Diterpenes from the Marine Algae of the Genus Dictyota

Species of the brown algae of the genus Dictyota are rich sources of bioactive secondary metabolites with diverse structural features. Excellent progress has been made in the discovery of diterpenes possessing broad chemical defensive activities from this genus. Most of these diterpenes exhibit significant biological activities, such as antiviral, cytotoxic and chemical defensive activities. In the present review, we summarized diterpenes isolated from the brown algae of the genus.


Introduction
Marine brown algae of the genus Dictyota, belonging to the family Dictyotaceae, are mainly distributed in subtropical and tropical oceans [1]. Structurally diverse secondary metabolites from members of this genus were found to possess a defensive property which greatly contributes to their successful survival and reproduction in complex and diverse marine environments [2]. At present, hundreds of bioactive natural products, including terpenes, phenols [3], sterols [4], fatty acids [5], and polysaccharides [6], have been isolated from marine brown algae of the genus Dictyota. Diterpenes are a large class of structurally diverse natural products which are widely found in marine organisms, including Dictyota species [7]. Some diterpenes are promising drug candidates due to their remarkable pharmacological activity [8][9][10]. Some diterpenes from Dictyota species are considered as the characteristic constituents of this genus, and give them taxonomic significance [1,11]. Diterpenes from members of this genus usually exhibit potent cytotoxic or antiviral activities [12,13].
In the present review, we systematically summarize the structures and bioactivities of diterpenes derived from members of the genus Dictyota, with more than 80 references cited. Up to the end of 2017, a total of 233 diterpenes had been isolated from Dictyota species, most of which were from the marine brown alga Dictyota dichotoma. It has been reported that many of these diterpenes possess several interesting bioactivities, including cytotoxic and antiviral activities.

Diterpenes of Group 1I
Based on the revised biogenetic scheme widely cited, Group II consists of diterpenes derived by a first cyclization of the geranyl-geraniol precursor between C-1 and C-11 [1]. The diterpene skeletons of this group comprise the dolabellane, dolastane, secodolastane etc. A total of 120 diterpenes of Group II, including 69 dolabellane diterpenes, were isolated from Dictyota species by the end of 2017, most of which exhibit biological properties, such as antibiotic [44], cytotoxic [45], antiviral [46], antibacterial [47], and protection activities against DNA damage [15] in addition to other

Diterpenes of Group 1I
Based on the revised biogenetic scheme widely cited, Group II consists of diterpenes derived by a first cyclization of the geranyl-geraniol precursor between C-1 and C-11 [1]. The diterpene skeletons of this group comprise the dolabellane, dolastane, secodolastane etc. A total of 120 diterpenes of Group II, including 69 dolabellane diterpenes, were isolated from Dictyota species by the end of 2017, most of which exhibit biological properties, such as antibiotic [44], cytotoxic [45], antiviral [46], antibacterial [47], and protection activities against DNA damage [15] in addition to other biological activities. Tables 4-6 summarize 120 diterpenes of Group II identified from Dictyota species (see at the end of this section).

Dolabellane Diterpenes
Dolabellane diterpenes bearing the 5,11-fused bicyclic skeleton constitute a large number of diterpenes with structural diversity, including specific hydroxylation, oxidation, epoxidation, and other reactions [48]. A total of 69 compounds have been isolated from the genus Dictyota, among which 25 have been found from D. dichotoma. Dolabellane diterpenes were originally isolated from the opistobmnch mollusc Dolabella californica in 1977 [48]. Later, they were isolated from other marine organisms, including sponges, sea whips, and brown algae of the genus Dictyota [49].
Besides D. dichotoma, other algae of this genus are also rich producers of bioactive dolabellane diterpenes ( Figure 5). Fifteen compounds 84-98 were isolated from D. pardarlis f. pseudohamata from Magnetic Island [53][54][55]. Compounds 98-102 were also reported from D. bartayresiana, collected from Hare Island in the Gulf of Mannar of the Indian Ocean [52]. Three dolabellane diterpenes, 103-105, were isolated from D. pfaffii. Three antiviral diterpenes, named dolabelladienols A-C (106-108), were found from the same species, collected from Atol das Rocas, Northeast Brazil [46]. Compound 103 showed potent anti-HIV-1 effect ranging from 60% to 90% in peripheral blood cells (PBMC) and macrophages infected with the human immunodeficiency virus (HIV) from 60% to 90%, respectively [56]. This compound also exhibited moderate inhibition against herpes virus at a concentration of 50 µM, and it was found to be moderately active against HIV-1 reverse transcriptase activity at a concentration of 40 µM [57]. Moreover, 103 also displayed significant antimalarial activity against Leishmania amazonensis with an IC 50 value of 44 µM [58]. Compound 104, an antifeedant against the sea urchin and generalist fishes [13], exhibited strong anti-HSV-1 activity with a CC 50 value of 185 ± 5 µM [57]. Compounds 106 and 107 exhibited strong anti-HIV-1 activity with IC 50 values of 2.9 and 4.1 µM, respectively [46]. Compound 109 was isolated from D. pfaffii which was collected from Atol das Rocas in Northeast Brazil, and it displayed strong anti-HSV-1 activity, reaching an inhibition of 87% at a concentrate of 50 µM [57]. Four antiviral diterpenes, 110-113, have been extracted from D. plectens which was collected from the South China Sea. These compounds showed specific inhibition against HA-mediated viral entry with an inhibition rate of 62% at 30.0 µM [16].
Besides D. dichotoma, other algae of this genus are also rich producers of bioactive dolabellane diterpenes ( Figure 5). Fifteen compounds 84-98 were isolated from D. pardarlis f. pseudohamata from Magnetic Island [53][54][55]. Compounds 98-102 were also reported from D. bartayresiana, collected from Hare Island in the Gulf of Mannar of the Indian Ocean [52]. Three dolabellane diterpenes, 103-105, were isolated from D. pfaffii. Three antiviral diterpenes, named dolabelladienols A-C (106-108), were found from the same species, collected from Atol das Rocas, Northeast Brazil [46]. Compound 103 showed potent anti-HIV-1 effect ranging from 60% to 90% in peripheral blood cells (PBMC) and macrophages infected with the human immunodeficiency virus (HIV) from 60% to 90%, respectively [56]. This compound also exhibited moderate inhibition against herpes virus at a concentration of 50 μM, and it was found to be moderately active against HIV-1 reverse transcriptase activity at a concentration of 40 μM [57]. Moreover, 103 also displayed significant antimalarial activity against Leishmania amazonensis with an IC50 value of 44 μM [58]. Compound 104, an antifeedant against the sea urchin and generalist fishes [13], exhibited strong anti-HSV-1 activity with a CC50 value of 185 ± 5 μM [57]. Compounds 106 and 107 exhibited strong anti-HIV-1 activity with IC50 values of 2.9 and 4.1 μM, respectively [46]. Compound 109 was isolated from D. pfaffii which was collected from Atol das Rocas in Northeast Brazil, and it displayed strong anti-HSV-1 activity, reaching an inhibition of 87% at a concentrate of 50 μM [57]. Four antiviral diterpenes, 110-113, have been extracted from D. plectens which was collected from the South China Sea. These compounds showed specific inhibition against HA-mediated viral entry with an inhibition rate of 62% at 30.0 μM [16]. Besides the above-mentioned algae, other member of the genus Dictyota are also producers of bioactive dolabellane diterpenes ( Figure 6). Compound 114 was isolated from D. divaricata collected from the Great Barrier Reef region of Northern Australia [40]. Compound 115 was isolated from D. volubilis [31]. On the other hand, 116-120 were isolated from Dictyota sp., collected near Portopalo. Compound 116 displayed significant in vitro cytotoxicity against KB cells [45]. Three antifouling compounds 121-123, were obtained during an investigation of a Mediterranean Dictyota sp. Compound 122 showed moderate antifouling activity against marine bacterial biofilm-forming bacteria D41 with an EC50 value of 110 μM, while compound 123 was weakly active with an EC50 value of 250 μM [41]. Four antifouling compounds 124-127 were isolated from Dictyota spp. collected from the Mediterranean coasts (France and Algeria) [23]. Both compounds 126 and 127 displayed weak anti-adhesion activity against D41 with an EC50 more than 100 μM. These compounds showed weak antibacterial activity against macrolide-resistant variant RN4220 with MIC values of 128 and 64 μg/mL, respectively [59]. Moreover, compound 127 exhibited selective inhibitory activity against the cyanobacterium Oscillatoria perornata with an IC50 value of 23.4 μM [19]. Besides the above-mentioned algae, other member of the genus Dictyota are also producers of bioactive dolabellane diterpenes ( Figure 6). Compound 114 was isolated from D. divaricata collected from the Great Barrier Reef region of Northern Australia [40]. Compound 115 was isolated from D. volubilis [31]. On the other hand, 116-120 were isolated from Dictyota sp., collected near Portopalo. Compound 116 displayed significant in vitro cytotoxicity against KB cells [45]. Three antifouling compounds 121-123, were obtained during an investigation of a Mediterranean Dictyota sp. Compound 122 showed moderate antifouling activity against marine bacterial biofilm-forming bacteria D41 with an EC 50 value of 110 µM, while compound 123 was weakly active with an EC 50 value of 250 µM [41]. Four antifouling compounds 124-127 were isolated from Dictyota spp. collected from the Mediterranean coasts (France and Algeria) [23]. Both compounds 126 and 127 displayed weak anti-adhesion activity against D41 with an EC 50 more than 100 µM. These compounds showed weak antibacterial activity against macrolide-resistant variant RN4220 with MIC values of 128 and 64 µg/mL, respectively [59]. Moreover, compound 127 exhibited selective inhibitory activity against the cyanobacterium Oscillatoria perornata with an IC 50 value of 23.4 µM [19].

Dolastane Diterpenes
Dolastane diterpenes containing the 5,7,6-tricyclic skeleton are another class of bioactive constituents of brown algal species of the genus Dictyota [60]. At present, a total of 38 dolastane diterpenes have been obtained from Dictyota species.

Dolastane Diterpenes
Dolastane diterpenes containing the 5,7,6-tricyclic skeleton are another class of bioactive constituents of brown algal species of the genus Dictyota [60]. At present, a total of 38 dolastane diterpenes have been obtained from Dictyota species.
Four dolastane diterpenes, 142-145, were isolated from D. divaricata, collected from the Virgin Islands [69]. Examination of the organic extract of D. indica, collected from Bulegi near the Karachi Coast of the Arabian Sea provided three diterpenes, dictinol (146), dictindiol (147), and dictintriol (148) [63]. Compounds 149-151 were reported from D. bartayresiana, collected in the Hare Island of the Gulf of Mannar of the Indian Ocean [52]. Three dolastane diterpenes, named isoamijiol (152), 14-deoxyamijiol (153), and amijidictyol (154), were isolated from D. linearis [70] and a total synthesis of compound 152 was accomplished [71]. Extracts of the mixed collections of two brown algae D. linearis and D. divaricata, from the Honduras Bay Islands, afforded seven dolastane diterpenes 137, 138, and 158-162. Compound 161 displayed a strong reversible inhibitory action of histamine on the guinea pig ileum at a concentration of 16 μg/mL. Compound 162 showed moderate decrease in the twitch height of rat hemidiaphragm preparation at a concentration of 16 μg/mL. Moreover, 162 displayed weak inhibition of cell division using an urchin egg assay [60]. Compound 163 was isolated from D. furcellata, collected from Cape Peron in Western Australia [72]. Two dolostane diterpenes 164 and 165, were isolated from Dictyota sp. from the Canary Islands [73] (Figure 9). Extracts of the mixed collections of two brown algae D. linearis and D. divaricata, from the Honduras Bay Islands, afforded seven dolastane diterpenes 137, 138, and 158-162. Compound 161 displayed a strong reversible inhibitory action of histamine on the guinea pig ileum at a concentration of 16 µg/mL. Compound 162 showed moderate decrease in the twitch height of rat hemidiaphragm preparation at a concentration of 16 µg/mL. Moreover, 162 displayed weak inhibition of cell division using an urchin egg assay [60]. Compound 163 was isolated from D. furcellata, collected from Cape Peron in Western Australia [72]. Two dolostane diterpenes 164 and 165, were isolated from Dictyota sp. from the Canary Islands [73] (Figure 9). Honduras Bay Islands, afforded seven dolastane diterpenes 137, 138, and 158-162. Compound 161 displayed a strong reversible inhibitory action of histamine on the guinea pig ileum at a concentration of 16 μg/mL. Compound 162 showed moderate decrease in the twitch height of rat hemidiaphragm preparation at a concentration of 16 μg/mL. Moreover, 162 displayed weak inhibition of cell division using an urchin egg assay [60]. Compound 163 was isolated from D. furcellata, collected from Cape Peron in Western Australia [72]. Two dolostane diterpenes 164 and 165, were isolated from Dictyota sp. from the Canary Islands [73] (Figure 9).

Secodolastane Diterpenes
Secodolastane diterpenes are a class of compounds derived by decyclization of the dolastane skeleton between C-8 and C-9 [74]. A total of 12 secodolastane diterpenes were found in D. indica, D. cervicornis, or D. dichotoma ( Figure 10).

Secodolastane Diterpenes
Secodolastane diterpenes are a class of compounds derived by decyclization of the dolastane skeleton between C-8 and C-9 [74]. A total of 12 secodolastane diterpenes were found in D. indica, D. cervicornis, or D. dichotoma ( Figure 10).

Dictyoxetane Diterpenes
A dictyoxetane diterpene 178 was isolated from D. dichotoma, collected from the coast of the Indian Ocean [51] (Figure 11).

Dictyoxetane Diterpenes
A dictyoxetane diterpene 178 was isolated from D. dichotoma, collected from the coast of the Indian Ocean [51] (Figure 11).

Dictyoxetane Diterpenes
A dictyoxetane diterpene 178 was isolated from D. dichotoma, collected from the coast of the Indian Ocean [51] (Figure 11).

Diterpenes of Group III
The diterpenes of this group are derived from cyclization of the geranyl-geraniol precursor between C-2 and C-10 or by ring contraction of the prenylated-germacrane [1]. Xenicane diterpenes, the main diterpenes of Group III, undergo oxidation, epoxidation, condensation, and other reactions to give rise to monocyclic, bicyclic, and tricyclic structures. Forty xenicane diterpenes were isolated from members of the genus Dictyota and most of them exhibited interesting biological activities, such as antiviral [16], anti-inflammatory [76], cytotoxic [12], antifungal [77], and other biological activities. Tables 7 and 8 summarize 55 diterpenes of Group III from Dictyota species (see in Section 4.1).

Xenicane Diterpenes
Xenicane diterpenes are a large class of marine diterpenes bearing a cyclononane ring as a common structural feature. The species of the genus Dictyota have been shown to be important producers of xenicane diterpenes since 40 xenicanes were isolated from members of this genus. Antiviral compounds, 179-183, were obtained from D. plectens from the South China Sea. Compound 181 showed moderate inhibition against HIV-1 replication with an IC 50 value of 21.9 ± 1.3 µM. Compound 183 displayed moderate antiviral activity against HA-mediated viral entry and strong anti-inflammatory activity against LPS-induced NO production at 10.0 µM [16]. Compound 184 was isolated from D. plectens, collected from the Xuwen coast, China and was found to exhibit a weak anti-inflammatory activity against LPS-induced NO production at 10.0 µM [76]. Two cytotoxic diterpenes, acetyldictyolal (185) and hydroxyacetyldictyolal (186), were isolated from D. dichotoma, collected at Oshoro Bay, Hokkaido [78]. Compound 185 displayed strong cytotoxicity against P-388, KB, NSCLCN6-L16 cell lines with EC 50 values ranging from 1.50 to 9.1 µg/mL and weak antifungal activity against Aspergillus fumigates (IPC864-64), Microsporum canis (IPC1687-87) and Trichophyton mentagrophytes (IPC1468-83) [50]. Dictyodial (187) and 4α-acetyldictyodial (188) were isolated from D. linearis, collected from the south coasts of Chios Island [38]. Compound 187 was also isolated from D. crenulata and D. flabellata, respectively. Compound 187 exhibited potent antibacterial activity against Staphylococcus aureus and Bacillus subtilis as well as antifungal activity against C. albicans [77]. Hydroxydictyodial (189), isolated from D. spinulosa collected from Kin, Okinawa was found to exhibit a potent antifeedant activity against the omnivorous fish Tilapia mossambica as well as antibiotic activity against S. aureus and B. subtilis [79]. Compound 190 was reported from D. divaricata from the Great Barrier Reef region of Northern Australia [27]. 17-Acetoxy-dictyodial (191), isolated from D. ciliolata collected from the Oualidia lagoon was found to exhibit moderate antifungal activity against C. albicans with MIC value of 50 µg/mL [80] (Figure 12).

Conclusions
The genus Dictyota is a rich source of various natural products with unprecedented pharmacological and biological activities. Significant progress has been made in the discovery of bioactive secondary metabolites from members of the genus Dictyota [90]. The overwhelming majority of those secondary metabolites are diterpenes, especially Group II diterpenes (120 compounds) accounting for almost half of the total diterpenes from the Dictyota species (233 compounds). The cosmopolite D. dichotoma, the species that produces diterpenes of all three groups

Conclusions
The genus Dictyota is a rich source of various natural products with unprecedented pharmacological and biological activities. Significant progress has been made in the discovery of bioactive secondary metabolites from members of the genus Dictyota [90]. The overwhelming majority of those secondary metabolites are diterpenes, especially Group II diterpenes (120 compounds) accounting for almost half of the total diterpenes from the Dictyota species (233 compounds). The cosmopolite D. dichotoma, the species that produces diterpenes of all three groups

Conclusions
The genus Dictyota is a rich source of various natural products with unprecedented pharmacological and biological activities. Significant progress has been made in the discovery of bioactive secondary metabolites from members of the genus Dictyota [90]. The overwhelming majority of those secondary metabolites are diterpenes, especially Group II diterpenes (120 compounds) accounting for almost half of the total diterpenes from the Dictyota species (233 compounds). The cosmopolite D. dichotoma, the species that produces diterpenes of all three groups (I-III), has been proven to be an important producer of diterpenes. A total of 78 structurally diverse diterpenes have been isolated from D. dichotoma.
Some diterpene skeletons from Dictyota species are the characteristic constituents of this genus, which have chemotaxonomic significance. For example, the majority of prenylated-guaiane and dolabellane diterpenes were isolated from D. dichotoma, while dolastane diterpenes are mainly found in three species D. dichotoma, D. divaricato, and D. linearis. Xenicane diterpenes, a class of chemical characteristic for the taxonomy of the genus Dictyota, are found in only a few Dictyota species, mainly in D. plectens.
However, there are a number of problems in drug discovery and development from Dictyota species, including the development of new techniques applied to discover more bioactive diterpenes, total synthesis, multi-target screening assay, and pharmacological mechanisms of drug candidates. Firstly, it is necessary to discover more bioactive secondary metabolites from Dictyota species using a combined multi-target screening assay, bioassay-guided separation with an LC-MS based metabolomics approach in further research. Secondly, few results have been achieved in the total synthesis of bioactive diterpenes. The total synthesis of compounds 152 and 222 has been successfully completed. More efforts should be devoted in improving the total synthesis of bioactive diterpenes from the genus Dictyota. Successful total synthesis would be beneficial for the structural optimization of natural diterpenes, for further biological activity evaluation, and for pharmacological and clinical applications. Thirdly, as for bioactivity evaluation, less than half of the diterpenes derived from the Dictyota species have been measured due to the limitations of bioactivity assays. Various biological activity assays, including multi-target screening assay, in vitro and animal experiments, should be improved to promote the discovery of new promising leader drugs.
This review summarized diterpenes derived from the genus Dictyota up to the end of 2017, providing valuable insight into the further discoveries of novel diterpenes from the genus Dictyota.
Author Contributions: J.C. collected a complete survey of all compounds isolated from the genus Dictyota; J.C., H.L. and Z.Z. wrote the manuscript; J.Z. and X.Y. interpreted and revised the results, and wrote the manuscript; Z.Z., X.X. and B.L. discussed the results scientifically and contributed to editing of the paper.