J. Adv. Biomed. & Pharm. Sci. 4 (2021) 124-133 Journal of Advanced Biomedical and Pharmaceutical Sciences Journal Homepage: http://jabps.journals.ekb.eg Chemical and Biological Diversity in Nephthea Soft Corals in the Current Decade: A Review Khaled M. Allam 1,*, Amgad I. M. Khedr 2,3, Ahmed E. Allam 4, Mohamed Salaheldin A. Abdelkader 5, Ehab S. Elkhayat 4, Mostafa A. Fouad 6 1 Department of Pharmacognosy, Faculty of Pharmacy, South Valley University, P.O. Box 83523, Qena, Egypt. Department of Pharmacognosy, Faculty of Pharmacy, Port Said University, Port Said P.O. Box 42526 Egypt. 3 Department of Pharmacognosy, Faculty of Pharmacy, Horus University-Egypt, New Damietta, P.O. Box 34518 Egypt. 4 Department of Pharmacognosy, Faculty of Pharmacy, Al-Azhar University, Assiut P.O. Box 71524, Egypt. 5 Department of Pharmacognosy, Faculty of Pharmacy, Sohag University, Nasr City, Eastern Avenue, P.O. Box 11432, Sohag, Egypt. 6 Department of Pharmacognosy, Faculty of Pharmacy, Minia University, P.O. Box 61519 Minia, Egypt. 2 Received: February 15, 2021; revised: Mars 15, 2021; accepted: Mars 30, 2021 Abstract Marine natural products play an important role within the innovation of promising compounds for drug development. The soft coral genus Nephthea considered a prolific source to discover potential drug candidates with biological potentials. This review provides a survey of all metabolites isolated from the genus Nephthea in the current decade, along with chemical structures and biological activities. The current review aimed to compare chemical and biological diversity in genus Nephthea soft corals. We listed 54 compounds including steroids and diterpenes. The steroids are the most abundant compounds of the genus Nephthea (74 %) followed by diterpenes (20%) and miscellaneous compounds (6%). The isolated compounds from genus Nephthea in the current decade have shown different biological activities as cytotoxic against different cancer cell lines (29 compounds), antiinflammatory (13 compounds), antifouling (3 compounds) and antibacterial (2 compounds). Key words Soft corals, Nephthea, Diterpenes, Steroids, Cytotoxicity. * Correspondence: Allam, Khaled M Tel.: 01004375740; Email Address: dr_khaled1986@yahoo.com J. Adv. Biomed. & Pharm. Sci. Allam et al. 1. Introduction The marine soft corals are bottom-living simple animals, which exist in colonies and thrive in water with less intense light [1]. Depending on the defensive mechanisms of accumulated secondary metabolites in their bodies or secreted to the surrounding, they can survive even in hostile environments [2-4]. These invertebrates are widely distributed worldwide and found on variety of habitat, more in tropical than temperate reef, and resemble an important part of coral reefs ecosystem [5-8]. Soft corals represent a huge source of metabolites and those belong to genus Nephthea (Kingdom: Animalia, Phylum: Cnidaria, Class: Anthozoa, Subclass: Octocorallia, Order: Alcyonacea, Family: Nephtheidae) are evidently observed as an interesting treasure of ubiquitous constituents [9]. Members of genus Nephthea are arborescent colonies with branched polyparium, stiff, Polyps arranged on the terminal branches only, with supporting bundle. Sclerites are spindles and unilateral spinose spindles; surface layer of base of stalk also with capstans and derivations of capstans, colour of the colonies include whitish, brownish red, pink, yellow and purple, Zooxanthellae are present [10]. The genus Nephthea includes twelve species namely; N. albida, N. armata, N. bayeri, N. brassica, N. chabrolii, N. columnaris, N. hainansis, N. erecta, N. mollis, N. Pacifica N. sinulata and N. specie. Steroids and diterpenes were the prevailing constituents [11-13]. During a previous genus survey, Amir et al., 2012 reported the isolation of 148 compounds [14]. Therefore, the current review updates and enriches the library of metabolites isolated from the genus Nephthea with all compounds isolated during the current decade, along with their biological potentials. We have reported 54 compounds including chemical structures and biological activities based on the data abstracted from the current literatures. 2. Classes of Secondary Metabolites 2.1. Steroids Steroids are widely distributed within most species of the genus. Due to the symbiotic relationship with intracellular algae, reporting wide array of steroids with unique substitution patterns and functionalities from species of the genus Nephthea [15]. The literature survey demonstrated the isolation of forty steroids within the current decade. Columnaristerols A-C (1-3) were isolated from the methylene chloride/methanol extract of N. columnaris which was collected from Taiwan. Columnaristerol A exhibited moderate in-vitro cytotoxicity against human lymphoma cell lines; MOLT-4 and SUP-T1with IC50 values of 18.4 and 25.3 μM, respectively [16]. Columnaristerol B and C exhibited weak anti-inflammatory activities in a human neutrophil model with IC 50 values higher than 10 μM [17]. Chemical analysis of the methylene chloride extract of N. mollis collected from Hurghada, Egypt, led to identification of ten 4α-methylated steroidal compounds; 23acetoxy-4α, 24-dimethyl-5α-cholest-24(28)-en-3β, 8β, 11β-triol (4), (22E,24R)-4α,23,24-trimethyl-5α -cholest-22-en-3β,8β,11β –triol (5), (22Z)-4α,24-dimethyl-5α -cholest-22-en-3β,8β,11β – triol (6), 4α,24-dimethyl-5α -cholest-24(28)-en-3β,8β,18-triol (7), (22E,24R)-4α,24-dimethyl-5α-cholest-22-en-3β,8β,18-triol (8), (22E)- 4α,24-dimethyl-5α -cholesta-22,24(28)-dien3β,8β,18-triol (9), (22E,24R)-4α,24-dimethyl-5α-cholest-22-en3β,8β,11β –triol (10), nebrosteroid A (11), nebrosteroid D (14) 125 and nebrosteroid M (22). Moreover, compound (4), (5) and (7) showed significant cytotoxicity against K-562 human chronic myelogenous leukemia cell line with IC50 of 5.4 ± 1.1 μM, 7.8 ± 0.7 μM and 8.6 ± 0.7 μM, respectively. In addition, these compounds displayed moderate toxicity against the human lung cancer cell line A-549 with IC50 values higher than 10 μM [18]. From the acetone fraction of N. chabrolii collected from Taiwan, Huang et al., isolated nebrosteroids A-E (11-15) and nebrosteroids G-H (16-17), all of which showed antiinflammatory activity. Compounds (11-13) at a concentration of 10 μM, reduced iNOS levels by 10.7 ± 0.5, 9.5 ± 1.0, 0 ± 0 and 32.9 ± 6.7 respectively. Compounds (14), (15) and (17) reduced iNOS levels to 0, 43.2 ± 7.8 and 76.8 ± 9.5 respectively and reduce COX-2 to 63.8 ± 10.8, 57.3 ± 5.2 and 72.1 ± 10.6, respectively [3]. Cheng et al, isolated four sterols; nebrosteroid I-L (18-21) from the acetone fraction of the N. chabrolii that collected from Taiwan. Moreover, compounds (18-21) displayed remarkable anti-inflammatory activity against RAW 264.7 macrophages [12]. The nebrosteroids N–S (23-28) were isolated from the acetone extract of N. chabrolii, also collected from Taiwan, the isolated compounds showed potent cytotoxic activities against mouse lymphocytic leukemia P-388 cell line with ED50 of 1.0, 1.1 and 1.2 μg/mL, respectively. Unfortunately, they were ineffective against human cytomegalovirus (HCMV) using human embryonic lung (HEL) cell line [19, 20]. Moreover, from the ethyl acetate fraction of the soft coral N. erecta that collected also from Taiwan; nephtheasteroid A (29) and nephtheasteroid B (30) were isolated. These compounds exhibited weak in-vitro cytotoxic activities against human chronic myelogenous leukemia (K562), human acute lymphocytic leukemia (Molt-4), human T lymphoblastoid (Sup-T1) and human leukemic monocyte lymphoma (U937), with IC50 values more than 20 μM, using the MTT assay [21]. Furthermore, 4α, 24-dimethyl-5α, cholest-8β, 18-dihydroxy, 22E-en-3β-ol (31) was isolated from the methylene chloride extract of Nephthea species, collected from Hurghada, Egypt, and it showed weak cytotoxicity against MCF-7, the breast cancer cell line [22]. Nephthoacetal (32) with its two derivatives; (18S)-18-O-acetylnephthoacetal (33) and (18R)-18-O-acetylnephthoacetal (34) were isolated from the alcoholic extract of Nephthea sp., collected from China. Compound (32) showed significant anti-fouling activity against the larvae of Bugula neritina L. with EC50 value of 2.5 μg/mL, while compounds (33) and (34) showed no anti-fouling potentials. On the opposite hand, compound (33) showed invitro cytotoxicity against the human cervical neoplastic cell line (HeLa), followed by compounds (32) and (34), with IC50 values of 10.2, 12.4 and 19.5 μg/mL, respectively [23]. Zhang et al, have isolated (12β, 22R)-12-acetoxy-22-hydroxy-cholesta-1,4dien-3-one (35) and its derivatives; (12β, 22R)-12, 22diacetoxy-cholesta-1, 4-dien-3-one (36), (22R)-18, 22diacetoxy-cholesta-1, 4-dien-3-one (37), (12β, 22R)-12hydroxy-22-acetoxy-cholesta-1, 4-dien-3-one (38) and (20R, 22R)-20-hydroxy-22-acetoxy-cholesta-1, 4-dien-3-one (39) from the alcoholic extract of Nephthea sp., collected from China. The isolated compounds showed cytotoxicity against HeLa cells with IC50 values 7.52 ± 0.21 to 18.73 ± 0.77 μg/mL [24]. Tabot et al., isolated compound; pregna-1, 4, 20-trien-3one (40) from the DCM fraction of Nephthea sp. It showed inhibitory activity against human colon adenocarcinoma SW480 cells (IC50 = 2.4 μg/ml) [25]. Here, we compile the steroids isolated from the genus Nephthea in the current decade as shown in table {1} and figures {1- 3}. J. Adv. Biomed. & Pharm. Sci. 126 Allam et al. Figure 1. Chemical structures of compounds (1-13) J. Adv. Biomed. & Pharm. Sci. Allam et al. 18 Δ5-6, 24-28 19 Δ5-6, 22-23 20 Δ5-6 127 Figure 2. Chemical structures of compounds (14-29) J. Adv. Biomed. & Pharm. Sci. 128 Allam et al. Figure 3. Chemical structures of compounds (30-40) J. Adv. Biomed. & Pharm. Sci. Allam et al. 129 2.2. Diterpenes The diterpenes are biologically active marine substances occurring mainly in sponges, algae, coelenterates, and mollusks. Marine diterpenes demonstrated clear structural distinctions from terraneous diterpenes. They are characterized by higher mass and uncommon functional groups[15]. Eleven bioactive diterpenes were isolated from soft corals of the genus Nephthea in the current decade figure {4}. Three cembrane diterpenes; namely 6-acetoxy-7, 8-epoxy-10-hydroxy-nephthenol acetate (41), 7, 8-epoxy-10-hydroxy-nephthenol acetate (42) and 10hydroxy-nephthenol acetate (43) were isolated from the alcoholic extract of N. species, collected from Malaysia. Compound (41) showed remarkable antibacterial activity against S. aureus and E. coli with a MBC/MIC ratio of 2.6 and 3.2, respectively, revealing a bactericidal antibiosis. Similarly, compound (47) showed bacteriostatic antibiosis with a ratio of 6.2 against both bacteria. Additionally, compounds (41) and (47) showed cytotoxic activities against Hela and MCF-7 cell lines, with IC50 values of (41.2 and 24.3) and (127.2 and 76.1) μg/mL, respectively [26]. Moreover, columnariol A (44) and B (45); 15-hydroxycembranoid diterpenes were obtained from N. columnaris collected from Taiwan. Both of the compounds have weak cytotoxic activities against MOLT 4, SUP-T1, U 937, DLD-1, LNC and MCF-7, with IC50 > 20 μg/mL [27]. Hsiao et al., isolated three cembrane diterpenes; epoxynephthenol (46), 2β-hydroxy-7β, 8α epoxynephthenol (47) and 2β-hydroxy-11α, 12β- epoxynephthenol (48) from the ethyl acetate extract of N. columnaris, collected from Taiwan. None of the compounds (46-48) showed cytotoxicity against MOLT-4, SUP-T1, U 937, DLD-1, LNCaP and MCF-7 with IC50 values exceeding 20 μg/mL[27]. Ishii et al., reported the isolation of 6-acetoxy-7,8-epoxynephthenol acetate (49) from the n-hexane fraction of the N. species [28]. A new norditerpene; chabrolene (50) was isolated from Nephthea sp., collected from Malaysia. It showed high repellent activity against the maize weevil Sitophilus zeamais [29]. Chabrolin A (51) was isolated from the methylene chloride fraction of N. chabrolii, collected from Taiwan and displayed cytotoxicity against P-388 with ED50 value of 4.21 μg/mL [30]. In the current decade, diterpenes isolated from various genus Nephthea members, are summarized in table {1} and figure {4}. Figure 4. Chemical structures of compounds (41-51) J. Adv. Biomed. & Pharm. Sci. Allam et al. 130 2.3. Miscellaneous compounds: Two sesquiterpenes; Kelsoenethiol (52) and dikelsoenyl ether (53) were isolated from the methylene chloride/methanol extract of N. erecta, collected from Taiwan. Kelsoenethiol displayed cytotoxicity against P-388 and HT-29 cell lines with ED50 values of 1.4 and 1.7 μg/mL, respectively [31]. A linear tetrapeptide; Leucyl-N-methyl-leucyl-leucylN-methyl-leucine (54), was obtained from N. species, collected from China. It showed weak cytotoxicity against human cancer cell line A549 and human liver carcinoma Hepg2 [19]. The miscellaneous compounds isolated from various members of the genus Nephthea in the current decade listed in table {1} and figure {5}. Figure 5: Chemical structures of compounds (52-54) Table 1: A list of different compounds isolated from the genus Nephthea in the current decade with its biological activities. No Steroids 1 2 3 4 Isolated compound Biological activities Species Ref. Cytotoxic activity Anti-inflammatory activity Anti-inflammatory activity Cytotoxic activity N. columnaris N. columnaris N. columnaris N. mollis [32] [32] [32] [18] Cytotoxic activity N. mollis [18] Cytotoxic activity N. mollis N. mollis N. mollis [18] [18] [18] N. mollis [18] N. mollis [18] 11 Columnaristerol A Columnaristerol B Columnaristerol C 23-Acetoxy-4α, 24-dimethyl-5α-cholest-24(28)-en-3β, 8β, 11β-triol (22E,24R)-4α,23,24-trimethyl-5α -cholest-22-en3β,8β,11β -triol (22Z)-4α,24-dimethyl-5α -cholest-22-en-3β,8β,11β –triol 4α,24-Dimethyl-5α -cholest-24(28)-en-3β,8β,18-triol (22E,24R)-4α,24-dimethyl-5α-cholest-22-en-3β,8β,18triol (22E)- 4α,24-dimethyl-5α -cholesta-22,24(28)-dien3β,8β,18-triol (22E,24R)-4α,24-dimethyl-5α-cholest-22-en-3β,8β,11β triol Nebrosteroid A [3, 18] 12 13 14 Nebrosteroid B Nebrosteroid C Nebrosteroid D Anti-inflammatory activity Anti-inflammatory activity Anti-inflammatory activity 15 16 17 18 19 20 21 22 23 Nebrosteroid E Nebrosteroid G Nebrosteroid H Nebrosteroid I Nebrosteroid J Nebrosteroid K Nebrosteroid L Nebrosteroid M Nebrosteroid N Anti-inflammatory activity Anti-inflammatory activity Anti-inflammatory activity Anti-inflammatory activity Anti-inflammatory activity Anti-inflammatory activity Anti-inflammatory activity N. chabrolii N. mollis N. chabrolii N. chabrolii N. chabrolii N. mollis N. chabrolii N. chabrolii N. chabrolii N. chabrolii N. chabrolii N. chabrolii N. chabrolii N. mollis N. chabrolii 5 6 7 8 9 10 Anti-inflammatory activity Cytotoxic activity [3] [3] [3, 18] [3] [3] [3] [12] [12] [12] [12] [18] [19] J. Adv. Biomed. & Pharm. Sci. Allam et al. No Isolated compound Biological activities 131 Species Ref. 24 25 26 27 28 29 30 31 Nebrosteroid O Nebrosteroid P Nebrosteroid Q Nebrosteroid R Nebrosteroid S Nephtheasteroid A Nephtheasteroid B 4α, 24-dimethyl-5α- cholest-8β, 18-dihydroxy, 22E-en-3β-ol Cytotoxic activity Cytotoxic activity Cytotoxic activity Cytotoxic activity Cytotoxic activity Cytotoxic activity Cytotoxic activity Cytotoxic activity N. chabrolii N. chabrolii N. chabrolii N. chabrolii N. chabrolii N. erecta N. erecta N. species [19] [19] [20] [20] [20] [21] [21] [22] 32 Nephthoacetal Antifouling activity and cytotoxic activity N. species [23] 33 (18S)-18-O-acetylnephthoacetal N. species [23] 34 (18R)-18-O-acetylnephthoacetal N. species [23] 35 36 37 38 (12β, 22R)-12-acetoxy-22-hydroxy-cholesta-1,4-dien-3-one (12β, 22R)-12, 22-diacetoxy-cholesta-1, 4-dien-3-one (22R)-18, 22-diacetoxy-cholesta-1, 4-dien-3-one (12β, 22R)-12-hydroxy-22-acetoxy-cholesta-1, 4dien-3-one (20R, 22R)-20-hydroxy-22-acetoxy-cholesta-1, 4dien-3-one Pregna-1,4,20-trien-3-one Antifouling activity and cytotoxic activity Antifouling activity and cytotoxic activity Cytotoxic activity Cytotoxic activity Cytotoxic activity Cytotoxic activity N. species N. species N. species N. species [23] [23] [23] [23] Cytotoxic activity N. species [23] Cytotoxic activity N. species [25] Antibacterial activity and cytotoxic activity Cytotoxic activity N. species [26] N. species [26] Cytotoxic activity Cytotoxic activity Cytotoxic activity Cytotoxic activity Antibacterial activity and cytotoxic activity Cytotoxic activity N. species N. columnaris N. columnaris N. columnaris N. columnaris [26] [27] [27] [27] [27] Repellent activity Cytotoxic activity N. columnaris N. species N. species N. chabrolii [27] [28] [29] [30] Cytotoxic activity N. erecta [31] Cytotoxic activity Cytotoxic activity N. erecta N. species [31] [19] 39 40 Diterpenes 41 6-Acetoxy-7, 8-epoxy-10-hydroxy-nephthenol acetate 42 43 44 45 46 47 7, 8-Epoxy-10-hydroxy-nephthenol Acetate 10-Hydroxy-nephthenol acetate Columnariol A Columnariol B Epoxynephthenol 2β-hydroxy-7β, 8α epoxynephthenol 48 49 50 51 2β-hydroxy-11α, 12β-epoxynephthenol 6-Acetoxy-7,8-epoxynephthenol acetate Chabrolene A Chabrolin Miscellaneous compounds: 52 Kelsoenethiol 53 54 Dikelsoenyl ether Leucyl-N-methyl-leucyl-leucyl-N-methyl-leucine J. Adv. Biomed. & Pharm. Sci. Allam et al. 132 3. Conclusion and future perspectives: Soft corals of the genus Nephthea, proven to be rich source for promising and biologically active compounds for the innovation of medicinal entities against different ailments. In this review, we reported 54 compounds in the current decade, along with their biological potentials based on the data collected from literatures, steroids were most abundant in the genus Nephthea with the percentage of (74 %) followed by diterpenes (20%) and miscellaneous compounds (6%) figure {6}. The isolated compounds showed diverse biological activities as; cytotoxic against different cancer cell lines (29 compounds), antiinflammatory (13 compounds), antifouling (3 compounds) and antibacterial (2 compounds) as shown in figure {7}. It was clear that the species N. chabrolii, N. columnaris, N. erecta, N. mollis and N. specie were the most studied during the current decade, figure {8}. Unfortunately, other species like N. albida, N. armata, N. bayeri, N. brassica, N. hainansis, N. pacifica and N. sinulata received less attention. Accordingly, more efforts should be done in studying these species to discover more of promising compounds which may afford lead chemotherapeutic compounds that may help in treatment of different diseases. Figure 8: Number of metabolites isolated from different species of the genus Nephthea in the current decade Figure 6. Percentage of different classes of metabolites distributed in the genus Nephthea in the current decade Acknowledgment I would like to express my sincere gratitude to pharmacognosy department, Faculty of pharmacy, South Valley University, Qena, for all facilities, support and encouragement offered to us during this work. Conflict of Interests There is no conflict of interests regarding the publication of this paper. 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