicillin-resistant
Staphylococcus epidermidis (MRSE), and vancomycin-resistant
Enterococcus faecalis and
E. faecium (VSE). Spiromastixones F–I (
171–
174) are also potent inhibitors of MRSA and MRSE, and are superior to levofloxacin. This activity increases with an increasing number of chlorines.
Figure 28.
Structures of spiromastixones A–O (
165–
179) from the fungus
Spiromastix sp. [
72].
Figure 28.
Structures of spiromastixones A–O (
165–
179) from the fungus
Spiromastix sp. [
72].
Marine bacteria also produce antibacterial compounds, including those that contain halogen. Merochlorins A–D (
180–
183) are novel meroterpenoids isolated from the marine bacterium
Streptomyces sp. strain CNH-189 from a California coastal sediment (
Figure 29) [
73,
74]. Both merochlorins A (
180) and B (
181) are active against MRSA (2–4 µg/mL), and
180 is active
in vitro against
Clostridium difficile.
Figure 29.
Structures of merochlorins A–D (
180–
183) from
Streptomyces sp. CNH-189 [
73,
74].
Figure 29.
Structures of merochlorins A–D (
180–
183) from
Streptomyces sp. CNH-189 [
73,
74].
Another California marine sediment contains
Streptomyces strains CNQ-329 and CNH-070, which produce the six novel napyradiomycins A–F (
184–
189) (
Figure 30) along with three previously known napyradiomycins B2–B4 (e.g., B3 =
190) [
75]. Of these metabolites, napyradiomycins A (
184) and B3 (
190) are the most active against MRSA (MIC 16 and 2 µg/mL, respectively).
Figure 30.
Structures of napyradiomycins A–F (
184–
189) from
Streptomyces CNQ-329 and CNH-070 [
75].
Figure 30.
Structures of napyradiomycins A–F (
184–
189) from
Streptomyces CNQ-329 and CNH-070 [
75].
A Chinese collection of the marine-derived
Streptomyces sp. SCS10 10428 has afforded the three new napyradiomycins
191–
193, in addition to several known analogues, including napyradiomycins B1 and B3 (
190) (
Figure 31) [
76]. Metabolites
191 and
192 are strongly active against
S. aureus ATCC 29213 (MIC 4 and 0.5 µg/mL, respectively), and all three napyradiomycins are active against
B. thuringiensis SCS10 BT01 and
B. subtilis SCS10 BS01 (MIC 1–6 µg/mL).
Figure 31.
Structures of napyradiomycins
191–
193 [
76].
Figure 31.
Structures of napyradiomycins
191–
193 [
76].
From a coastal sediment in Germany there was isolated the novel salimabromide (
194), produced by the marine myxobacterium
Enhygromxya salina (
Figure 32) [
77]. This structurally unusual compound has modest activity only against
Arthrobacter cristallopoedes.
Figure 32.
Structure of salimabromide (
194) from the marine myxobacterium
Enhygromxya salina [
77].
Figure 32.
Structure of salimabromide (
194) from the marine myxobacterium
Enhygromxya salina [
77].
Cyanobacteria (blue-green algae) are prodigious producers of biologically active organohalogen natural products, and a collection of
Leptolyngbya crossbyana found overgrowing on Hawaiian coral yielded the new honaucins A–C (
195–
197) (
Figure 33) [
78]. All three compounds inhibit quorum sensing against
Vibrio harveyi BB120 (IC
50 5.6, 17.6, and 14.6 µM, respectively), and to a lesser extent towards
E. coli JB525. Interestingly, the synthetic brominated and iodinated analogues of honaucin A (
195) are more active in quorum sensing inhibition than the natural honaucin A itself. A Guamanian cyanobacterium which is very similar to
Lyngbya produces the novel biologically active lipids pitinoic acids A–C (
198–
200), which inhibit quorum sensing in the Gram-negative bacterium
Pseudomonas aeruginosa (
Figure 33) [
79].
Figure 33.
Structures of honaucins A–C (
195–
197) from the cyanobacterium
Leptolyngbya crossbyana [
78], and pitinoic acids A–C (
198–
200) from a cyanobacterium [
79].
Figure 33.
Structures of honaucins A–C (
195–
197) from the cyanobacterium
Leptolyngbya crossbyana [
78], and pitinoic acids A–C (
198–
200) from a cyanobacterium [
79].
3. Antifungal Activity
In addition to their often potent antibacterial activity (
vide supra), many marine sponges contain halogenated metabolites with powerful antifungal properties. The new tetramic acid glycoside, aurantoside K (
201), was isolated from a Fijian sponge belonging to the genus
Melophlus (
Figure 34) [
80]. Auranotoside K is a demethylated analogue of the previously known aurantoside I. Although devoid of antibacterial, antimalarial, and cytotoxicity in the assays examined,
201 displays broad antifungal activity towards
Candida albicans (wild type ATCC 32354 and amphotericin-resistant ATCC 90873; MIC 31.25 and 1.95 µg/mL, respectively),
Cryptococcus neoformans,
Aspergillus niger,
Penicillium sp.,
Rhizopus sporangia, and
Sordaria sp. The Indonesian sponge
Theonella swinhoei has yielded the new aurantoside J (
202), which is an epimer of the previously known auranotoside G (
Figure 34) [
81]. The new
202 differs from aurantoside G at the anomeric center C-1′ of the xylose sugar unit. Antifungal activity of
202 is negligible compared to that of aurantosides G and I.
Figure 34.
Structure of aurantoside K (
201) from the sponge
Melophlus sp. [
80] and aurantoside J (
202) from the sponge
Theonella swinhoei [
81].
Figure 34.
Structure of aurantoside K (
201) from the sponge
Melophlus sp. [
80] and aurantoside J (
202) from the sponge
Theonella swinhoei [
81].
A Red Sea specimen of
Theonella swinhoei contains the antifungal glycopeptide theonellamide G (
203) (
Figure 35), which is very similar to the known theonellamide A, lacking only a methyl group on the
p-bromophenylalanine and a hydroxyl group in the α-aminoadipic acid group [
82]. Theonellamide G shows potent antifungal activity against both wild and amphotericin B-resistant strains of
Candida albicans; IC
50 4.49 and 2.0 µM, respectively. The positive control amphotericin B had 1.48 µM against the wild type
Candida albicans.
Figure 35.
Structure of theonellamide G (
203) from the sponge
Theonella swinhoei [
82].
Figure 35.
Structure of theonellamide G (
203) from the sponge
Theonella swinhoei [
82].
The New Zealand sponge
Hamigera tarangaensis has yielded a suite of new hamigerans (
204–
211) (
Figure 36), in addition to several known related hamigerans [
83]. Hamigeran G (
205) also exists as an enol tautomer, and hamigeran F (
204) undergoes what appears to be an acid-catalyzed retro-aldol transformation (observed in a CDCl
3 solution of
204). Hamigeran G selectively inhibits the growth of two strains of the yeast
Saccharomyces cerevisiae.
Figure 36.
Structures of hamigerans
204–
211 from the sponge
Hamigera tarangaensis [
83].
Figure 36.
Structures of hamigerans
204–
211 from the sponge
Hamigera tarangaensis [
83].
The indolo[3,2-
a]carbazole
72 from the deep-water sponge
Asteropus sp. is antifungal towards
Candida albicans (MIC 25 µg/mL), but
73 is not [
48]. Similarly, purpuroine D (
61) is active against
C. albicans (IC
50 19.03 ± 0.12 µg/mL), and purpuroines A (
59), C (
60), and D (
61) inhibit the human disease-causing
Aspergillus fumigates (IC
50 28.58 ± 0.52, 26.07 ± 0.55, 25.56 ± 0.44 µg/mL, respectively) [
46]. The previously cited nakijinamine A (
79) shows antifungal activity towards
C. albicans (IC
50 0.25 µg/mL),
Cryptococcus neoformans (IC
50 0.5 µg/mL), and
Trichophyton mentagrophytes (IC
50 0.25 µg/mL). Less activity against
C. albicans is seen with nakijinamines B (
80) and F (
81) (IC
50 8 µg/mL each) [
50]. The
Agelas sponge metabolites, agelasines O (
86), P (
87), Q (
88), R (
89), and T (
91) show varying degrees of activity against the fungi
C. albicans,
Aspergillus niger,
Trichophyton mentagrophytes, and
Cryptococcus neoformans, with the greatest activity towards the latter fungus by Q (
88) and R (
89) (IC
50 8.0 µg/mL each) [
52]. Similarly, these four fungi species are inhibited by the
Agelas bromopyrroles
93–
97, especially mukanadin G (
97) against
C. albicans and
Cryptococcus neoformans (IC
50 16 and 8.0 µg/mL, respectively) [
53]. In addition to the
Agelas sp. sponge metabolites agelamadins A (
98) and B (
99) [
54], the new agelamadins C–E (
212–
214) (
Figure 37) are also present in this sponge [
84]. Antifungal activity is displayed against
Cryptococcus neoformans by agelamadins A (
98), B (
99), C (
212), and E (
214) (IC
50 8.0, 4.0, 32, 32 µg/mL, respectively [
54,
84].
Figure 37.
Structures of agelamadins C–E (
212–
214) from the sponge
Agelas sp. SS-162 [
84].
Figure 37.
Structures of agelamadins C–E (
212–
214) from the sponge
Agelas sp. SS-162 [
84].
Further examination of
Agelas spp. (SS-162 and SS-156) sponges from Okinawa reveals the presence of nagelamides U–W (
216–
218) [
85], X–Z (
219–
221) [
86], 2-debromonagelamide U (
222), 2-debromomukanadin (
223), and 2-debromonagelamide P (
224) [
87] (
Figure 38). Antifungal activity against several fungi is summarized in
Table 7, for which nagelamide Z (
221) shows significant activity towards all four fungi.
Marine algae can exhibit antifungal activity and several recent examples are described. The red alga
Laurencia composita, collected from Pingtan Island, China, has afforded novel chamigranes, the laurecomins A–D (
225–
228) (
Figure 39) [
88]. Of these, laurecomin B (
226) is antifungal towards
Colletotrichum lagenarium (inhibitory diameter of 10 mm).
A collection of
Laurencia okamurai from Nanji Island, China, has furnished several new brominated sesquiterpenes,
seco-laurokamurone (
229), laurepoxyene (
230), 3β-hydroperoxyaplysin (
231), 3α-hydroperoxy-3-epiaplysin (
232), 8,10-dibromoisoaplysin (
233), and laurokamurene D (
234) (
Figure 40) [
89]. Antifungal activity of
230–
233 is tabulated in
Table 8.
Figure 38.
Structures of nagelamides U–Z (
216–
221) and
222–
224 from
Agelas spp. sponges [
85,
86,
87].
Figure 38.
Structures of nagelamides U–Z (
216–
221) and
222–
224 from
Agelas spp. sponges [
85,
86,
87].
Table 7.
Antifungal activity of nagelamides U–Z (
216–
221) and
222–
224 [
85,
86,
87].
Table 7.
Antifungal activity of nagelamides U–Z (216–221) and 222–224 [85,86,87].
| Compound (IC50 µg/mL) |
---|
Fungus | 216 | 218 | 219 | 220 | 221 | 222 | 223 | 224 |
---|
Candida albicans | 4 | 4 | 2.0 | 2.0 | 0.25 | – | – | – |
Trichophyton mentagrophytes | – | – | 16 | <32 | 4.0 | 16 | – | 32 |
Cryptococcus neoformans | – | – | <32 | <32 | 2.0 | 32 | 32 | – |
Aspergillus niger | – | – | 32 | <32 | 4.0 | – | – | – |
Figure 39.
Structures of laurecomins A–D (
225–
228) from the red alga
Laurencia composita [
88].
Figure 39.
Structures of laurecomins A–D (
225–
228) from the red alga
Laurencia composita [
88].
Figure 40.
Structures of brominated sesquiterpenes
229–
234 from the red alga
Laurencia okamurai [
89].
Figure 40.
Structures of brominated sesquiterpenes
229–
234 from the red alga
Laurencia okamurai [
89].
Table 8.
Antifungal activity of brominated sesquiterpenes
230–
233 from the red alga
Laurencia okamurai [
89].
Table 8.
Antifungal activity of brominated sesquiterpenes 230–233 from the red alga Laurencia okamurai [89].
| Compound a |
---|
Fungus | 230 | 231 | 232 | 233 | Amphotericin B b | Fluconazole b |
---|
Cryptococcus neoformans (32609) | >64 | 4 | 8 | >64 | 1 | 1 |
Candida glabrata (537) | 2 | 4 | >64 | >64 | 2 | 1 |
Trichophyton rubrum | 32 | 16 | >64 | >64 | 1 | >64 |
Aspergillus fumigatus (07544) | >64 | >64 | >64 | >64 | 2 | 8 |
The red alga
Symphyocladia latiuscula from the coast of Qingdao, China, is a rich source of brominated phenols, and several new examples have been discovered (
235–
245) (
Figure 41) [
90,
91,
92]. Bromocatechols
235,
242, and
244 display moderate activity against
Candida albicans (MIC 37.5, 10, and 25 µg/mL, respectively) [
90,
91,
92].
Weak antifungal activity is observed for gemmacolides T–Y (
7–
12) against
Microbotryum violaceum and
Septoria tritici, in the zone of inhibition ranging from 9.5–17 mm [
31]. Two of the
Synoicum sp. ascidian eudistomins, Y
2 (
132) and the non-brominated Y
1, show potent to moderate activity against
Candida albicans (MIC 6.25 and 50 µg/mL, respectively) [
65]. The other eudistomins Y
3–Y
7 are inactive against the four fungal strains tested. A study of the bryozoan
Chartella membranaceatruncata, collected in Kandalaksha Bay, the White Sea, resulted in the characterization of 2,4,7-tribromotryptamine (
246) (
Figure 42), which displays potent activity towards
Candida albicans and
Saccharomyces cereviseae, although this result was not quantified [
93].
Figure 41.
Structures of symphyocladins A–G (
236–
242) and other bromophenols from the red alga
Symphyocladia latiuscula [
90,
91,
92].
Figure 41.
Structures of symphyocladins A–G (
236–
242) and other bromophenols from the red alga
Symphyocladia latiuscula [
90,
91,
92].
Figure 42.
Structure of 2,4,7-tribromotryptamine (
246) from the bryozoan
Chartella membranaceatruncata [
93].
Figure 42.
Structure of 2,4,7-tribromotryptamine (
246) from the bryozoan
Chartella membranaceatruncata [
93].
Several marine-derived bacteria have antifungal properties, such as strepchloritide B (
47), from
Streptomyces sp. OUCMDZ-1703, towards
Candida albicans (13 ± 0.5 mm inhibitory diameter zone) [
42], and the extraordinarily complex forazoline A (
247), from
Actinomadura sp. cultivated from the ascidian
Ecteinascidia turbinata, towards
Candida albicans (MIC 16 µg/mL) [
94]. This unique marine polyketide is also active
in vivo in a disseminated candidiasis model in mice, with no toxicity. This important antifungal compound may prove to be a clinical candidate to treat
Candida albicans fungal infections in humans such as candidiasis, which affects some 400,000 people annually with a mortality rate of 46%–75% [
95]. Indeed, fungal infections of all types cause 1.5 million deaths per year worldwide [
96].
Figure 43.
Structure of forazoline A (
247) from
Actinomadura sp. [
94].
Figure 43.
Structure of forazoline A (
247) from
Actinomadura sp. [
94].
The fungal metabolite isochromophilone XI (
164), from
Bartalinia robillardoides, is active against the fungus
Trichophyton rubrum (IC
50 41.5 µM), but not against
Candida albicans and
Septoria tritici [
71]. The Baltic Sea cyanobacterium
Anabaena cylindrica Bio33, cultivated in the laboratory, has provided the antifungal lipopeptides balticidins A–D (
248–
251) (
Figure 44) [
97,
98]. These complex metabolites are active towards
Candida maltosa with inhibition zones for balticidins A–D of 12, 15, 9, and 18 mm, respectively [
97]. Antifungal activity with these compounds is also observed against
C. albicans,
Candida krusei,
Aspergillus fumigatus,
Microsporum gypseum,
Mucor sp., and
Microsporum canis. No antibacterial activity is observed for these compounds.
Figure 44.
Structures of balticidins A–D (
248–
251) from the cyanobacterium
Anabaena cylindrica Bio33 [
97,
98].
Figure 44.
Structures of balticidins A–D (
248–
251) from the cyanobacterium
Anabaena cylindrica Bio33 [
97,
98].
6. Antitumor Compounds
Of enormous concern to all mankind is cancer—the inexorable transformation of normal cells and the proliferation of cancerous cells into tumors. The marine environment provides an array of metabolites active against cancer cells.
Amongst all marine life, sponges have afforded the vast majority of anti-tumor compounds. The Vietnamese sponge
Penares sp. contains the novel alkaloids,
322 and
323 (
Figure 59), the former of which is moderately cytotoxic to the human tumor cell lines HL-60 (lung) and HeLa (cervix), IC
50 16.1 and 33.2 µM, respectively, whereas
323 is inactive [
126].
Figure 59.
Structures of
322 and
323 from the sponge
Penares sp. [
126].
Figure 59.
Structures of
322 and
323 from the sponge
Penares sp. [
126].
The novel polyketides, PM050489 (
324) and PM060184 (
325), were isolated from the Madagascan sponge
Lithoplocamia lithistoides (
Figure 60) [
127]. Both are tubulin-binders, and show excellent growth inhibition against human tumor cells, including HT-29 (colon), A-549 (lung), and MDA-MB-231 (breast), with GI
50 values of 0.46, 0.38, and 0.45 (
324) and 0.42, 0.59, and 0.71 (
325) nM, respectively.
Figure 60.
Structures of PM050489 (
324) and PM060184 (
325) from the sponge
Lithoplocamia lithistoides [
127].
Figure 60.
Structures of PM050489 (
324) and PM060184 (
325) from the sponge
Lithoplocamia lithistoides [
127].
The new sesterterpenoid phobaketals N (
326) (
Figure 61) isolated from a Korean
Phorbas sp. sponge has potent cytotoxicity against the human pancreas cell line (Panc-1) and the human renal cell lines (A498 and ACHN) with IC
50 11.4, 18.7, and 24.4 µM, respectively [
128]. Of the two nonbrominated phorbaketals (L and M) also isolated from this sponge, only phorbaketal L shows cytotoxicity (A498, 17.3 µM).
Figure 61.
Structure of phorbaketal N (
326) from the sponge
Phorbas sp. [
128].
Figure 61.
Structure of phorbaketal N (
326) from the sponge
Phorbas sp. [
128].
A Micronesian specimen of a
Suberea sp. sponge has afforded four new psammaplysins (
327–
330) and four new ceratinamines (
331–
334) (
Figure 62), along with nine previously known bromotyrosine analogues [
129]. Whereas the ceratinamines are essentially devoid of cytotoxicity against a panel of human cancer cell lines, the psammaplysins are quite active (
Table 10). Included in the table are some of the isolated known analogues and the positive control doxorubicin.
Two new brominated acetylenes,
335 and
336, were isolated from a collection of
Haliclona sp. sponge living in Saudi Arabia waters (
Figure 63) [
130]. Both are active towards MCF-7 human breast cancer cells, IC
50 32.5 and 50.8 µM, respectively, but not against HepG2 (human hepatocellular carcinoma), WI-38 (skin carcinoma), and Vero (African green monkey kidney).
Callyspongiolide (
337) is a novel macrolide characterized from the Indonesian sponge
Callyspongia sp. (
Figure 64) [
131]. This metabolite exhibits potent cytotoxicity against L5178Y mouse lymphoma cells, human Jurkat J16 T and Ramos B lymphocytes with IC
50 values of 320, 70, and 60 nM, respectively.
Figure 62.
Structures of psammaplysins
327–
330 and ceratinamines
331–
334 from the
Suberea sp. sponge [
129].
Figure 62.
Structures of psammaplysins
327–
330 and ceratinamines
331–
334 from the
Suberea sp. sponge [
129].
Table 10.
Growth inhibition (GI
50 µM) of psammaplysins and known analogues against human cancer cell lines [
129].
Table 10.
Growth inhibition (GI50 µM) of psammaplysins and known analogues against human cancer cell lines [129].
Compound | HCT-15 | PC-3 | ACHN | MDA-MB-21 | NUGC-3 | NIC-H23 |
---|
psammaplysin X (327) | 3.3 | 2.3 | 3.3 | 1.2 | 3.5 | 6.4 |
10-hydroxypsammaplysin X (328) | 3.5 | 2.1 | 2.5 | 0.8 | 4.0 | 3.5 |
psammaplysin A | 3.9 | 6.9 | 5.1 | 4.3 | 3.8 | 12.4 |
psammaplysin B | 4.0 | 2.7 | 1.6 | 0.53 | 2.5 | 3.7 |
psammaplysin D | 24 | 25 | 27 | 21 | 26 | 27 |
psammaplysin E | 7.4 | 3.7 | 10.3 | 3.9 | 4.0 | 7.0 |
19-hydroxypsammaplysin E | 3.8 | 1.4 | 2.3 | 0.51 | 2.3 | 3.6 |
moloka’iamine | >70 | >70 | >70 | >70 | >70 | >70 |
7-hydroxymoloka’iamine | >70 | >70 | >70 | >70 | >70 | >70 |
ceratinamine | >70 | >70 | >70 | >70 | >70 | >70 |
hydroxyceratinamine | >70 | >70 | >70 | >70 | >70 | >70 |
doxorubicin | 1.4 | 0.52 | 2.0 | 1.8 | 0.51 | 1.9 |
Figure 63.
Structures of brominated acetylenes
335 and
336 from the
Haliclona sp. sponge [
130].
Figure 63.
Structures of brominated acetylenes
335 and
336 from the
Haliclona sp. sponge [
130].
Figure 64.
Structure of callyspongiolide (
337) from the sponge
Callyspongia sp. [
131].
Figure 64.
Structure of callyspongiolide (
337) from the sponge
Callyspongia sp. [
131].
From a sponge of the Petrosiidae family were isolated two new macrolides, phormidolides B (
338) and C (
339) (
Figure 65) [
132], which are structurally related to the known phormidolide A and oscillariolide. The new macrolides display growth inhibition of these human cancer cell lines: A-549 (lung), HT-29 (colon), and MDA-MB-231 (breast) with IC
50 values for
338/
339 of 1.4/1.3, 1.3/0.8, and 1.0/0.5 µM, respectively.
Figure 65.
Structures of phormidolides B (
338) and C (
339) from a sponge of the Petrosiidae family [
132].
Figure 65.
Structures of phormidolides B (
338) and C (
339) from a sponge of the Petrosiidae family [
132].
The Bahamas sponge
Spirastrella mollis contains mollenyne (
340) (
Figure 66), a highly cytotoxic chlorodibromohydrin towards HCT-116 (human colon cancer cells) with IC
50 1.3 µg/mL [
133]. The positive control etoposide has IC
50 0.55 µg/mL.
A collection of the sponge
Theonella swinhoei from Japanese waters (Tanegashima, Kagoshima Prefecture) has provided bromotheoynic acid (
341) (
Figure 67) [
134]. This new brominated C
17 acetylenic acid inhibits the cell proliferation of U937 and HL60 (human leukemia), A549 and H1299 (human lung), and HEK293 (human embryonic kidney) with values of IC
50 24, 27, 58, 72, and 40 mg/mL, respectively. Bromotheoynic acid also inhibits the maturation of starfish (
Asterina pectinifera) oocytes at a concentration of 100 ng/mL.
Figure 66.
Structure of mollenyne (
340) from the sponge
Spirastrella mollis [
133].
Figure 66.
Structure of mollenyne (
340) from the sponge
Spirastrella mollis [
133].
Figure 67.
Structure of bromotheoynic acid (
341) from the sponge
Theonella swinhoei [
134].
Figure 67.
Structure of bromotheoynic acid (
341) from the sponge
Theonella swinhoei [
134].
The sponge
Stylissa sp. from the Derawan Islands in Indonesia has yielded four new brominated alkaloids,
342–
345 (
Figure 68), along with eight known analogues, including
346–
353 [
135]. All compounds were screened for their cytotoxicity towards mouse lymphoma cells L5187Y (
Table 11), but only
342,
348,
350, and
351 show strong activity in this screen. The presence of an
N-methyl and a carbonyl group in the imidazole ring increases activity (
342 vs. 346; and
350/
351), and the presence or absence of bromine may not always have a positive influence on the activity (
346 vs. 347).
Figure 68.
Structures of brominated alkaloids
342–
353 from the sponge
Stylissa sp. [
135].
Figure 68.
Structures of brominated alkaloids
342–
353 from the sponge
Stylissa sp. [
135].
Table 11.
Cytotoxicity of brominated alkaloids
342–
353 against mouse lymphoma cells L5187Y [
135].
Table 11.
Cytotoxicity of brominated alkaloids 342–353 against mouse lymphoma cells L5187Y [135].
Alkaloid | L5178Y% of Inhibition Concentration (10 µg/mL) | EC50 |
---|
342 | 86.1 | 3.5 |
343 | 8.1 | – |
344 | 10.2 | – |
345 | 6.6 | – |
346 | 7.5 | – |
347 | 15.1 | – |
348 | 89.3 | 9.0 |
349 | 1.7 | – |
350 | 99.6 | 1.8 |
351 | 101.0 | 2.1 |
352 | 9.0 | – |
353 | 33.8 | – |
Kahalalide F (control) | – | 6.3 |
An examination of the Thai sponge
Smenospongia sp. gathered in the Andaman Sea has uncovered the novel 6′-iodoaureol (
354) and the bromoindoles
355–
359 (
Figure 69), isolated from a natural source for the first time, along with several other known natural products [
136]. The new compounds,
354–
359, and the known
360–
362 were screened against a battery of human cell lines for cytotoxicity (
Table 12). Only 5,6-dibromotryptamine (
362) shows good activity against MOLT-3 (human leukemia) and HeLa cells, with non-halogenated aureol (
360) and
355 showing some modest cytotoxicity against HL-60 and HeLa, respectively.
Figure 69.
Structures of 6′-iodoaureol (
354), aureol (
360), and indoles
355–
362 from the sponge
Smenospongia sp. [
136].
Figure 69.
Structures of 6′-iodoaureol (
354), aureol (
360), and indoles
355–
362 from the sponge
Smenospongia sp. [
136].
Table 12.
Cytotoxicity of
354–
362 against human cancer cells (IC
50 µM) [
136].
Table 12.
Cytotoxicity of 354–362 against human cancer cells (IC50 µM) [136].
Compound | MOLT-3 | HepG2 | A549 | HuCCA-1 | HeLa | HL-60 | MDA-MB-231 |
---|
354 | 39.8 | 44.7 | 68.2 | 63.6 | 61.4 | 43.2 | 44.7 |
355 | >100 | 36.1 | >100 | >100 | 13.0 | >100 | >100 |
357 | >100 | >100 | >100 | >100 | >100 | >100 | >100 |
358 | >100 | >100 | >100 | >100 | 69.3 | – | >100 |
359 | >100 | >100 | >100 | >100 | 69.3 | – | >100 |
360 | 24.8 | 29.2 | 76.4 | 87.6 | 62.1 | 14.6 | 29.7 |
361 | 73.2 | >100 | >100 | >100 | 7.81 | 64.3 | >100 |
362 | 5.4 | 23.1 | 78.6 | 23.6 | 9.4 | – | 34.1 |
Etoposide | 0.03 | – | – | – | – | 1.18 | – |
Doxorubicin | – | 0.69 | 0.43 | 0.69 | 0.38 | – | 0.62 |
Two studies of the chemical content of the Caribbean sponge
Smenospongia aurea, collected in the Bahamas along the coast of Little Inagua, has led to the chlorinated smenamides A (
363) and B (
364), and smenothiazoles A (
365) and B (
366) (
Figure 70) [
137,
138]. Whereas the smenamides exhibit selectivity and nanomolar cytotoxic activity towards Calu-1 (lung) cancer cells, the smenothizoles are equally active and selective against A2780 (ovarian) cancer cells.
Figure 70.
Structures of smenamides A (
363) and B (
364), and smenothiazoles A (
365) and B (
366) from the sponge
Smenospongia aurea [
137,
138].
Figure 70.
Structures of smenamides A (
363) and B (
364), and smenothiazoles A (
365) and B (
366) from the sponge
Smenospongia aurea [
137,
138].
The first naturally occurring trimeric hemibastadin, sesquibastadin 1 (
367), was characterized from the sponge
Ianthella basta, found in Ambon, Indonesia (
Figure 71) [
139]. The known bastadins 3, 6, 7, 11, and 16 were also isolated. Whereas sesquibastadin 1 does not display cytotoxicity against L5178Y cells (mouse lymphoma), bastadins 6, 7, 11, and 16 do inhibit cell proliferation, with IC
50 values of 1.5, 5.3, 3.7, and 1.9 µM, respectively. However, sesquibastadin 1 is a potent protein kinase inhibitor as seen in a later section.
Figure 71.
Structure of sesquibastadin 1 (
367) from the sponge
Ianthella basta [
139].
Figure 71.
Structure of sesquibastadin 1 (
367) from the sponge
Ianthella basta [
139].
The Red Sea sponge
Pseudoceratina arabica from Hurghada at the Egyptian coast contains the new ceratinines A–E (
368–
372) (
Figure 72), in addition to several known brominated alkaloids [
140]. Screening of all isolated compounds against the highly metastatic MDA-MB-251 human breast cancer cell line reveals that only the known subereamolline A (
373) is highly active, showing IC
50 1.7 µM.
Figure 72.
Structures of ceratinines A–E (
368–
372) and subereamolline A (
373) from the sponge
Pseudoceratina arabica [
140].
Figure 72.
Structures of ceratinines A–E (
368–
372) and subereamolline A (
373) from the sponge
Pseudoceratina arabica [
140].
An Australian version of
Pseudoceratina verrucosa has furnished the new pseudoceralidinone A (
374) and aplysamine 7 (
375) (
Figure 73), in addition to the known aerophobin 2, fiscularin 2, and fistularin 3 (not shown) [
141]. Of these five bromotyrosines, only aplysamine 7 (
375) shows cytotoxicity towards PC3 (prostate) cancer cells with IC
50 4.9 µM. All five compounds are inactive against HeLa (cervical) and NFF (human neonatal foreskin fibroblast) cells (IC
50 > 10 µM).
Figure 73.
Structures of pseudoceralidinone A (
374) and aplysamine 7 (
375) from
Pseudoceratina verrucosa [
141].
Figure 73.
Structures of pseudoceralidinone A (
374) and aplysamine 7 (
375) from
Pseudoceratina verrucosa [
141].
The South China Sea sponge
Acanthella cavernosa has afforded the new cavernenes A–D (
376–
379), kalihinenes E (
380) and F (
381), and kalihipyran C (
382) (
Figure 74), in addition to several known analogues [
142]. These metabolites were screened against several human cancer cell lines (
Table 13). Cavernenes A and B display modest cytotoxicity towards HCT-116, and cavernene D shows slight activity against all five cell lines. The other new compounds (
378,
379,
381,
382) are inactive across the board.
Figure 74.
Structures of cavernenes A–D (
376–
379), kalihinenes E (
380) and F (
381) and kalipyran C (
382) from the sponge
Acantella cavernosa [
142].
Figure 74.
Structures of cavernenes A–D (
376–
379), kalihinenes E (
380) and F (
381) and kalipyran C (
382) from the sponge
Acantella cavernosa [
142].
Table 13.
Cytotoxicity of
376,
377,
380, and selected known analogues against human cell lines (IC
50 µM) [
142].
Table 13.
Cytotoxicity of 376, 377, 380, and selected known analogues against human cell lines (IC50 µM) [142].
Compound | HCT-116 | A549 | HeLa | QGY-7701 | MDA-MB-231 |
---|
376 | 6.31 | >50 | >50 | >50 | >50 |
377 | 8.99 | >50 | >50 | >50 | >50 |
380 | 14.36 | >50 | 13.36 | 17.78 | 12.84 |
kalihipyran A | >50 | 13.09 | 11.19 | 13.53 | >50 |
15-formamido-kalihinene | >50 | 17.53 | 14.74 | 16.39 | >50 |
10-formamido-kalihinene | >50 | 6.98 | 13.30 | 14.53 | 6.84 |
kalihinene X | 12.25 | 8.55 | 10.59 | 13.02 | 7.46 |
kalihinene Y | >50 | 17.12 | 10.05 | 14.41 | 15.23 |
camptothecin | 9.25 | 2.32 | 6.98 | 4.05 | 0.50 |
A number of known marine organohalogens were examined for possible cytotoxicity against cancer cell lines during the period covered by this review. To conserve space, their structures are not shown. A review of the antitumor activity of the
Jaspis sponges is available [
143]. The
Fascaplysinopsis sp. sponge metabolite fascaplysin displays excellent cytotoxicity against chemoresistant SCLC (small cell lung cancer) cell lines, by multiple mechanisms [
144]. Other cell lines are also discussed. The
Suberea sp. sponge alkaloids ma’edamines A and B display significant cytotoxicity against COLO 205 (human colon cancer), MCF-7 (human breast cancer), and A549 (human lung) with IC
50 values of 7.9/10.3, 6.9/10.5, and 12.2/15.4 for ma’edamines A/B, respectively [
145]. Synthetic analogues show activity against three breast cancer cell lines representing hormone receptor positive and HER2 positive breast cancer [
146]. The bis-indole alkaloid 6″-debromohamacanthin A from a
Spongosorites sp. sponge inhibits angiogenesis in human umbilical vascular endothelial cells and mouse embryonic cells [
147]. The
Pseudoceratina sp. alkaloids ceratamines A and B disrupt microtubule dynamics, which provides an explanation for their pronounced antimitotic activity (lower micromolar) [
148]. The well known dibromo-dihydroxyoxocyclohexenyl acetonitrile has excellent activity against the K562 leukemia cell line (IC
50 1.4 µg/mL) [
149]. The known spirastrellolides A and B were isolated from the sponge
Epipolasis sp. for the first time as free acids, and not as methyl esters. Both macrolides are cytotoxic to HeLa cells, with IC
50 20 and 40 nM, respectively [
150].
The previously cited dictyodendrins F–I (
74–
77) (
Figure 14) are cytotoxic towards the SW620 (human colon) cancer cell line with IC
50 values of 8.5, 2.0, 16, and 10 µM, respectively. Dictyodendrin J is not cytotoxic. None of the five compounds is cytotoxic towards the multi-drug resistant variant SW620 Ad300 [
49]. The kalihinols M–T (
100–
107) (
Figure 18) were screened against several human cancer cell lines, along with some previously known kalihinols, and show weak to modest cytotoxicity (
Table 14) [
55].
The aforementioned new hamigerans F–J (
204–
208) (
Figure 36) all show some degree of cytotoxicity towards HL-60 (human promyelocytic leukemia) with F (
204), G (
205), and
209 showing IC
50 values of 4.9, 2.5, and 5.6 µM, respectively. The known hamigeran B is 3.4 µM [
83]. The two most active hamigerans, G and B, share the same electrophilic 1,2-dione functionality. Of the three psammaplysins
252–
254 (
Figure 45), psammaplysin F (
254) is moderately cytotoxic against the HepG2 human carcinoma cell line (IC
50 3.7 µM). Psammaplysins G (
253) and H (
252) show IC
50 values of 17.4 and >40 µM, respectively [
104].
Table 14.
Cytotoxicity of kalihinols M–T (100–107) and related kalihinols against human cancer cell lines (IC
50 µM) [
55].
Table 14.
Cytotoxicity of kalihinols M–T (100–107) and related kalihinols against human cancer cell lines (IC50 µM) [55].
Kalihinol | HCT-116 | H1299 | CT-26 |
---|
kalihinol O (102) | 5.97 | – | – |
kalihinol P (103) | 10.68 | 26.21 | – |
kalihinol Q (104) | 20.55 | – | – |
kalihinol R (105) | 13.44 | – | – |
kalihinol E | 18.31 | – | – |
kalihinol A | 17.40 | – | – |
10-epi-kalihinol X | 8.21 | – | – |
10-epi-kalihinol I | 28.67 | – | – |
10-β-formamidokalihinol-A | – | – | 28.82 |
Red marine algae are also an excellent source of novel antitumor compounds with genus
Laurencia in the limelight. A collection of
Laurencia similis from the South China Sea has yielded the novel enantiomeric spiro-trisindoles similisines A (
383) and B (
383b), along with the new oxindole
384 (
Figure 75) [
151]. The racemate
383 was separated into similisines A and B by enantioselective HPLC. All three compounds were screened against eight human cancer cell lines but only oxindole
384 shows (weak) activity against HL-60 (leukemia) and JURKA (leukemia) with values of IC
50 35.06 and 53.27 µM, respectively.
Figure 75.
Structures of similisines A (
383a) and B (
383b), and oxindole
384 from
Laurencia similis [
151].
Figure 75.
Structures of similisines A (
383a) and B (
383b), and oxindole
384 from
Laurencia similis [
151].
An extensive examination of
Laurencia viridis from the Canary Islands led to seven new brominated polyether triterpenoids, 15-dehydroxythyrsenol A (
385), prethyrsenol A (
386), 13-hydroxyprethyrsenol A (
387) [
152], iubol (
388), 22-hydroxy-15(28)-dehydrovenustatriol (
389) [
153], and saiyacenols A (
390) and B (
391) [
154] (
Figure 76), along with two new non-brominated analogues 1,2-dehydropseudodehydrothyrsiferol and secodehydrothyrsiferol (not shown) [
153]. These new oxasqualenoids were screened against several human cancer cell lines (
Table 15). Jurkat cells are clearly the most sensitive to these brominated polyethers. The non-brominated secodehydrothyrsiferol shows IC
50 2.5 µM in this assay.
Figure 76.
Structures of polycyclic triterpenoids
385–
391 from
Laurencia viridis [
152,
153,
154].
Figure 76.
Structures of polycyclic triterpenoids
385–
391 from
Laurencia viridis [
152,
153,
154].
Table 15.
Cytotoxicity of polycyclic triterpenoids
385–
391 against human cancer cell lines (IC
50 µM) [
152,
153,
154].
Table 15.
Cytotoxicity of polycyclic triterpenoids 385–391 against human cancer cell lines (IC50 µM) [152,153,154].
Compound | Jurkat a | MM144 b | HeLa c | CAD-ES-1 |
---|
385 | 7.6 | 7.3 | 23.0 | 16.5 |
386 | 8.2 | 10.2 | 29.0 | 14.5 |
387 | 7.2 | 15.5 | 26.0 | 3.1 |
388 | 3.5 | 13.0 | 27.0 | 11.0 |
389 | 2.0 | – | 2.9 | – |
390 | 7.8 | 27.0 | 27.5 | 25.5 |
391 | 2.7 | 11.0 | 24.5 | 14.0 |
The polybromoindoles from
Laurencia brongniarii (
Figure 21) were tested for cytotoxicity, but in this group only 2,4,5,6-tetrabromo-3-methylthioindole shows activity against Hep3B (liver carcinoma) and MCF-7 (breast carcinoma); IC
50 7.7 and 10.5 µM, respectively. For comparison, the non-halogenated doxorubicin has values of IC
50 1.2 and 1.5 µM, respectively. Other cell lines examined were HepG2, MDA-MB-231, and A549 [
62]. Of the six new laurane-type sesquiterpenes from
Laurencia okamurai (
Figure 40), only 3β-hydroperoxyaplysin (
231) and 3β-hydroxyaplysin show any cytotoxicity towards the A-549 cell line (IC
50 35.3 and 15.4 µM, respectively. All other compounds are IC
50 > 100 µM [
89]. The known bis-(2,3-dibromo-4,5-dihydroxyphenyl)methane from
Laurencia nana and
Rhodomela confervoides displays significant growth inhibition against some cell lines (IC
50 µg/mL): HeLa (17.6), RKO (colon; 11.4), HCT-116 (colon; 10.6), BEL-7402 (hepatoma; 8.7), U87 (glioblastoma; 23.7), and HUVEC (vascular endothelial; 30.2). Moreover, this compound induces detachment of the cancer cells and apoptosis, and inhibits metastasis [
155]. Although the
Asparagopsis taxiformis cyclopentenones mahorone (
108) and 5-bromomahorone (
109) (
Figure 19) are not cytotoxic towards several human cancer cell lines (A549, HepG2, HT29, and MCF7), mahorone is cytotoxic against healthy liver cells (54% growth inhibition at 5 µM) [
58]. The bromoditerpene from
Sphaerococcus coronopifolius, sphaerodactylomelol (
122) (
Figure 21), shows some cytotoxicity and anti-proliferative property against HepG-2 cells (IC
50 720 and 280 µM, respectively). The known sphaerococcenol shows IC
50 43 µM for anti-proliferative activity. For comparison, cisplatin and tamoxifen have IC
50 values of 75 and 46 µM, respectively [
63]. In contrast, bromophycoic acid E (
131) from
Callophycus sp. (
Figure 22) shows cytotoxicity of IC
50 6.8 µM as the mean value of 14 human cancer cell lines. The other bromophycoic acids are less active [
64]. The South African
Plocamium suhrii has provided the new halogenated monoterpenes
392 and
393 (
Figure 77) and the known
394–
398 [
156]. These compounds were screened against the human esophageal cancer cell line WHCO1 with the following IC
50 values (µM):
392 (9.3),
393 (7.9),
394 (6.6),
395 (9.9),
396 (8.5),
397 (8.4), and
398 (15.1). For comparison, cisplatin has IC
50 13 µM. Tetrachloro monoterpene
393 was previously isolated from
Plocamium corallorhiza but not fully characterized [
156].
Figure 77.
Structures of halogenated monoterpenes from
Plocamium suhrii [
156].
Figure 77.
Structures of halogenated monoterpenes from
Plocamium suhrii [
156].
The
Synoicum sp. eudistomins Y
2–Y
7 (
132–
137) (
Figure 23) were screened against A549 cancer cells, but only the previously known eudistomin Y
9 shows cytotoxicity (IC
50 17.9 µM) (doxorubicin has LC
50 3.3 µM) [
65]. Another known
Synoicum sp. ascidian metabolite, prunolide A, is cytotoxic to breast cancer cell lines at <1 µM [
122]. The newest member of the synoxazolidinone family of metabolites from
Synoicum pulmonaria is synoxazolidinone C (
399) (
Figure 78), which is cytotoxic to several human cancer cell lines: A2058 (melanoma), MCF-7 (breast), and HT-29 (colon) at IC
50 30.5 µM. This compound also kills normal lung fibroblast cells (MRC-5) at the same concentration [
157].
Figure 78.
Structure of synoxazolidinone (
399) from the ascidian
Synoicum pulmonaria [
157].
Figure 78.
Structure of synoxazolidinone (
399) from the ascidian
Synoicum pulmonaria [
157].
The tunicate
Diazona cf
formosa living off the coast of Timor Island, near Indonesia, has afforded the novel tanjungides A (
400) and non-halogenated B (
401) (
Figure 79) [
158]. Cytotoxicity of these bromoindoles was assayed against A549, HT29, and MDA-MB-231 human cancer cell lines. The data show that tanjungide A (
400) is strongly active against the three cell lines: IC
50 0.33, 0.19, and 0.23 µM, respectively. Tanjungide B is much less active (IC
50 2.50, 2.31, and 1.63 µM, respectively).
Figure 79.
Structures of tanjungides A (
400) and B (
401) from the tunicate
Diazona cf
formosa [
158].
Figure 79.
Structures of tanjungides A (
400) and B (
401) from the tunicate
Diazona cf
formosa [
158].
The two new chlorinated didemnins
402 and
403 were isolated from the tunicate
Trididemnum solidum from Little Cayman island along with the known nonchlorinated didemnins A (
404) and B (
405) (
Figure 80) [
159]. All four didemnins were evaluated for cytotoxicity against human cancer cells (
Table 16), and all strongly inhibit cell proliferation in the cancer cell lines, especially didemnuns A and B, but not in the noncancerous VERO cell line.
Figure 80.
Structures of didemnins
402–
405 from the tunicate
Trididemnum solidum [
159].
Figure 80.
Structures of didemnins
402–
405 from the tunicate
Trididemnum solidum [
159].
Table 16.
Anti-cell proliferative activity of didemins
402–
405 (IC
50 µM) [
159].
Table 16.
Anti-cell proliferative activity of didemins 402–405 (IC50 µM) [159].
Didemnin | SK-MEL a | KB b | BT-549 c | SK-OV-3 d | VERO e |
---|
402 | 0.12 | 0.26 | 0.16 | 0.26 | 4.8 |
403 | 0.06 | 0.42 | 0.16 | 0.38 | 2.08 |
404 | 0.055 | 0.16 | 0.07 | 0.16 | 4.78 |
405 | 0.022 | 0.09 | 0.02 | 0.1 | 0.15 |
Doxorubicin | 1.1 | 1.66 | 1.01 | 1.66 | 14 |
The Formosan soft coral
Klyxum molle has afforded 11 new eunicellin-type diterpenoids, klymollins I–S (
406–
416) four of which, I–L, contain chlorine (
Figure 81) [
160]. Of the klymollins screened for cytotoxicity against the human cancer cell lines K562 myeloblastoid (leukemia), Molt-4 (lymphoblastic leukemia), and T47D (breast carcinoma) only klymollin M (
410) shows activity: ED
50 7.97, 4.35, and 8.58 µM, respectively.
Figure 81.
Structures of klymollins I–S (
406–
416) from the soft coral
Klyxum molle [
160].
Figure 81.
Structures of klymollins I–S (
406–
416) from the soft coral
Klyxum molle [
160].
The earlier discussed gemmacolides and dichotellides from the gorgonian
Dichotella gemmacea (
Figure 1 and
Figure 2) display some antitumor properties [
30,
31,
32,
33,
34,
161]. Against the human cancer cell lines A549 (lung adenocarcinoma) and MG63 (osteosarcoma), gemmacolides V (
9) and Y (
11) show IC
50 values of <1.5 and <0.3 µM, respectively, against A549; and gemmacolide Y has IC
50 < 0.3 µM towards MG63. The positive control adriamycin gives IC
50 2.8 and 3.2 µM for these two cell lines, respectively [
31]. Juncin R shows 5.6 µM towards MG63 cells [
30]. Of gemmacolides G–M, only gemmacolide J shows good growth inhibition against A549 cells (IC
50 < 1.4 µM) [
33]. The dichotellides F–U are not cytotoxic to the human cancer cell lines SW1990, MCF-7, HepG2, and H460 cell lines, but dichotellide C displays (marginal) activity towards SW1990 (pancreatic) with IC
50 45 µM (fluorouracil, IC
50 121 µM) [
34]. A later tour de force examination of
Dichotella gemmacea revealed the presence of 18 new gemmacolides AA–AR (
417–
434) (
Figure 82) [
161]. The most cytotoxic compound in the A549 and MG63 cell line assays is gemmacolide AH (
424) with IC
50 for both cell types (adriamycin: IC
50 2.8 and 3.2 µM).
Figure 82.
Structures of gemmacolides AA–AR (
417–
434) from the gorgonian
Dichotella gemmacea [
161].
Figure 82.
Structures of gemmacolides AA–AR (
417–
434) from the gorgonian
Dichotella gemmacea [
161].
A study of the cochliomycins A–C (
39–
41) (
Figure 5) reveals no cytotoxicity against A549 and HepG2 cancer cells, but the related LL-Z1640-1 shows modest activity; IC
50 44.5 and 98.6 µM, respectively [
37]. The structurally related resorcylic acid lactones, greensporones
435–
448 (
Figure 83) from the aquatic fungus
Halenospora sp., were assayed for antitumor activity [
162]. However, only greensporone C (
439) shows significant cytotoxicity against the cell lines MDA-MB-435 (melanoma) and HT-29 (colon) with IC
50 2.9 and 7.5 µM, respectively.
The sponge-derived fungus
Stachybotry sp. HH1 ZDDS1F1-2 has yielded several sesquiterpenoids and xanthones, totaling 15 compounds. In addition to the two new xanthones, stachybogrisephenones A (
449) and B (
450), the three known compounds grisephenone A (
451),
452, and
453 are cytotoxic towards U937, HeLa, and K562 cell lines (
Figure 84) [
163]. Grisephenone A (
451) has IC
50 22.5 and 14.6 µM towards U937 and HeLa cells, respectively. Compound
452 has IC
50 22.3 and 14.0 µM against K562 and HeLa, respectively, and
453 shows IC
50 7.2 µM against the HeLa cell line.
In addition to the new griseofulvins
454 and
455, the mangrove-derived (
Pongamia pinnata) fungus
Nigrospora sp. MA75 has afforded the quinone
456, along with several known compounds (griseofulvins, xanthones, benzophenones) (
Figure 85) [
164]. Non-halogenated compound
456 is cytotoxic to these human cancer cell lines: MCF-7 (breast), SW1990 (pancreas), HepG2 (hepatocellular liver), NCI-H460 (lung), DU145 (prostate), and SMMC7721 (hepatocellular liver) with these respective IC
50 values (µg/mL): 4, 5, 20, 11, 17, and 7 µg/mL. For comparison, fluorouracil shows IC
50 4, 16, 14, 1, 0.4, and 2 µg/mL, respectively.
Figure 83.
Structures of greensporones
435–
448 from the freshwater aquatic fungus
Halenospora sp. [
162].
Figure 83.
Structures of greensporones
435–
448 from the freshwater aquatic fungus
Halenospora sp. [
162].
Figure 84.
Structures of benzophenones
449–
452 and xanthone
453 from
Stachybotry sp. HH1 ZDDS1F1-2 [
163].
Figure 84.
Structures of benzophenones
449–
452 and xanthone
453 from
Stachybotry sp. HH1 ZDDS1F1-2 [
163].
Figure 85.
Structures of
454–
456 from the fungus
Nigrospora sp. MA75 [
164].
Figure 85.
Structures of
454–
456 from the fungus
Nigrospora sp. MA75 [
164].
The marine-derived
Aspergillus sp. SCS10 FO63 fungus produces seven new averantin-type chlorinated anthraquinones
457–
463 (
Figure 86) along with five known analogues [
165]. From this group, only 6-
O-methyl-7-chloroaverantin (
458) exhibits good cytotoxicity against SF-268 (glioblastoma), MCF-7 (breast), and NCI-H460 (lung) with IC
50 values of 7.11, 6.64, and 7.42 µM, respectively. For comparison, cisplatin has IC
50 values of 4.59, 10.23, and 1.56 µM, respectively.
Figure 86.
Structures of chlorinated averantin anthraquinones
457–
463 from the fungus
Aspergillus sp. SCS10 FO63 [
165].
Figure 86.
Structures of chlorinated averantin anthraquinones
457–
463 from the fungus
Aspergillus sp. SCS10 FO63 [
165].
The
Homaxinella sponge-derived fungus,
Gymnascella dankaliensis, has furnished the new polyketide dankastatin C (
464) (
Figure 87) [
166]. This compound displays pronounced cell growth inhibition of the murine P388 leukemia cell line with EC
50 57 ng/mL (comparable to 5-fluorouracil with EC
50 78 ng/mL).
Figure 87.
Structure of dankastatin C (
464) from the fungus
Gymnascella dankaliensis [
166].
Figure 87.
Structure of dankastatin C (
464) from the fungus
Gymnascella dankaliensis [
166].
The seagrass (
Thalassia hemprichii)-derived fungi Polyporales PSU-ES44 and PSU-ES83 have yielded the new polyporapyranones A–H (
465–
472) (
Figure 88), along with eight known analogues [
167]. Of these compounds, only
465 shows moderate activity against Vero cells (IC
50 6.93 µg/mL), and no polyporapyranone is active against MCF-7 cells. For comparison, ellipticine has IC
50 1.28 µg/mL against these African green monkey kidney fibroblast (Vero) cells.
A strain of the fungus
Chaetomium globosum, which was obtained from the marine fish
Mugil cephalus, has produced three new azaphilones, chaetomugilin S (
473), dechloro-chaetomugilin A (chaetomugilin T) (
474), and dechloro-chaetomugilin D (chaetomugilin U) (
475) (
Figure 89) [
168]. Chaetomugilin S (
473) is modestly active towards these cell lines: P388, HL-60, L1210, and KB (IC
50 46.0, 39.1, 43.7, and 34.5, respectively).
Figure 88.
Structures of polyporapyranones A–H (
465–
472) from the fungi Polyporales PSU-ES44 and PSU-ES83 [
167].
Figure 88.
Structures of polyporapyranones A–H (
465–
472) from the fungi Polyporales PSU-ES44 and PSU-ES83 [
167].
Figure 89.
Structures of chaetomugilins S, T, and U (
473–
475) from the fungus
Chaetomium globosum [
168].
Figure 89.
Structures of chaetomugilins S, T, and U (
473–
475) from the fungus
Chaetomium globosum [
168].
Three new azaphilones, isochromophilones X–XII (
476–
478), have also been found in the fungus
Diaporthe sp., which was isolated from the mangrove plant
Rhizophora stylosa of Hainan Province, China (
Figure 90) [
169]. The familiar sclerotioramine and isochromophilone VI were also isolated. This is the first example of azaphilones being found in
Diaporthe. Isochromophilone X (
476) displays moderate cytotoxicity against MCF-7 (breast), SGC-7901 (gastric), SW1116 (colorectal), A549 (lung), and A375 (melanoma) with IC
50 values of 14.90, 16.84, 24.15, 26.93, and 35.75 µM. The other azaphilones have >50 µM against these cell lines.
Figure 90.
Structures of isochromophilones X–XII (
476–
478) from the fungus
Diaporthe sp. [
169].
Figure 90.
Structures of isochromophilones X–XII (
476–
478) from the fungus
Diaporthe sp. [
169].
A marine-derived
Penicillium sp., which was isolated from seawater on the French coast, has yielded an analogue of fumagillin, ligerin (
479) (
Figure 91) [
170]. Evaluation of ligerin against these cancer cell lines: KB (nasopharyngeal), AT6-1 (murine prostatic), POS1 and OSRGa (murine osteosarcoma), and L929 (murine fibroblasts) shows antiproliferative activity against all of these cell lines except KB cells. The highest activity of ligerin is seen in the POS1 cell line (IC
50 117 nM), which is 20 times more active than the other cell lines. An Antarctic deep-sea fungus,
Penicillium sp. PR19N-1, has yielded the four novel chlorine-containing sesquiterpenes
480–
483 (
Figure 91) [
171]. The known non-chlorinated eremofortine C is also present.
Figure 91.
Structures of ligerin (
479) and
480–
483 from the fungi
Penicillium spp. [
170,
171].
Figure 91.
Structures of ligerin (
479) and
480–
483 from the fungi
Penicillium spp. [
170,
171].
Cyanobacteria continue to be a major supplier of novel natural products, including halogenated metabolites. The freshwater cyanobacterium
Nostoc sp. (UIC 10274) from Illinois has afforded the two new carbamidocyclophanes F (
484) and G (
485) (
Figure 92) [
172], both of which are antiproliferative against the human cancer cell lines MDA-MB-435 (breast) and HT-29 (colon) with IC
50 0.5–0.7 µM for both
484 and
485. The cyanobacterium
Fischerella sp. (SAG 46.79), a rich source of chlorinated indoles, contains the four new fischerindoles
486–
489 (
Figure 92) [
173]. Of these four compounds only
487 (deschloro 12-
epi-fischerindole I nitrile) shows (weak) cytotoxicity towards HT-29 cells (ED
50 23 µM). Compounds
488/
489 are the first carbazole-type fischerindoles to be discovered.
Figure 92.
Structures of carbamidocyclophanes F (
484) and G (
485) from the cyanobacterium
Nostoc sp., and fischerindoles
486–
489 from the cyanobacterium
Fischerella sp. [
172,
173].
Figure 92.
Structures of carbamidocyclophanes F (
484) and G (
485) from the cyanobacterium
Nostoc sp., and fischerindoles
486–
489 from the cyanobacterium
Fischerella sp. [
172,
173].
Lyngbya genus is a prolific producer of organohalogens and the Taiwanese
Lyngbya majuscule has afforded the known isomalyngamide A (
490) and the new isomeric A-1 (
491) (
Figure 93) [
174]. Both compounds are antiproliferative towards MCF-7 and MDA-MG-231 cells (IC
50 4.6 and 2.8 µM, respectively, for
490), and they inhibit the migration of MDA-MB-231 cells (IC
50 0.060 and 0.337 µM, for
490 and
491, respectively). Consistent with an antimetastatic mechanism for these isomalyngamides is that they both inhibit α-2,3-sialyltransferase (IC
50 77.2 and 65.7 µM for
490 and
491, respectively).
Figure 93.
Structures of isomalyngamides A (
490) and A-1 (
491) from the cyanobacterium
Lyngbya majuscule [
174].
Figure 93.
Structures of isomalyngamides A (
490) and A-1 (
491) from the cyanobacterium
Lyngbya majuscule [
174].
The new malyngamide 2 (
492) was characterized from a Papua New Guinea collection of
Lyngbya sordida (
Figure 94) [
175]. Cytotoxicity towards H-460 (lung) is modest at IC
50 21 µM. The Red Sea
Moorea producens (formerly
Lyngbya majuscula) produces malyngamide 4 (
493) (
Figure 94), along with five known analogues [
176]. This compound is weakly inhibitory to the human cancer cell lines MDA-MB-231, A549, and HT-29 (GI
50 44, 40, and 50 µM, respectively).
Figure 94.
Structures of malyngamides 2 (
492) from
Lyngbya sordida and 4 (
493) from
Moorea producens [
175,
176].
Figure 94.
Structures of malyngamides 2 (
492) from
Lyngbya sordida and 4 (
493) from
Moorea producens [
175,
176].
The previously presented coibacins A–D (
297–
300) from the Panamanian
Oscillatoria sp. (
Figure 53) show cytotoxicity against the H460 (lung) human cancer cell line, with coibacin D having the highest activity (IC
50 11.4 µM) [
114]. A collection of
Moorea bouillonii from the Palmya Atoll in the Central Pacific Ocean has led to the discovery of five novel lyngbyabellins,
494–
498 (
Figure 95) [
177]. Lyngbyabellin N (
498) is very similar to the known lyngbyabellin H. Although
494–
497 are inactive in the H-460 cytotoxicity screen,
498 shows a range of activity in this cell line, IC
50 0.0048–1.8 µM, which may result from solubility difficulties in the assay medium. However, in the HCT-116 colon cancer cell line,
498 gives the reproducible and very potent IC
50 40.9 ± 3.3 nM.
Figure 95.
Structures of lyngbyabellins
494–
498 from the cyanobacterium
Moorea bouillonii [
177].
Figure 95.
Structures of lyngbyabellins
494–
498 from the cyanobacterium
Moorea bouillonii [
177].
Like terrestrial bacteria, marine bacteria can synthesize extremely complex natural products, most notably by marine-derived
Streptomyces sp. A Bahamas marine sediment has provided
Streptomyces variabillis (SNA-020) that produces ammosamide D (
499) (
Figure 96) [
178]. This newest member of the ammosamide family has modest activity in the human cancer cell line MIA PaCa-2 (pancreas), IC
50 3.2 µM. Similarly, a marine sediment from the San Clemente, California, coast has yielded chlorizidine A (
500) (
Figure 96) [
179]. This metabolite, with the unprecedented 5
H-pyrrolo[2,1-
a]isoindol-5-one ring system, is strongly cytotoxic to the human cell line HCT-116 (colon), IC
50 3.2–4.9 µM.
Figure 96.
Structures of
Streptomyces sp. ammosamide D (
499) and chlorizidine A (
500) [
178,
179].
Figure 96.
Structures of
Streptomyces sp. ammosamide D (
499) and chlorizidine A (
500) [
178,
179].
The earlier discussed strepchloritides A (
46) and B (
47) (
Figure 7), from
Streptomyces sp. OUCMDZ-1703, are cytotoxic against the MCF-7 (breast) cell line; IC
50 9.9 and 20.2 µM, respectively [
42]. The deep-sea derived
Streptomyces sp. SCS10 03032 has provided the remarkable spiroindimicins A–D (
501–
504) (
Figure 97) [
180]. Spiroindimicin B (
502) shows moderate activity against B16 (mouse melanoma), H460 (human lung), and CCRF-CEM (human leukemia): 5, 12, and 4 µg/mL, respectively. Spiroindimicin C (
503) towards HepG2 (human hepatocellular liver) and H460 gives: 6 and 15 µg/mL, respectively. Spiroindimicin D (
504) is slightly less active, and A (
501) is inactive in all five cell lines, including MCF-7 (breast). For comparison, 5′-hydroxystaurosporine shows IC
50 values of 8, 2, 8, and 5 µg/mL for HepG2, B16, H460, and CCRF-CEM, respectively. This same
Streptomyces sp. contains indimicins A–E (
505–
509) and lynamicins F (
510) and G (
511) (
Figure 97) [
181]. Of this collection, only indimicin B (
506) is cytotoxic to the MCF-7 cell line, IC
50 10.0 µM. No cytotoxicity is observed for the other indimicins when tested against SF268, MCF-7, H460, and HepG2.
The aforementioned napyradiomycins
184–
193 (
Figure 30 and
Figure 31) [
75,
76] display antitumor activity towards the human colon cell line HCT-116 with these cytotoxicity values (IC
50 µg/mL): napyradiomycin A (
184) (4.19), B (
185) (>20), C (
186) (>20), D (
187) (16.1), E (
188) (4.81), F (
189) (9.42), B2 (3.18), B3 (
190) (0.19), and B4 (1.41) [
75]. The effect of chlorine on the cytotoxicity is noteworthy (
i.e., napyradiomycins A
vs. B, and F
vs. B2). A La Jolla, California, coastal sediment has afforded the actinomycete strain CNQ525, which produces the novel napyradiomycins
512–
515 (
Figure 98) [
182]. Assays of these compounds against the HCT-116 human colon cell line are as follows for the most active napyradiomycins (IC
50 µM): CNQ525.538 (
514) (6), B1 (2), B3 (
190) (3), A80915A (3), A80915B (<1), and A809150 (<1). The etoposide control has 1 µM.
Figure 97.
Structures of spiroindimicins A–D (
501–
504) and indimicins A–E (
505–
509) and lynamicins F (
510) and G (
511) from
Streptomyces sp. SCS10 03032 [
180,
181].
Figure 97.
Structures of spiroindimicins A–D (
501–
504) and indimicins A–E (
505–
509) and lynamicins F (
510) and G (
511) from
Streptomyces sp. SCS10 03032 [
180,
181].
Figure 98.
Structures of napyradiomycins
512–
515 from actinomycete strain CNQ525 [
182].
Figure 98.
Structures of napyradiomycins
512–
515 from actinomycete strain CNQ525 [
182].
The thermophilic bacterium
Thermovibrio ammonificans, collected from the walls of a deep-sea hydrothemal vent on the East Pacific Rise, has provided two additional ammonificins, C (
516) and D (
517) (
Figure 99) [
183]. The
ortho dibromophenyl ring is unique amongst natural organohalogens. Both ammonificins C and D induce apoptosis at 2 and 3 µM, respectively, in a standard apoptosis assay with W2 and D3 cells.
Figure 99.
Structures of ammonificins C (
516) and D (
517) from
Thermovibrio ammonificans [
183].
Figure 99.
Structures of ammonificins C (
516) and D (
517) from
Thermovibrio ammonificans [
183].
Despite their bland appearance, bryozoans (“moss animals”) are the repository of incredibly complex natural products, many of which are heavily brominated. The Patagonian bryozoan
Aspidostoma giganteum contains a wealth of such organobromines, the aspidostomides A–H (
518–
525) and aspidazide A (
526) (
Figure 100) [
184]. The only cytotoxic member (IC
50 < 10 µM) of this collection is aspidostomide E (
522), which displays IC
50 7.8 µM towards the human cell line 786-O (renal carcinoma).
Figure 100.
Structures of aspidostomides A–H (
518–
525) and aspidazide A (
526) from the bryozoan
Aspidostoma giganteum [
184].
Figure 100.
Structures of aspidostomides A–H (
518–
525) and aspidazide A (
526) from the bryozoan
Aspidostoma giganteum [
184].
The Indian Ocean nudibranch,
Aldisa andersoni, has afforded two phorbazoles, 9-chlorophorbazole D (
527) and
N1-methylphorbazole A (
528) (
Figure 101), in addition to the known phorbazoles A, B, and D [
185]. Both new phorbazoles show modest growth inhibition against the human cell lines A549, MCF-7, SKMEL-28 (melanoma), Hs683 (oligodendroglioma), and U373 (glioblastoma) in the range of IC
50 18–29 µM and 19–34 µM for
527 and
528, respectively. These data are comparable or superior to the IC
50 levels observed with carboplatin and temozolomide.
Figure 101.
Structures of phorbazoles
527 and
528 from the nudibranch
Aldisa andersoni [
185].
Figure 101.
Structures of phorbazoles
527 and
528 from the nudibranch
Aldisa andersoni [
185].
The Antarctic nudibranch
Austrodoris kerguelenensis, collected near Palmer Station, produces sixteen new and some old diterpenoid glyceride esters, the palmadorins, several of which inhibit human erythroleukemia (HEL) cells. These are palmadorins A (
529), B (
530), D (
531), M (
532), N (
533), and O (
534) (
Figure 102) [
186]. One contains chlorine, the inactive palmadorin L (
535) (
Figure 102) [
186]. The growth inhibition data for the active palmadorins are (IC
50 µM): A (8.7), B (8.3), D (16.5), M (4.9), N (6.3), and O (13.4), respectively.
Figure 102.
Structures of palmadorins (
529–
535) from the nudibranch
Austrodoris kerguelenensis [
186].
Figure 102.
Structures of palmadorins (
529–
535) from the nudibranch
Austrodoris kerguelenensis [
186].
Larger marine animals like gastropod molluscs are known to produce biologically active metabolites, some of which contain halogen. The anticancer properties of the lamellarins, which were first isolated from a marine mollusc, have been reviewed [
187].
The Australian gastropod
Dicathais orbita contains the well-known 6-bromoisatin which is active against the human cancer cell lines HT-29 and Caco2. It inhibits cell cycle progression of HT-29 cells by arresting some cells in the G2/M phase, and induces apoptosis [
188,
189]. The Egyptian sea hare
Aplysia oculifera has provided two new halogenated sesquiterpenes, oculiferane (
536) and
epi-obtusane (
537) (
Figure 103) [
190]. Both compounds are cytotoxic (IC
50 < 10 µg/mL) to the human cell lines PC-3 (prostate), A549, MCF-7, HepG2, and HCT 116, with these IC
50 values (
536/
537): 3.9/3.1, 3.1/0.96, 5.6/5.9, 3.3/2.4, and 5.9/4.1 µg/mL, respectively.
537 is comparable to 5-fluorouracil against A-549 (0.96
vs. 0.90 µg/mL).
Figure 103.
Structures of oculiferane (
536) and
epi-obtusane (
537) from the sea hare
Aplysia oculifera [
190].
Figure 103.
Structures of oculiferane (
536) and
epi-obtusane (
537) from the sea hare
Aplysia oculifera [
190].
7. Antioxidants and Antiinflammation
Because antioxidants can have anti-inflammatory activity, these two categories are combined.
Like terrestrial phenolic compounds, marine phenols with antioxidant properties are well known, and several recent examples have appeared. The red alga
Rhodomela confervoides from Liaoning Province, China, has afforded 19 bromophenols, six of which are new (
538–
543) (
Figure 104) [
191]. Two known examples,
544 and
545, are included because they are active in the radical scavenging assays. All 19 bromophenols were subjected to both the DPPH (1,1-diphenyl-2-picrylhydrazyl) and the ABTS (2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)diammonium salt) free radical scavenging assays. Most of the bromophenols display more potent antioxidant activity than either BHT (butylated hydroxytoluene) or ascorbic acid. For the DPPH assay the most active compound is
539 (IC
50 7.43 µM) followed by
544 >
543 >
545 >
538. In the ABTS assay
543 is the most active, followed by
544 >
545 >
541.
Figure 104.
Structures of bromophenols
538–
545 from the alga
Rhodomela confervoides [
191].
Figure 104.
Structures of bromophenols
538–
545 from the alga
Rhodomela confervoides [
191].
Another study of
Rhodomela confervoides has led to the discovery of five new nitrogen-containing bromophenols
546–
550 (
Figure 105) in addition to nine known analogues such as
551 [
192]. In the DPPH assay bromophenol
546 shows the strongest activity (IC
50 5.22 µM) (BHT, IC
50 82.1 µM), followed by
548 >
547 >
551. In the ABTS assay,
551 is the most active, more active than ascorbic acid. The antioxidant capacity of these bromophenols seems to be correlated with the number of hydroxyl groups (or phenolic rings).
Figure 105.
Structures of bromocatechols
546–
551 from the alga
Rhodomela confervoides [
192].
Figure 105.
Structures of bromocatechols
546–
551 from the alga
Rhodomela confervoides [
192].
A specimen of the red alga
Symphyocladia latiuscula from the coast of Qingdao, Shandong Province, China, has furnished the new bromocatechols
552 and
553 (
Figure 106) [
193]. Both are modest radical scavengers in the DPPH assay with IC
50 14.5 and 20.5 µg/mL, respectively. Ascorbic acid shows IC
50 7.82 µg/mL. The red alga
Vertebrata lanosa, collected from Ullsfjorden, Norway, afforded the new bromocatechol
554 and the known
555–
557 (
Figure 106) [
194]. Their antioxidant capacity was screened using these assays: ORAC (oxygen radical absorbance capacity), CAA (cellular antioxidant activity), and CLPAA (cellular lipid peroxidation antioxidant activity). This study is the first to measure the cellular antioxidant activity of bromocatechols. The antioxidant activity is highest for
555 followed by
554, and then
556 and
557. At concentrations as low as 10 µg/mL, bromocatechol
555 inhibits 68% of oxidation in the CAA assay. By comparison, the known antioxidants quercetin and luteolin at this same concentration (10 µg/mL) inhibit the oxidation of the CAA substrate (2′,7′-dichlorofluorescin) to the extent of 92% and 58%, respectively.
Several marine sponges exhibit antioxidant behavior. The new 5,6-dibromo-
l-hypaphorine (
558) (
Figure 107), along with four known bromoindoles, was isolated from the sponge
Hyrtios sp. living in Fiji [
195]. This new bromoindole displays significant antioxidant ability in the ORAC assay, only 4-fold less active than Trolox (a water-soluble analogue of Vitamin E). A study of the antioxidant activity of the known
Zyzzya fuliginosa sponge metabolites, zyzzyanones and makaluvamines reveals that the presence of a phenolic ring is essential for maximum activity in both the ABTS and APPH assays, and that a
p-hydroxystyryl unit as in the makaluvamines (e.g.,
559) is more important than a simple phenolic ring as in the zyzzyanones (e.g.,
560) (
Figure 107) [
196].
Figure 106.
Structures of bromocatechols
552–
556 from the red algae
Symphyocladia latiuscula and
Vertebrata lanosa [
193,
194].
Figure 106.
Structures of bromocatechols
552–
556 from the red algae
Symphyocladia latiuscula and
Vertebrata lanosa [
193,
194].
Figure 107.
Structures of
558–
560 from the sponges
Hyrtios sp. and
Zyzza fuliginosa [
195,
196].
Figure 107.
Structures of
558–
560 from the sponges
Hyrtios sp. and
Zyzza fuliginosa [
195,
196].
The novel iodinated acetylenic acid sponge metabolites
561–
564, isolated from the South Korean
Suberites mammilaris (
561 and
562) and
Suberites japonicus (
563 and
564), were examined for their antiinflammatory activity (
Figure 108) [
197]. The methyl esters
561 and
562 strongly inhibit nitric oxide (NO) production from RAW 264.7 murine macrophase cells, with IC
50 3.9 and 7.0 µM, respectively. However, in BV2 microglia cells, the methyl esters of
563 and
564 are the most active in NO inhibition: IC
50 3.1 and 1.8 M, respectively. All four methyl esters attenuate the production of PGE
2 (prostaglandin E2) from RAW 264.7 and BV2 cells as induced by LPS (lipopolysaccharide).
The previously cited 4,5,6-tribromo-2,3-bis(methylthio)indole (
121) (
Figure 21) dramatically reduces the expression of both the pro-inflammatory enzyme
i-NOS (inducible nitric oxide synthase) and COX-2 (cyclooxygenase) in LPS-activated RAW 264.7 cells. This indole has superior antiinflammatory activity relative to the other bromoindoles in this study [
62]. Likewise, pitinoic acid B (
199) (
Figure 33) in LPS-stimulated differentiated THP-1 (human acute monocytic leukemia) cells decreases the level of the pro-inflammatory cytokines TNF-α (tumor necrosis factor alpha) and IL-6 (interleukin 6), which probably accounts for the antiinflammatory effects of
200 [
79]. Coibacin B (
298) (
Figure 53) also inhibits the gene transcription of the cytokines TNF-α, IL-6, IL-1b, and
i-NOS. In the latter assay for NO production
298 has IC
50 5 µM [
114]. The didemnins from the tunicate
Trididemnum solidum (
Figure 80) have pronounced antiinflammatory activity, particularly didemnin B (
405), which inhibits
i-NOS and NF-κB (nuclear factor-kappa B) expression, with IC
50 0.002 and 0.03 µM, respectively. Chlorinated didemnin
402 shows IC
50 0.4 and 0.26 µM, respectively [
159]. Malyngamide 2 (
492) (
Figure 94) has a value of IC
50 8.0 µM in LPS-induced RAW 264.7 macrophages for the inhibition of NO production [
175]. The herdmanines A–D (
565–
568) (
Figure 109) from the Korean ascidian
Herdmania momus inhibit the mRNA expression of
i-NOS, and thereby suppress NO production with IC
50 values of 90 and 9 µM, for
567 ad
568, respectively. These two herdmanines also inhibit PGE
2 production via the reduced mRNA expression of COX-2, and herdmanine D (
568) inhibits the mRNA expression of IL-6 [
198].
Figure 108.
Structures of iodinated acetylenic acids
561–
564 from the sponges
Suberites mammilaris and
S. japonicus [
197].
Figure 108.
Structures of iodinated acetylenic acids
561–
564 from the sponges
Suberites mammilaris and
S. japonicus [
197].
Figure 109.
Structures of herdmanines A–D (
565–
568) from the ascidian
Herdmania momus [
198].
Figure 109.
Structures of herdmanines A–D (
565–
568) from the ascidian
Herdmania momus [
198].
The Taiwanese gorgonian
Junceella fragilis has afforded eight new 8-hydroxybriarane diterpenoids, frajunolides L–O (
569–
572) [
199] and P–S (
573–
576) [
200] (
Figure 110). The antiinflammatory activities of these frajunolides were examined by measuring superoxide generation and elastase release by human neutrophils in response to fMLP/CB (formylmethionyl-leucyl-phenylalanine/dihydrocytochalasin B. These data are summarized in
Table 17. A similar set of briarane diterpenoids was characterized in the gorgonian
Junceella juncea, juncenolides M–O (
577–
579) (
Figure 111) [
201]. The antiinflammatory activity of these juncenolides is shown in
Table 17. Of the frajunolides L–S, P and Q are the most active on both superoxide anion generation and elastase release. Of the juncenolides M–O, O is the most active and N shows inhibition against elastase release. The gorgonian
Briareum sp. collected in Taiwan yielded the novel dichlorinated briarenolide J (
580) (
Figure 111), which also displays antiinflammatory activity (
Table 17) [
202]. It would appear that frajunolide S (
576) is identical with juncenolide M (
577).
Figure 110.
Structures of frajunolides L–S (
569–
576) from the gorgonian
Junceella fragilis [
199,
200].
Figure 110.
Structures of frajunolides L–S (
569–
576) from the gorgonian
Junceella fragilis [
199,
200].
Figure 111.
Structures of juncenolides M–O (
577–
579) from the gorgonian
Junceella juncea [
201].
Figure 111.
Structures of juncenolides M–O (
577–
579) from the gorgonian
Junceella juncea [
201].
Table 17.
Effect of frajunolides L–S (569–576), juncenolides M–O (577–579), and briarenolide J (580) on superoxide anion generation and elastase release in response to fMLP/CB.
Table 17.
Effect of frajunolides L–S (569–576), juncenolides M–O (577–579), and briarenolide J (580) on superoxide anion generation and elastase release in response to fMLP/CB.
| % Inhibition a |
---|
Compound | Superoxide Anion | Elastase Release |
---|
frajunolide L (569) | 18.7 | 16.2 |
frajunolide M (570) | 2.0 | 13.3 |
frajunolide N (571) | 0.6 | 22.3 |
frajunolide O (572) | 8.3 | 17.2 |
frajunolide P (573) | 32.5 | 35.6 |
frajunolide Q (574) | 28.7 | 34.1 |
frajunolide R (575) | 9.7 | 16.0 |
frajunolide S (576) | 5.8 | −4.5 |
juncenolide M (577) | 7.6 | 15.9 |
juncenolide N (578) | 6.7 | 29.0 |
juncenolide O (579) | 27.6 | 35.9 |
briarenolide J (580) | 14.98 | 9.96 |
genistein | 65.0 | 51.6 |
Marine bacteria have yielded some antiinflammatory compounds, such as
Streptomyces sp. CNS284 which produces 2-bromo-1-hydroxyphenazine (
581) (
Figure 112), which has some activity in the NF-κB-luciferase assay (IC
50 73 µM) [
203]. Several synthetic analogues are more active than
581 and show potent inhibition of
i-NOS expression and display chemoprevention, QR1 (quinone reductase 1) induction and QR2 (quinone reductase 2) inhibition. The two novel phenazines,
582 and
583, were characterized from the same
Streptomyces sp. CNS284 along with the known lavanducyanin (
584) (
Figure 112) [
204]. All three phenazines inhibit TNF-α-induced NF-κB activity (IC
50 4.1, 24.2, and 16.3 μM, respectively), and LPS-induced NO production (IC
50 > 48.6, 15.1, and 8.0 µM, respectively). The blocking of PGE
2 production was even more efficient (IC
50 7.5, 0.89, and 0.63 µM, respectively). This study also shows that lavanducyanin inhibits the activity of COX-1 and COX-2, in addition to the production of NO and PGE
2.
Figure 112.
Structures of phenazines (
581–
584) from
Streptomyces sp. CNS284 [
203,
204].
Figure 112.
Structures of phenazines (
581–
584) from
Streptomyces sp. CNS284 [
203,
204].
8. Enzymatic and Molecular Activity
Overshadowed by the biological effects presented in the previous sections are molecular interactions between the marine natural products and the target molecules (enzymes, peptides, and other small biological molecules) that are the root cause of these effects. A review of the targeting of marine natural products to cytoskeletal proteins has appeared [
205].
Several marine brominated natural products are protein kinase inhibitors. Purpuroines A (
59) and D (
62) (
Figure 11) are selective inhibitors of the kinase LCK (lymphocyte-specific protein tyrosine kinase) with IC
50 2.35 and 0.94 µg/mL, respectively. Purpuroine D is inhibitory towards PLK1 (serine/threonine-protein kinase) with IC
50 0.94 µg/mL. For comparison, staurosporine shows IC
50 3.73 and 0.92 µg/mL for LCK and PLK1, respectively. All of the purpuroines are weak inhibitors to CDK2 (cyclin-dependent kinase 2) (IC
50 > 50 µg/mL) [
46]. The study of the massadines (
Figure 12) re-established that the known debromohymenialdisine and hymenialdisine are nanomolar kinase inhibitors of CDK5/P25 (cyclin-dependent kinase 5), CD1δ (casein kinase 1), and GSK3β (glycogen synthase kinase 3β): IC
50 0.4, 0.1, and 0.2 µM, respectively, for debromohymenialdisine, and IC
50 0.16, 0.03, and 0.07 µM, respectively, for hymenialdisine [
47]. The novel sesquibastadin 1 (
367) and bastadin 3 (
Figure 71) are strong inhibitors of at least 22 protein kinases (IC
50 0.1–6.5 µM). For example sesquibastadin 1 causes potent inhibition of the receptor tyrosine kinases EGF-R and VEGF-R2 (both IC
50 0.6 µM), and of T1E2 (IC
50 0.6 µM). Bastadin 3 is a potent inhibitor of Aurora A and B (IC
50 0.1 and 0.5 µM, respectively). This bastadin inhibits all of the examined kinases at submicromolar activity. The other bastadins 6, 7, 11, and 16 are either inactive or much less active, exactly the opposite to their cell proliferation inhibitory activity (
vide supra) [
139]. A study of the known ageladine A, and synthetic analogues, against a battery of kinases shows that ageladine A has modest activity towards the tyrosine kinase DYRK1A and Pim 1 [
206]. The Indonesian sponges
Stylissa massa and
Stylissa flabelliformis yielded 25 bromopyrroles, including the new dispacamide E (
585) and
586 (
Figure 113) [
207]. All isolated compounds were assayed against these protein kinases: DYRK1A, CDK5, GSK-3, CLK-1, CK-1, CDK1, CDK2/A, CDK9/cyclin T, and
Plasmodium falciparum glycogen synthase kinase-3 (
PfGSK-3). Dispacamide E is particularly active against GSK-3, DYRK1A and CK-1 (IC
50 2.1, 6.2, and 4.9 µM, respectively). The known hymenine and some hymenialdisine derivatives are very active against
PfGSK-3 with IC
50 in the nanomolar range [
207]. The red alga
Laurencia similis from the Hainan coast, China, has afforded five new polybrominated compounds,
587–
591 (
Figure 114) [
208]. The brominated
N-bromo-2-naphthylamines
588–
590 are remarkably unique structures, unlike the brominated diphenyl ether
587 and benzophenone
591, for which many examples are known. Metabolites
587 and
591 are inhibitory towards PTP1B (protein tyrosine phosphatase B) with IC
50 2.97 and 2.66 µM, respectively. The Yesinia outer protein (YopE), which is also a protein tyrosine phosphatase, is inhibited by pseudoceramines B (
52) and D (
54) (
Figure 9), with IC
50 19 and 6 µM, respectively [
44]. This enzyme is essential for bacterial virulence of the Gram-negative
Yersinia spp.
Figure 113.
Structures of dispacamide E (
585) and pyrrole
586 from the sponges
Stylissa massa and
Stylissa flabelliformis [
207].
Figure 113.
Structures of dispacamide E (
585) and pyrrole
586 from the sponges
Stylissa massa and
Stylissa flabelliformis [
207].
Figure 114.
Structures of polybromides
587–
591 from the red alga
Laurencia similis [
208].
Figure 114.
Structures of polybromides
587–
591 from the red alga
Laurencia similis [
208].
The known helicusin A which was isolated from the fungus
Bartalina robillardoides strain LF550 along with three new chloroazaphilones (
Figure 27), shows inhibition of acetylcholinesterase (IC
50 2.1 µM) (the positive control hyperzine has IC
50 < 0.1 µM). In this study the known deacetylsclerotiorin inhibits phosphodiesterase 4 (IC
50 2.79 µM), as does isochromophilone XI (
164), albeit weaker (IC
50 8.30 µM). (The positive control rolipam has 0.75 µM) [
71]. The new pulmonarins A (
592) and B (
593) (
Figure 115), isolated from the clonial ascidian
Synoicum pulmonaria living on the coast of Tromsø, Norway, are reversible, noncompetitive inhibitors of acetylcholinesterase; K
i = 90 µM and 20 µM, respectively. Relative to
593, the Calabar bean alkaloid physostigmine has K
i = 30 nM [
209]. The South China Sea sponge
Xestospongia testudinaria has yielded the novel mutafuran (
594) (
Figure 115) along with three known bromine-containing polyacetylenes [
210]. Mutafuran shows significant acetylcholinesterase activity (IC
50 0.64 µM). The positive control tacrine, which is used to treat early stage Alzheimer’s disease, has IC
50 0.41 µM.
Figure 115.
Structures of pulmonarins A (
592) and B (
593) from the ascidian
Synoicum pulmonaria [
209] and mutafuran H (
594) from the sponge
Xestospongia testudinaria [
210].
Figure 115.
Structures of pulmonarins A (
592) and B (
593) from the ascidian
Synoicum pulmonaria [
209] and mutafuran H (
594) from the sponge
Xestospongia testudinaria [
210].
Several marine organohalogens discovered in the timeframe of this survey are protease inhibitors. The
Ianthella sp. sponge metabolites dictyodendrin F, H, I, and J (
Figure 14) are potent inhibitors of BACE 1 (β-secretase 1) with IC
50 values of 1.0–2.0 µM). Only dictyodendrin G (
75) is inactive [
49]. The known cyanobacterium fischerindole hapalosin inhibits the 20s proteasome (IC
50 12 µM), whereas the other fischerindoles isolated in this study (
Figure 92) are inactive [
173]. Extensive studies of the cyanobacteria
Microcystis aeruginosa and
Microcystis spp. in Israel and India have revealed several novel aeruginosins. These are aeruginosin GE686 (
595), GE766 (
596), GE730 (
597), GE810 (
598), GE642 (
599) [
211], IN608 (
600), IN652 (
601) [
212], LH650A (
602), LH650B (
603), LH606 (
604), and the nonchlorinated microviridin LH1667 [
213] (
Figure 116). Several known analogues were also isolated from these blooms. The aeruginosins are inhibitors of the serine proteolytic enzymes trypsin and thrombin. The trypsin inhibitory activities (IC
50 µM) are best realized for GE686 (
595), 3.2; GE730 (
597), 2.3; IN608 (
600), 4.3; IN652 (
601), 4.1; and LH606 (
604), 18.5. The thrombin inhibitory activities (IC
50 µM) are best seen for GE686 (
595), 12.8; GE730 (
597), 12.9; LH650A (
602), 1.8; LH650B (
603), 1.8; and LH606 (
604) 2.5. Microviridin inhibits chymotrypsin, IC
50 2.8 µM [
211,
212,
213].
Figure 116.
Structures of aeruginosins
595–
604 from the cyanobacteria
Microcystis aeruginosa and
Microcystis spp. [
211,
212,
213].
Figure 116.
Structures of aeruginosins
595–
604 from the cyanobacteria
Microcystis aeruginosa and
Microcystis spp. [
211,
212,
213].
Figure 117.
Structures of bromotyrosines
605–
611 from the sponges
Aplysinella sp. and
Callyspongia sp. [
214,
215].
Figure 117.
Structures of bromotyrosines
605–
611 from the sponges
Aplysinella sp. and
Callyspongia sp. [
214,
215].
Some marine sponge metabolites increase the production of ApoE (apoliproprotein E), an important enzyme that mediates cholesterol metabolism, which has implication in the treatment of Alzheimer’s disease. The Great Barrier Reef, Australia, sponge
Aplysinella sp. has afforded three new aplysinellamides A–D (
605–
607) and aplysamine-1-
N-oxide (
608) (
Figure 117) along with six known analogues. Amongst the latter, aplysamine-1 displays ApoE-modulating activity by increasing by 2-fold the secretion of ApoE from human astrocytoma cells at a concentration of 30 µM [
214]. Likewise, the Australian sponge
Callyspongia sp. has yielded the new bromotyrosines
609–
611, along with ten known compounds (
Figure 117). Of these,
610 shows weak ability to increase ApoE from human astrocytoma cells (CCF-STTG1) at a concentration of 40 µM [
215].
The sponge
Xestospongia testudinaria has yielded five new brominated fatty acids,
612–
616 (
Figure 118), which include testufuran A (
612), similar to mutafuran H (
594) (
Figure 115) isolated from the same sponge. An additional 11 known brominated acetylenic acids were also characterized. Most of these 16 bromo carboxylic acids stimulated the secretion of the protein hormone adiponectin, which regulates glucose levels and fatty acid breakdown, from differentiated ST-13 preadipocytes. These compounds do not exhibit agonistic activity against PPAR-γ (the peroxisome proliferator-activated receptor) [
216].
The ascidian
Herdmania momus has yielded seven new herdmanines E–K (
617–
623) (
Figure 119), some of which demonstrate significant PPAR-γ activation in Ac2F rat liver cells. The active examples are I (
621) and K (
623). For example, the latter herdmanine K exhibits strong PPAR-γ activation at 1 and 10 µg/mL concentrations, with greater potency than the antidiabetic drug rosiglitazone. The known (–)-leptoclinidamine B was also isolated from the ascidian and is only slightly less active than
623 [
217].
Figure 118.
Structures of bromo carboxylic acids
612–
616 from the sponge
Xestospongia testudinaria [
216].
Figure 118.
Structures of bromo carboxylic acids
612–
616 from the sponge
Xestospongia testudinaria [
216].
Figure 119.
Structures of herdmanines E–K (
617–
623) from the ascidian
Herdmania momus [
217].
Figure 119.
Structures of herdmanines E–K (
617–
623) from the ascidian
Herdmania momus [
217].
Figure 120.
Structures of placotylenes A (
624) and B (
625) from the sponge
Placospongia sp. [
218] and chalinulasterol (
626) from the sponge
Chalinula molitba [
219].
Figure 120.
Structures of placotylenes A (
624) and B (
625) from the sponge
Placospongia sp. [
218] and chalinulasterol (
626) from the sponge
Chalinula molitba [
219].
The two rare iodinated polyacetylenes, placotylenes A (
624) and B (
625), were characterized in the Korean sponge
Placospongia sp. (
Figure 120). Placotylene A inhibits osteoclast differentiation of bone marrow-derived macrophages, perhaps by decreasing the expression of RANKL (receptor activator of nuclear factor-κB ligand). This marine polyacetylene could represent a lead compound for osteoporosis treatment [
218]. The Caribbean sponge
Chalinula molitba has afforded the novel chlorinated sterol disulfate, chalinulasterol (
626) (
Figure 120). Despite the resemblance of chalinulasterol to the known PXR (pregnane X receptor) agonist solomonsterol A (
627), no activity is observed for the former sterol. This important receptor regulates expression of drug metabolizing and detoxifying enzymes [
219].
Two sets of metabolites from the ascidian
Synoicum sp. exhibit inhibition of the peptidase-type proteins sortase A and isocitrate lyase, two enzymes that have important functions in the virulence and survival of pathogenic bacteria. Thus, of the eudistomins cited earlier (
Figure 23), Y
4 (
134) and Y
5 (
135) show modest activity toward sortase A (SrtA) (IC
50 163.2 and 146.4 µM, respectively), whereas Y
2 (
132) shows IC
50 50.2 µM against isocitrate lyase (ICL) [
65]. Of the brominated aromatic furanones examined (
Figure 24), cardiolide E (
138) inhibits SrtA (IC
50 78.8 µM), and cardiolides E (
138) and I (
142) show IC
50 8.9 and 10.8 µM, respectively, for SrtA [
67]. These
Synoicum metabolites also inhibit the enzyme Na
+/K
+-ATPase (sodium-potassium adenosine triphosphatase) as follows: Y
4 (
134), Y
6 (
136), Y
7 (
137), cardiolide E (
138), and cardiolide I (
142) give these values: 7.5, 10.1, 11.3, 2.5, and 5.0 µM, respectively [
65,
67]. This enzyme is a sodium-potassium pump with several functions.
A combined Curacao and Papua New Guinea collection of cyanobacteria has yielded five new vinylchloride metabolites, janthielamide A (
628), kimbeamides A–C (
629–
631), and kimbelactone A (
632) (
Figure 121). Janthielamide A came from the collection at Jan Thiel Bay in Curacao, and the latter four metabolites came from the collection at Kimbe Bay, New Britain, Papua New Guinea. Janthielamide A (
628) exhibits Na
+ channel blocking in murine Neuro-2a cells (IC
50 11.5 µM), and also antagonizes induced Na
+ influx in neurons (IC
50 5.2 µM). Kimbeamide A (
629) displays similar Na
+ blocking activity at a concentration of 20 µg/mL, but it, along with the
630–
632, undergoes oxidative decomposition [
220].
The new isomalbrancheamide B (
633), along with three known analogues, was isolated from the fungus
Malbranchea aurantiaca (
Figure 122). Isomalbrancheamide B (
633) and the known malbrancheamide (
634) and malbrancheamide B (
635) are classical CaM (calmodulin) inhibitors, whereas the nonchlorinated premalbrancheamide (
636) is not. Malbrancheamide (
634) is the most active, and it binds to the same hydrophobic pocket as the antipsychotics chlorpromazine and trifluoperazine, two classical CaM inhibitors [
221].
Figure 121.
Structures of janthielamide A (
628), kimbeamides A–C (
629–
631), and kimbelactone A (
632) from cyanobacteria [
220].
Figure 121.
Structures of janthielamide A (
628), kimbeamides A–C (
629–
631), and kimbelactone A (
632) from cyanobacteria [
220].
Figure 122.
Structures of malbrancheamides
633–
636 from the fungus
Malbranchea aurantiaca [
221].
Figure 122.
Structures of malbrancheamides
633–
636 from the fungus
Malbranchea aurantiaca [
221].
The previously cited 5,6-dibromo-
l-hypaphorine (
558) (
Figure 107) from the sponge
Hyrtios sp. is a weak inhibitor of bee venom phospholipase A
2 (PLA
2). Relative to the positive control, manoalide (IC
50 0.5 µM),
558 has IC
50 0.20 mM [
195]. The red alga
Laurencia okamurai has yielded the new chamigrane, okamurene E (
637), and the new C
12-acetogenin, okamuragenin (
638) (
Figure 123), along with the known okamurenes A–D and nine known sesquiterpenes and four known C
15-acetogenins. All of these compounds were evaluated for toxicity against brine shrimp (
Artemia salina). Of all compounds, only 7-hydroxylaurene (
639) expressed lethal toxicity with LD
50 1.8 µM [
222].
Figure 123.
Structures of okamurene E (
637) and okamuragenin (
638) from the red alga
Laurencia okamurai, and 7-hydroxylaurene (
639) [
222].
Figure 123.
Structures of okamurene E (
637) and okamuragenin (
638) from the red alga
Laurencia okamurai, and 7-hydroxylaurene (
639) [
222].
The marine-derived fungus
Aspergillus sp. SCSGAF0093 produces nine mycotoxins, four of which are new, aluminiumneoaspergillin (
640), zirconiumneoaspergillin (
641), aspergilliamide (
642), and ochratoxin A
n-butyl ester (
643) (
Figure 124). This is the first report of marine-based ochratoxins (ochratoxin and the methyl ester were also isolated), and the first discovery of a zirconium complex (
641) in nature [
223]. All nine compounds exhibit some toxicity to brine shrimp. The most toxic compounds in this assay are
643, ochratoxin A, and ochratoxin A methyl ester, with IC
50 4.14, 13.74, and 2.59 µM, respectively.
Figure 124.
Structures of mycotoxins
640–
643 from the fungus
Aspergillus sp. SCSGAF0093 [
223].
Figure 124.
Structures of mycotoxins
640–
643 from the fungus
Aspergillus sp. SCSGAF0093 [
223].
The innocent-looking, but ominous cone snails (genus
Conus) comprise about 700 species and are widely distributed in the world’s oceans [
224]. It is estimated that these cone snails contain more than 50,000 distinct toxins, since the venom in each
Conus species consists of 40–200 individual peptides with a unique biological action [
225,
226,
227]. Many of these
Conus sp. peptides contain 6-bromotryptophan [
3], the function of which has been suggested to block proteolytic degradation since the large bromine makes the peptide a poor fit for docking in the active site of chymotrypsin [
228]. Recent studies have established the binding site of α-conotoxin Vc1.1 from
Conus victoria on the nicotinic α9α10 acetylcholine receptor, making this toxin a potential novel treatment for neuropathic pain [
229]. A similar α-4/6-conotoxin TxID has been identified in
Conus textile. It also blocks nicotinic acetylcholine receptors [
230]. The conopeptide MVIIA (Ziconotide; Prialt) was approved by the U.S. FDA in 2004 for the treatment of severe pain.