Alcyonium Octocorals: Potential Source of Diverse Bioactive Terpenoids

Alcyonium corals are benthic animals, which live in different climatic areas, including temperate, Antarctic and sub-Antarctic waters. They were found to produce different chemical substances with molecular diversity and unique architectures. These metabolites embrace several terpenoidal classes with different functionalities. This wide array of structures supports the productivity of genus Alcyonium. Yet, majority of the reported compounds are still biologically unscreened and require substantial efforts to explore their importance. This review is an entryway to push forward the bio-investigation of this genus. It covers the era from the beginning of reporting metabolites from Alcyonium up to March 2019. Ninety-two metabolites are presented; forty-two sesquiterpenes, twenty-five diterpenes and twenty-five steroids have been reported from sixteen species.


Introduction
The marine environment is represented by two-thirds of the earth and epitomizes harsh parameters. It has a wide range of temperature; ranged from −1.5 • C to 350 • C, pressure ranged from 1 to over 1000 atmosphere, light ranged from complete darkness to extensive photic zones and nutritional-rich till nutrient-spar [1][2][3].
Thirty-four animal phyla were taxonomically identified, however, thirty-six were found in a marine habitat. The marine species counts around 240,000 known species, albeit less than five percent of the deep sea has been explored [4,5]. Production of the unique metabolites from marine organisms could be explained by the harsh and competitive conditions. Although the terrestrial sources are providing unique bioactive metabolites, the marine organisms produce a considerable number of unprecedented bioactive substances, which have a great possibility to be a lead drug [6]. Blunt and his co-workers reported that the identified marine metabolites estimated to be 31,000 (i.e., 1000 substances per year) [7]. The molecular structures associated, particularly, produced from marine organisms, are varying from low molecular weight to complex form [8][9][10][11][12][13][14]. These metabolites enhance marine

Sesquiterpenes
The chemical diversity of the aforementioned sesquiterpenoidal classes emphases the importance of genus Alcyonium as a potential source of novel metabolites. A bicyclic sesquiterpenoidal, guaiazulene (1), a pigment obtained from Alcyonium sp., which was collected from the North East Bay, Great Palm Island of Australia. It was used as a taxonomical marker for the gorgonian soft coral [22]. Chemical investigation of the Mediterranean A. coralloides, collected from the French East Pyrenean, yielded two novel sesquiterpenes (+)-coralloidin-A (2), and (−)-coralloidin-B (3) (Figure 4 and Table 1) [23]. Novel eudesmane sesquiterpenes, coralloidin C, D and E (4-6) have been identified from the same species. The absolute stereochemistry of 4 was estimated by application of the exciton-coupling method and confirmed by interpretation of the negative and positive cotton effects after measuring the Circular Dichroism spectra [24].
A south African nudibranch, Leminda millecra, was investigated chemically and led to the isolation of four novel aromadendrane and aphnamalane, namely, millecrone A and B (7 and 8), and

Sesquiterpenes
The chemical diversity of the aforementioned sesquiterpenoidal classes emphases the importance of genus Alcyonium as a potential source of novel metabolites. A bicyclic sesquiterpenoidal, guaiazulene (1), a pigment obtained from Alcyonium sp., which was collected from the North East Bay, Great Palm Island of Australia. It was used as a taxonomical marker for the gorgonian soft coral [22]. Chemical investigation of the Mediterranean A. coralloides, collected from the French East Pyrenean, yielded two novel sesquiterpenes (+)-coralloidin-A (2), and (−)-coralloidin-B (3) (Figure 4 and Table 1) [23]. Novel eudesmane sesquiterpenes, coralloidin C, D and E (4-6) have been identified from the same species. The absolute stereochemistry of 4 was estimated by application of the exciton-coupling method and confirmed by interpretation of the negative and positive cotton effects after measuring the Circular Dichroism spectra [24].
NCI's CEM-SS cell line assay was designed to evaluate the metabolites which have effect at any stage of HIV virus reproductive cycle and fortunately, rietone (12) showed moderate effect. It was remarkable that A. fauri collected during this study was found growing on living Hadromerida sponges (Tethya species) and certain study has been done indicated that there is no chemical affinities or similarity between A. fauri and sponge or other soft coral, regarding the production of metabolites [28].   [29]. These metabolites were the first illudalane sesquiterpenoidal derivatives, which were reported from marine organisms. The stereochemistry of the alcyopterosins A south African nudibranch, Leminda millecra, was investigated chemically and led to the isolation of four novel aromadendrane and aphnamalane, namely, millecrone A and B (7 and 8), and millecrol A and B (9 and 10). It was surprising that the same metabolites were obtained from the organic extract of spicules in the dissected digestive glands of the soft corals A. foliatum and A. valdiviae [25,26]. Although millecrone B (8) was inactive against the growth of Candida albicans mellicrone A showed inhibition at 50 g/disk; while millecrol A and B (9 and 10) showed antimicrobial activity against Staphylococcus aureus and Bacillus subtilis [25,26].
As known, furanosesquiterpenoid (11) has been identified from the bay of Naples octocoral A. palmatum. This compound and its congeners (e.g., 2,4-disubstituted furanosesquiterpene) play a role in the taxonomy of the Alcyonacea order [27].
A. fauri is an endemic southern Africa soft coral, has been investigated and yielded three sesquiterpene hydroquinones, rietone (12), 8 -acetoxyrietone (13) and 8 -desoxyrietone (14) [28]. The NCI's CEM-SS cell line assay was designed to evaluate the metabolites which have effect at any stage of HIV virus reproductive cycle and fortunately, rietone (12) showed moderate effect. It was remarkable that A. fauri collected during this study was found growing on living Hadromerida sponges (Tethya species) and certain study has been done indicated that there is no chemical affinities or similarity between A. fauri and sponge or other soft coral, regarding the production of metabolites [28].  [29]. These metabolites were the first illudalane sesquiterpenoidal derivatives, which were reported from marine organisms. The stereochemistry of the alcyopterosins showed a different configuration of the hydroxylated position (C-10). Compound 22 was levorotatory while 23 and 27 were dextrorotatory. The absolute stereochemistry was established by the implementation of the modified Mosher method led to the establishment of the chemical structures of 23, 26, and 27 had 10S configuration, while 22 was 10R. Compound 19 showed mild cytotoxicity against Hep-2 (human larynx carcinoma) cell line (IC 50 13.5 µM), while compounds 15, 17, and 22 were cytotoxic against HT-29 (human colon carcinoma) at 10 µg/mL. Further investigation of the same USA group and marine organisms led to the identification of two novel tricyclic sesquiterpenoids, paesslerins A and B (30-31) [30]. of 23, 26, and 27 had 10S configuration, while 22 was 10R. Compound 19 showed mild cytotoxicity against Hep-2 (human larynx carcinoma) cell line (IC50 13.5 μM), while compounds 15, 17, and 22 were cytotoxic against HT-29 (human colon carcinoma) at 10 μg/mL. Further investigation of the same USA group and marine organisms led to the identification of two novel tricyclic sesquiterpenoids, paesslerins A and B (30-31) [30].
Examination of A. utinomii, was collected from the Gulf of Suze, led to the isolation of three cembranoidal derivatives with the same molecular weight, alcyonol-A (46), alcyonol-B (47), and alcyonol-C (48). The difference between the chemical structure of compounds 46 and 47 is mainly in the location of the hydroxyl group [34].
Alcyonolide (55) is an unusual diterpenoidal acetate, was isolated from an Okinawan soft coral Alcyonium sp. [38]. Alcyonolide-5 (56) is a triacetate derivative, obtained from Alcyonium sp. collected from Lamont Reef in the Capricorn Bunker group [39]. These metabolites were believed to be derived from a xenicin-type precursor.
Examination of A. utinomii, was collected from the Gulf of Suze, led to the isolation of three cembranoidal derivatives with the same molecular weight, alcyonol-A (46), alcyonol-B (47), and alcyonol-C (48). The difference between the chemical structure of compounds 46 and 47 is mainly in the location of the hydroxyl group [34].  (Figure 8). The two structures are peculiar with a rare (7Z)-configuration. This feature is rare in cembranoids [35]. A study from the same group reported three novel metabolites; 3,7-cyclized cembranoid (Coralloidolide C, 51), O-bridged diketonic cembranolide (Coralloidolide D, 52) and diketonic epoxycembranolide (coralloidolide E, 53) [36]. Further investigation of the same species and same group led to reporting of the first example of 2, 6-cyclized cembranolide (Coralloidolide F, 54) [37].  (63). Carbon skeleton of valdivones is eunicellin-type which closely related to sarcodictyins. The difference between them is the location of the ether ring however they produced by different soft corals (i.e., A. valdivae (order Alcyonacea) and Sarcodictyon roseum (order Stolonifera)). Valdivones A (59) and B (60) show strong inhibition of chemicallyinduced inflammation in the mouse ear assay, however, no inhibition on the bee venom phospholipase A. Finally, the valdivones showed no effect against a standard panel of bacteria and fungi [42].
A diterpene of the prenylbicyclogermacrane skeleton wasn't widely occurred among marine organisms. Fortunately, A. palmatum was collected from Mazara de1 Vallo (West Sicily), led to the isolation of palmatol (64). Palmatol showed toxicity against Gumbosia offinis as well as cytotoxic against brine shrimp (Artemia salina) [43].
Xenicane-type diterpenoid was reported from Alcyonium, for instance, zahavin A (65), and zahavin B (66), were isolated from a specimen of A. aureum, which collected at depth more than 28 m at Sodwane Bay, South Africa. The two compounds showed a cytotoxic effect against P-388 mouse leukemia, A-549 human lung carcinoma, MEL-28 human melanoma, and HT-29 human colon carcinoma [44].
Pukalide (67) has been reported from soft coral A. antarticum, which was collected during the XVII Italian campaign in Antartica off Terra Nova Bay [32]. It is a known diterpene, which was previously reported from Sinularia abrupta. Pukalide showed feeding-deterrence against Carassius auratus at a concentration of 50 μg/mL [32,45].   Molecules 2019, 24,1370 Alcyonolide (55) is an unusual diterpenoidal acetate, was isolated from an Okinawan soft coral Alcyonium sp. [38]. Alcyonolide-5 (56) is a triacetate derivative, obtained from Alcyonium sp. collected from Lamont Reef in the Capricorn Bunker group [39]. These metabolites were believed to be derived from a xenicin-type precursor.
Patagonicol (58) (Figure 9), a new diterpene of eunicellin skeleton has been reported from the Soft coral A. patagonicum collected from the Xisha islands off the south China Sea. Its structure was confirmed by X-ray diffraction [41].

Steroids
Gorgosterol (68) has been reported from A. molle, collected at Pioneer Bay, Orpheus Island. Its structure was elucidated based on I H-NMR spectral data and other physical properties [40].
A diterpene of the prenylbicyclogermacrane skeleton wasn't widely occurred among marine organisms. Fortunately, A. palmatum was collected from Mazara de1 Vallo (West Sicily), led to the isolation of palmatol (64). Palmatol showed toxicity against Gumbosia offinis as well as cytotoxic against brine shrimp (Artemia salina) [43].
Xenicane-type diterpenoid was reported from Alcyonium, for instance, zahavin A (65), and zahavin B (66), were isolated from a specimen of A. aureum, which collected at depth more than 28 m at Sodwane Bay, South Africa. The two compounds showed a cytotoxic effect against P-388 mouse leukemia, A-549 human lung carcinoma, MEL-28 human melanoma, and HT-29 human colon carcinoma [44].
Pukalide (67) has been reported from soft coral A. antarticum, which was collected during the XVII Italian campaign in Antartica off Terra Nova Bay [32]. It is a known diterpene, which was previously reported from Sinularia abrupta. Pukalide showed feeding-deterrence against Carassius auratus at a concentration of 50 µg/mL [32,45].

Steroids
Gorgosterol (68) has been reported from A. molle, collected at Pioneer Bay, Orpheus Island. Its structure was elucidated based on I H-NMR spectral data and other physical properties [40].
A soft coral, Alcyonium sp., which was collected from the coast of southern Taiwan and found to produce 3α,7α,12α-triacetoxy-5β-cholanic acid (73). Its structure was assigned on the basis of spectroscopical data and its configuration was further supported by molecular mechanics calculations [47].
Alcyonium is considered as a potential source for nitrogenous and non-nitrogenous terpenoidal derivatives. By the way, A. paessleri produces rare nitrogen containing illudalane sesquiterpene (alcyopterosins B, C, E, F, G, H, J and M) [29]. Thus, this review focused on elaborating the future plan for the natural products researchers to investigate the disremembered genus Alcyonium.

Conclusions
Alcyonium could be considered as a potential source of bioactive terpenoidal metabolites. The engagement of different approaches played a significant role in the facilitation of the forthcoming drug discovery process. Remarkable, many marine metabolites displaying fascinating molecular structures with diverse pharmacological effects have been reported from genus Alcyonium during the last four decades (1981-2019). Of the 92 distinctive structures accounted for in this review, 67 (72.8%) are terpenoidal metabolites. Figure 12 illustrates terpenoidal metabolites produced by 16 species. The majority (41.8%) of the presented compounds were produced by three species; A. paessleri (17 compounds, 18.5%), A. coralloides (12 compounds, 12.0%) and A. gracillimum (11 compounds, 12.0%), respectively.

Conflicts of Interest:
The authors declare no conflict of interest.   Funding: This research received no external funding.

Conflicts of Interest:
The authors declare no conflict of interest.