Chemical Diversity in Species Belonging to Soft Coral Genus Sacrophyton and Its Impact on Biological Activity: A Review

One of the most widely distributed soft coral species, found especially in shallow waters of the Indo-Pacific region, Red Sea, Mediterranean Sea, and also the Arctic, is genus Sacrophyton. The total number of species belonging to it was estimated to be 40. Sarcophyton species are considered to be a reservoir of bioactive natural metabolites. Secondary metabolites isolated from members belonging to this genus show great chemical diversity. They are rich in terpenoids, in particular, cembranoids diterpenes, tetratepenoids, triterpenoids, and ceramide, in addition to steroids, sesquiterpenes, and fatty acids. They showed a broad range of potent biological activities, such as antitumor, neuroprotective, antimicrobial, antiviral, antidiabetic, antifouling, and anti-inflammatory activity. This review presents all isolated secondary metabolites from species of genera Sacrophyton, as well as their reported biological activities covering a period of about two decades (1998–2019). It deals with 481 metabolites, including 323 diterpenes, 39 biscembranoids, 11 sesquiterpenes, 53 polyoxygenated sterols, and 55 miscellaneous and their pharmacological activities.


Introduction
Classification of alcyonacean corals, subclass Octocorallia implies the existence of polyps with eight tentacles, which differentiates them from hexacorallian Scleractinia corals. Alcyonaceans are sessile large invertebrate with distinct stalk and a smooth, mushroom-shaped top known as capitulum, and their tissue comprises sclerites, which give support to the colony [1,2]. Traditionally, identification and classification of most soft coral have been carried out by sclerite classification. Sarcophyton covers 35 species, and another six species of Sarcophyton were described [3][4][5][6][7][8]. Later, [9] reported that, within Sarcophyton samples, Sarcophyton glaucum contains six different genetic clades, signifying that this morphologically heterogeneous species was mysterious [10]. Studies revealed that Structural elucidation of the isolates was established by their spectral data and chemical correlation, as (7R,8S)-dihydroxydeepoxy-ent-sarcophine 120 was found to be the enantiomer of (7S,8R)dihydroxydeepoxysarcophine 123 and compound 121 has a unique butyl ester group at C-16 [53].
Five isolated cembranoids, sarcocrassocolides A-E 137-141, together with sinularolide 142, were isolated from S. crassocaule. Structural elucidation of the compounds was determined through spectral analysis, and the absolute configuration of sarcocrassocolide A 137 was investigated by modified Mosher's method. It is worth mentioning that sarcocrassocolides A-D 137-140 possessed a tetrahydrofuran group with a seldomly found 4,7-ether bond, which was discovered previously in Eunicea mammosa soft coral [57,58]. Another seven cembranoids with α-methylene-γ-lactonic group and rare trans 6,7-disubstituted double bond, uncovered earlier only in soft coral Eunicea pinta, identified as sarcocrassocolides F-L 143-149, were isolated from S. crassocaule [59]. Besides the abovementioned sarcocrassocolides, another three sarcocrassocolides, M-O 150-152, from S. crassocaule, were identified. Through structural analysis, sarcocrassocolide N 151 was found to have the same relative configuration of sarcocrassocolide M 150, while sarcocrassocolide O 152 was found to be the 13-deacetoxy derivative of sarcocrassocolide M 150 [60]. Three more cembranoids, sarcocrassocolides P-R 153-155, were identified, and their structures were investigated by an extensive spectral study [61].
Methyl sarcotroates A and B 172 and 173 two diterpenes, along with sarcophytonolide M 174, a precursor for the former two compounds, were isolated from S. trocheliophorum, and their biogenetic pathways were proposed, in which isomaration, cycloaddition followed by oxidation of compound 174 led to the formation of both compounds 172 and 173. The authors also studied the absolute configuration of methyl sarcotroate B 173 through TDDFT ECD calculations, helping in determining the absolute configurations for methyl sarcotroate A 172 and sarcophytonolide M 174 by a biogenetic relationship and ECD comparison, respectively [67].
From the ethyl acetate extract of S. ehrenbergi two diterpenes were isolated, acetyl ehrenberoxide B 194 and ehrenbergol C 195. Ehrenbergol C 195 shared a structure similar to lobocrasol 193, isolated from Lobophytum crassum [71]. Yet, relative stereochemistry of carbon-7 and carbon-8 in ehrenbergol C 195 differed from lobocrasol 193 in hydroxy group and a conjugated enone evidenced by the IR spectrum at 3444 and 1696 cm −1 , respectively [72].
Cembranoid diterpenes, 7-keto-8α-hydroxy-deepoxysarcophine 216 similar to compound 13, in which the carbon at carbon-3 and carbon-11 were presumed to be in E configuration established on compound 13 derivatives; this was established through spectral data. 7β-chloro-8α-hydroxy-12acetoxy-deepoxysarcophine 217 was close to 7-keto-8α-hydroxy-deepoxysarcophine 216 except for the disappearance of ketone signal at C-7 which co-exists with the presence of an up fielded signal at δ62.9 (C-7), a downfield of C-20 and the presence of carbonyl and methyl group at 170 and 22.2, respectively, were isolated from S. ehrenbergi. [79]. From S. trocheliophorum, sarsolenane diterpenes and capnosane diterpenes were obtained. Sarsolenane diterpenes are uncommon in nature, symbolized only by sarsolenone isolated from S. solidum. Two sarsolenane diterpenes, dihydrosarsolenone 218, methyl dihydrosarsolenoneate 219, and two capnosane diterpenes, sarsolilides B and C 220 and 221, together with sarsolilide A 222 were isolated. Dihydrosarsolenone 218 resulting from sarsolenone 223 by terminal double bond Δ 15 reduction followed by the oxidation of C-18 gave methyl dihydrosarsolenoneate 219. Capnosane diterpenes were first isolated from S. solidum and S. trocheliphorum. The only example reported with α, β-unsaturated ε-lactone subunit was sarsolilide A 222, from S. solidum, in which, the hydration of the exomethylene group provided carbon-10 epimers, sarsolilides B and C 220 and 221 [80] Ethyl acetate extract of S. trocheliophorum yielded twenty-three isolates, of which nineteen were cembranoids with unique capnosane skeleton identified as trocheliophols A-S 224-242 and two analogues, 4-epi-sarcophytol L 243 and sarcophyolide C 182. The structures were investigated by a full spectral data, and their absolute configurations were established through modified Mosher's assay, CD and X-ray diffraction. Trocheliophols C 226, E 228, F 229, and M 236 all possessed a structure similar to sarcophytolide C 176, while, trocheliophol Q 240 was identified as the C-8 methoxylated model of trocheliophol F 229. However, trocheliophol R 241 possessed a similar structure to trocheliophol F 229 but it differed in the presence of the methoxy group [81].
Chemical determination of S. elegans CH2Cl2/MeOH extract resulted in isolation of four cembranoids identified as sarcophelegans A-D 244-247. Sarcophelegan A 244 was found to be the 11,12-epoxy derivative of sarcophelegan C 246. Through X-ray crystallographic examination using anomalous scattering of Cu Kα radiation, sarcophelegan A 244 structure was verified. Moreover, sarcophelegan C 246 was found to be the 7-hydrogenated derivative of sarcophelegan B 245 [18].
Three isolates; trocheliane 254, tetracyclic biscembrane and two cembranoid diterpenes, sarcotrocheldiols A and B 255 and 256, were isolated from S. trocheliophorum. Their relative configuration and structure of the isolates were investigated by spectral data [84].
From S. ehrenbergi eight cembranoids, sarcophytonoxides A-E 282-286 were identified. Sarcophytonoxide A 282, a cembrane diterpene with epoxide, dihydrofuran, acetyl group and three olefin bonds were confirmed by spectral data analysis while sarcophytonoxide D 285 was the deacetylated form of sarcophytonoxide C 284 which has a structure similar to sarcophytonoxide A 282. However, sarcophytonoxide C 283 differed in the chemical shift of C-19, C-6, C-7, and C-9 because of the 7,8-double bond configuration or chiral center of C-6. However, sarcophytonoxide E 286 differed in the position of acetyl group and the exocyclic double bond. [91]. From S. trocheliophorum a sarsolenane diterpene, secodihydrosarsolenone 287 was identified [92].
Isolation of seven diterpenes were reported from S. ehrenbergi and identified as sarcoehrenbergilids A-C 302-304 together with sinulolides A and B 305 and 306. The absolute configuration of sarcoehrenbergilid A 301 was investigated by scattering of CaKα radiation with the flack parameter [95]. Moreover, sarcoehrenbergilid D-F 307-309, diterpenes isolated from S. ehrenbergi were isolated and their absolute configurations were investigated by experimental and TDDFT-simulated ECD spectra. Sarcoehrenbergilid D 307 was found to differ from compound 301 only in stereochemistry [96]. Furthermore, five cembranes diterpenes, Sarcoehrenolides A-E 310-314 were isolated from S. ehrenbergi. Their chemical structures were determined through extensive spectral data. All isolates were related to ehrenbergol D 251 in structure, having an α,β-unsaturatedγlactone group at carbon-6 to carbon-19, however, they differ in migration of double bonds and/or oxidative configurations. Additionally, the absolute configuration of sarcoehrenolide A 310 was investigated by a single-crystal X-ray diffraction assay by Cu Kα radiation, and the absolute configurations of sarcoehrenolides B 311 and D 313 by TDDFT/ECD calculations [97].

Biscembranes
Four biscembranes, bisglaucumlides A-D 325-328 were isolated from S. glaucum. Spectral data showed that bisglaucumlide A 325 possessed a biscembranoid skeleton. Bisglaucumlide B 326 was confirmed to be 32-acetylbisglaucumlide A by the positive Cotton effect in the CD spectrum. As for bisglaucumlide C 327 it was found to be the geometrical isomer of bisglaucumlide B 326 while considering the geometry of the C-4 olefin. Bisglaucumlide D 328 was an isomer to bisglaucumlide C 327, its absolute configuration indicated an anticlockwise relation among the enone chromopores revealing a negative Cotton effect CD spectrum [102]. Moreover, chemical investigation of S. glaucum extract yielded two biscembranes with an uncommon α, β-unsaturated ε-lactone, Glaucumolides A and B 329-330 [103].
Ximaolides A-G 331-337, seven biscembranoid, together with methyl tortuosoate A 338 where isolated from S. tortuosum. Their structures were elucidated through spectral analysis and Ximaolide A 331 and E 335 relative stereochemistry were investigated using X-ray diffraction method. The authors demonstrated that methyl tortuosoate A 338 could be the biogenetic precursor for all isolated metabolites since their upper parts were closely related to compound 338 [104].
A cembranolide diterpene identified as isosarcophytonolide D 339, an isomer to the previously isolated compound 41 from S. tortuosum, along with two biscembranes, bislatumlides A and B 340-341, were isolated from S. latum. A detailed spectral analysis revealed that the structure of bislatumlide B 341 matched that of bislatumlide A 340. However, 13 C NMR data revealed a significant difference from compound 340 in the chemical shifts of carbon-19 and carbon-10 demonstrating the Z nature of Δ 11 olefin in compound 340. Thus, compound 340 was found to be the 11Z isomer of bislatumlide B 341. Interestingly the authors have proposed a biosynthetic pathway for bislatumlides A and B 340-341 in which isosarcophytonolide D 339 was found to be one of the precursors for bislatumlide A 340. Moreover, the authors investigated the effect of long-term storage in CDCl3, where it showed isomerization of bislatumlide A 340 to bislatumlide B 341 at ∆ 11 [105].
Investigation on S. elegans extract led to the isolation of six biscembranoids identified as sarcophytolides G-L 348-353, together with biscembranoids, lobophytones H, Q, K, W, U 354-358. Isolates structure were determined by spectroscopic analysis. Absolute configuration of the compound sarcophytolide G 348 was determined using Mosher reaction [22,107]. From the methanol extract of S. pauciplicatum, sarcophytolides M and N 359 and 360, along with lobophytone O 361, were isolated [108].
Two biscembranoids, sarelengans A and B 362 and 363, were reported from S. elegans. Their chemical structures were investigated by spectral and chemical methods, and the absolute configuration of sarelengans A determined by single crystal X-ray diffraction. Sarelengans A and B 362 and 363 possessed a conjuncted trans-fused A/B-ring between two cembranoid entities. The authors mentioned that this structure feature led to an uncommon biosynthetic pathway including a cembranoid-∆ 8 instead of cembranoid-∆ 1 unit in endo-Diels-Alder cycloaddition [94]. Figure 5 summarizes biscembranes isolated from Sacrophyton sp.
Chemical investigation of the polar fraction of S. trocheliophorum, yielded two poly-hydroxy steroids, identified through extensive spectral analysis as zahramycins A and B 404 and 405. Zahramycin A 404 was characterized by the existence of oxirane ring at carbon-5 and carbon-6, while zahramycin B 405 possessed a keto-hydroxy sterol structure [117].
An infrequent prostaglandin was isolated from S. crassocaule, (5Z)-9,15-dioxoprosta-5,8(12)-dien-1-oate 438 based on spectral analysis. This was the first time to report a prostaglandin with a C-15 keto group from natural origin [123]. Furthermore, from the ethyl acetate and n-butanol fractions of S. crassocaule, two isolated metabolites identified as sarcophytonone 439 a tetra-substituted quinone, and sarcophytonamine 440 a quaternary amine were reported. It might be valuable to know that these quinone derivatives are scarce in marine organisms and only sarcophytonone 439 was identified in S. mayi [124].
Five compounds were isolated from S. infundibuliforme, three were reported O-glycosylglycerol known as sarcoglycosides A-C 441-443 and chimyl alcohol and hexadecanol 444 and 445.
Methyl tortuoate A and methyl tortuoate B 476 and 477, two tetracyclic tetraterpenoids, together with methyl sartortuoate 478 and methyl isosartortuoate 479, were reported from S. tortuosum. Methyl tortuoate A 476 was similar to methyl sartortuoate 478 in structure, except for the presence of secondary hydroxyl group in methyl tortuoate A 476 and absence of one tertiary hydroxyl functional group and conjugated diene. As for, methyl tortuoate B 477, it was found to be similar to methyl isosartortuoate 479 in structure, but with no hydroxyl group at C-27 [131]. Tetraterpenoid, methyl tortuoate C 480 after further investigation of the same ethanolic extract of S. tortuosum was isolated and a full spectral data was done to investigate its structure [132]. Another tetracyclic tetraterpenoid; methyl tortuoate D 481, was also reported from S. tortuosum and was identified using direct infusion electrospray ionization mass spectrometry [133]. Figure 8 summarizes miscellaneous isolated from Sacrophyton sp.

Cytotoxic Activity
The capability of 13-Acetoxysarcocrassolide 9 was investigated, as a cytotoxic agent against gastric carcinoma using MTT method, colony formation method, cell morphology assessments, and wound-healing method. It suppressed the development and migration of gastric cancer cells in a dose-dependent manner and initiated both early and late cell death examined by flow cytometer assay [134]. The authors mentioned that there was a relationship between the structure of sarcrassin A, B, D, and E 76, 77, 79, and 80, and emblide 81, and its activity, showing that loss of acetoxy group as in crassocolide C 84 led to loss of activity against all tested cell lines. While, acetylation at 4-OH position in crassocolide B 83 resulted in a decrease in activity cytotoxicity. However, the existence of two hydroxy moiety present at carbon-3 and carbon-4 and no oxidation at carbon-13 as in crassocolide D 85 showed potent activity against MCF-7 and A549 cell lines. While, crassocolide A 82 and F 87 exhibited potent activity toward Hep G2, MCF-7, MDA-MB-231 and A549, because of the 5-O-acetyl group [46]. Furthermore, crassocolide H and L 90 and 94, from S. crassocaule, showed strong activity toward KB, Hela, and Daoy cell lines owing to the presence of Cl atom at C-11 instead of OH group in crassocolide H 90 [47].
Sarcocrassocolides A-D 137-140, showed potent activity toward MCF-7, WiDr, HEp-2 and Daoy cell lines [58]. The authors maintained that the existence of acetoxy group at C-13 was important for activity. Sarcocrassocolides F-I 143-146, showed cytotoxicity toward all or part cell lines. However, sarcocrassocolide I 146 was most potent toward Daoy, HEp-2, MCF-7 and WiDr cell lines while sarcocrassocolide J and L 147 and 149 13-deacetoxy derivatives, were least potent against all tested cell lines with ED50 = >20 μM. Furthermore, hydroxy moiety at carbon-8 improve the cytotoxic activity in contrast with carbon-8 hydroperoxy-bearing correspondents sarcocrassocolide F and H 143 and 145 were most potent toward MCF-7 [59].

Anti-Inflammatory Activity
Sarcocrassocolide M 150 could be a leading anti-inflammatory. Sarcocrassocolides M-O 150-152 might be beneficial anti-inflammatory agents because of the structure relationship and the existence of β-hydroperoxy moiety at carbon-7 [60]. Sarcocrassocolides F-L 137-143 activity was attributed to the ring-opening of the α,β-unsaturated-β-ether ketone group leading to an increase in the enzyme inhibitory activity [58]. Sarcoehrenolide A, B, and D 310, 311, and 313 and ehrenbergol D 251 showed significant TNF-α inhibition in which sarcoehrenolide B 311 was most active due to the existence of acetoxy at carbon-18. A structure activity relationship was demonstrated in which the keto moiety at carbon-13 and hydroxyl group at carbon-18 could be responsible for the slight increase in activity. However, the presence of carbomethoxy moiety at carbon-18 led to a reduction in activity [97].

Antidiabetic Activity
Methyl sarcotroate B 173 has strong inhibitory activity toward PTP1B because of the hydroperoxide group which binds to the active site of the Cys residue [67]. Potency of sarcophytonolide N 50 and sarcrassin E 80 may be because of the existence of methyl ester moiety at carbon-18, which significantly increases the enzyme inhibitory activity toward human PTP1B enzyme [39].

Antimicrobial Activity
Sarcophytolide 32 showed a strong antibacterial activity toward methicillin-sensitive S. aureus Newman strain because of the diene at C-1/C-3 [41]. The crude extract exhibited antimicrobial activity toward most of the examined bacteria, yeasts, and fungi. [77]. Trocheliophols H, I, L, N, O, and R 231, 232, 235, 237, 238, and 241, 4-epi-sarcophytol L 243 showed antibacterial activity toward Xanthomonas vesicatoria, Agrobacterium tumefaciens, Pseudomonas lachrymans, Bacillus subtilis, and Staphylococcus aureus. The authors mentioned that the structure activity relationship and the existence of exomethylene group at C-8 add to the antibacterial activity, while H-3β orientation, which was present only in compound trocheliophol S 242, gave the most potent activity against the selected bacteria [81]. The toxicity of the novel γ-lactones compounds butenolides 430-433 were evaluated by using shrimp bioassay, and bioactivity was shown. Additionally, they showed activity against Grampositive bacteria only [122].

Miscellaneous
Anticonvulsant activity of ceramide 469, measured in vivo by the pentylenetetrazole (PTZ)induced seizure assay, has successfully opposed the lethality of pentylenetetrazole in mice. It showed also a significant anxiolytic activity when used in the light-dark transition box. This could be caused possibly by GABA and serotonin receptors modulation [135]. Table 1 summarizes the main biological activities of secondary metabolites from genus Sacrophyton.

Conclusions
Based on reviewing the available current literature, a huge library of metabolites was isolated, and it possessed unique structures. Up to 481 compounds with different structures belonging to different chemical classes were reported from the Sarcophyton species. The chemical structures were classified as terpenoids (majority), biscembranes, polyhydroxylated sterols, sesquiterpenes (minority), and miscellaneous compounds. S. trocheliophorum gave the highest number of compounds. Members of genus Sarcophyton possessed valuable and interesting biological activities, such as antibacterial, cytotoxicity, antifungal, and antidiabetic.