Marine Sponges of the Genus Callyspongia: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Lucas Hilário Sousa.

In this entreviewy, information about the common metabolites of the Callyspongia genus were grouped, as well as studies of the biological activity of these compounds. Through NMR data, 212 metabolites were identified from genus Callyspongia (15 species and Callyspongia sp.), belonging to classes such as polyacetylenes, terpenoids, steroids, alkaloids, polyketides, simple phenols, phenylpropanoids, nucleosides, cyclic peptides, and cyclic depsipep-tides. A total of 109 molecules have been reported with bioactive activity, mainly cytotoxic and antimicrobial (antibacterial and antifungal) action. 

  • Callyspongia
  • demosponges
  • polyacetylenes
  • anticancer action

1. Introduction

The genus Callyspongia (Callyspongiidae) encompasses a group of demosponges including 261 described species, of which approximately 180 have been accepted after taxonomic reviews. The marine organisms of Callyspongia are distributed in tropical ecosystems, especially in the central and western Pacific, but also in the regions of the Indian, the West Atlantic, and the East Pacific Oceans. The reason for the interest in the genus Callyspongia is related to its potential production of bioactive compounds. In this review, we group the chemical information about the metabolites isolated from the genus Callyspongia, as well as studies of the biological activity of these compounds. Through NMR data, 212 metabolites were identified from genus Callyspongia (15 species and Callyspongia sp.), belonging to classes such as polyacetylenes, terpenoids, steroids, alkaloids, polyketides, simple phenols, phenylpropanoids, nucleosides, cyclic peptides, and cyclic depsipeptides. A total of 109 molecules have been reported with bioactive activity, mainly cytotoxic and antimicrobial (antibacterial and antifungal) action.

2. Chemical Aspects of Callyspongia species

NMR spectroscopy-based studies on Callyspongia unidentified species (Callyspongia sp.) along with other 15 identified species (C. abnormis, C. aerizusa, C. bilamellata, C. californica, C. diffusa, C. fibrosa, C. fistularis, C. flammea, C. implexa, C. lindgreni, C. pseudoreticulata, C. siphonella, C. spinosissima, C. truncata and C. vaginalis) resulted in the structural characterization of 212 isolated metabolites from different classes: polyacetylenes; terpenoids and steroids; alkaloids; simple phenols and phenylpropanoids; nucleosides; cyclic peptides and cyclic depsipeptides; polyketides; and miscellaneous.
These substances were described according to the extract used in the isolation, relevant structural characteristics, and the elucidation data based on NMR data. This information is presented in together with additional information such as chemical formula, type of metabolite, one-dimensional NMR data, geographic location, and references related to the compound obtention in Callyspongia species. Regarding the 1D NMR data, the chemical shifts, the solvent and frequency used in process, and the coupling constant of all compounds, were investigated. In addition, although NMR was the only spectroscopic information reported in this study, mainly due to the large volume of data, other techniques were used in the primary studies to support structural identification and elucidation, such as: specific rotation, X-ray crystallography, Thin-Layer Chromatography (TLC), melting point, two-dimensional NMR spectroscopy, Mass Spectrometry (EM), and spectroscopy in the infrared (IR) and ultraviolet (UV) regions.

2.1. Polyacetylenes

The polyacetylenes aikupikanynes A (1), B (2) and C (3), D (4), E (5) and F (6) and octahydrosiphonochalyne (7) were isolated from methanol (MeOH) extract of Callyspongia sp., a red sea sponge [27][1]. Other metabolites were also isolated: callimplexen A (8) from Callyspongia implexa (MeOH/Dichloromethane (CH2Cl2) 1:1 extract) [28][2]; callyberynes A (9), B (10) and C (11) from Callyspongia sp. (MeOH/CH2Cl2 3:1 extract) [21][3]; 9 and 11 from Callyspongia truncata (MeOH extract) [29][4]; and the diacetylene Callydiyne (12) from Callyspongia flammea (MeOH extract) [30][5]. Polyacetylenes 1–12 (Figure 1) were elucidated by 1H and 13C NMR and have unsaturated hydrocarbon moieties associated with olefinic and alkynyl double and triple bonds, respectively. The only symmetrical compound is 12 and structures 4, 5 and 6 have characteristics of fatty acyls.
Marinedrugs 19 00663 g001a 550Marinedrugs 19 00663 g001b 550Marinedrugs 19 00663 g001c 550
Figure 1. Structures of polyacetylenes isolated from Callyspongia species.
Six polyacetylene diols were obtained from studies based on Callyspongia genus. 14,15-dihydrosiphonodiol (13), Callyspongidiol (14) and siphonodiol (15) were isolated from Ethyl acetate (EtOAc) extract of Callyspongia sp. [31][6]; 13 and 15 from ethanol (EtOH) extract of Callyspongia lindgreni [32][7]; from these later, only 15 from Callyspongia lindgreni (CH2Cl2 extract) [33][8] and Callyspongia truncata (MeOH extract) [29][4]. Two isomeric structures were isolated from Callyspongia sp. (EtOH extract): (3S,18S,4E,16E)-eicosa-1,19-diyne-3,18-diol-4,16-diene (16a) and (−)-(4E,16E)-icosa-4,16-diene-1,19-diyne-3,18-diol (16b). Compound 16a has also been identified in Callyspongia pseudoreticulata (MeOH extract) [34,35][9][10]. In addition, callyspongendiol (17) was isolated from Callyspongia siphonella (CH2Cl2/MeOH 1:1 extract) [8[11][12],36], and Tetrahydrosiphonodiol (18) from Callyspongia lindgreni (EtOH extract) [32][7]. Polyacetylene Diols 13–18 are open chain unsaturated hydrocarbons (Figure 1) that have their structures elucidated by 1H and 13C NMR. The regiochemistry patterns for the two hydroxyls in the structures vary considerably depending on the metabolite, having close proximity in 13, 14, 15 and 18. Isomers 16a and 16b are the only structures with symmetric atom connectivity; they differ from each other according to the configuration of stereogenic centers.
A total of 12 polyacetylene alcohols were obtained from Callyspongia species: (3R,4E,28Z)-hentriacont-4,28-diene-1,23,30-triyn-3-ol (19), Callyspongenols A (20), B (21), C (22) and D (23), Callysponynes A (24) and B (25), dehydroisophonochalynol (26), siphonellanols A (27), B (28) and C (29) and siphonchalynol (30) (Figure 1). Studies involving Callyspongia sp. afforded different metabolites depending on the solvent used in the extraction: acetone (19) [37][13], MeOH/CH2Cl2 1:1 (20–22 and 26) [38][14] and EtOAc (24 and 25) [39][15] extracts; while those related to Callyspongia siphonella were obtained from MeOH/CH2Cl2 1:1 (23 and 26) [8,36][11][12] and MeOH (26–30) [40][16] extracts. The polyacetylene alcohols were elucidated by 1H and 13C NMR, but only 19–29 present elucidative data.
Studies involving Callyspongia truncata resulted in obtaining the acetylenic sulfate fatty acid callysponginol sulfate A (31) from a mixture of H2O, MeOH, CHCl3, and EtOAc extracts [41][17]. The methanolic extract provided callyspongins A (32) and B (33) [29[4][18],42], as well as callytriols A (34), B (35), C (36), D (37), and E (38) [29][4]. The polyacetylene lipids callyspongynes A (39) and B (40) were also isolated from an ethanolic extract of Callyspongia sp. [43][19]. The metabolites 32–40 were elucidated by 1H and 13C NMR and have an oxygenated and unsaturated aliphatic structure with double and triple bonds (Figure 1). Compounds 32 and 33 are derived from siphonodiol and along with 31 are classified as sulfated compounds. Metabolites 34–38 have three hydroxyls, while 39 and 40 are simple monoalcohol.
Four metabolites were isolated from ethanolic extracts from different species: (6Z,9Z,12Z,15Z)-1,6,9,12,15-octadecapenten-3-one (41) (Callyspongia sp.) [17][20], (4Z,7Z,10Z,13Z)-4,7,10,13-hexadecatetraenoic acid (42) (Callyspongia sp.) [17][20], petroselenic acid (43) (Callyspongia siphonella) [7][21], and callyspongynic Acid (44) (Callyspongia truncata) [44][22]. In addition, glycerolipid 3-octadecyloxy-propane-1,2-diol (45) was obtained from 95% EtOH + MeOH/CH2Cl2 1:1 extracts [45][23], and batyl alcohol (46) from methanolic extract, both from Callyspongia fibrosa [23][24]; the polyacetylenic amide callyspongamide A (47) was isolated from Callyspongia fistularis (MeOH/CH2Cl2 1:1 extract) [46,47,48][25][26][27]. Among the elucidated compounds, only 41, 44, 45, and 47 have 1H and 13C NMR data reported. Compound 46 was characterized by 1H NMR only, while 41 and 44–47 present the spectroscopic data. The metabolites are structurally distinct, but some similarities are visible (Figure 1). Substance 41 has a conjugated ketone system, while 42–44 have carboxyl groups, among which 44 also has a hydroxyl unit. Glycerolipids 45 and 46 are the only saturated compounds having hydroxyls and ether oxygen, with the only structural difference between them being the presence of an additional methylene unit in 45. Double and triple bonds, an aromatic unit, and an amide form compound 47.

2.2. Terpenoids and Steroids

The diterpenes callyspinol (48) and isocopalanol (49) were isolated, respectively, from Callyspongia spinosissima (MeOH extract) [49][28] and Callyspongia sp. (acetone extract) [50][29]. Compounds 48 and 49 were elucidated by 1H and 13C NMR and are structurally different (Figure 2): 48 has only one ring and a double bond, and is monooxygenated, while 49 has a three-membered ring and is saturated and polyoxygenated. Four Callyspongia sp. triterpenes were also isolated: akaterpin (50) from an acetone extract [51][30] and ilhabelanol (51), ilhabrene (52), and isoakaterpin (53) from an extraction with EtOH followed by MeOH [11][31]. The molecules 50–53 (Figure 2) were characterized by 1H and 13C NMR and they are oxygenated, sulfated, and formed by cyclic and aromatic units.
Marinedrugs 19 00663 g002a 550Marinedrugs 19 00663 g002b 550Marinedrugs 19 00663 g002c 550Marinedrugs 19 00663 g002d 550
Figure 2. Structures of terpenoids and steroids from Callyspongia species.
A total of 38 sipholane triterpenoids were isolated from Callyspongia sipholena (Siphonochalina Siphonela): (2S,4aS,5S,6R,8aS)-5-(2-((1S,3aS,5R,8aS,Z)-1-hydroxy-1,4,4,6-tetramethyl-1,2,3,3a,4,5,8,8a-octahydroazulen-5-yl)-ethyl)-4a,6-dimethyloctahydro-2H-chromene-2,6-diol (54) [52][32]; dahabinone A (55) [53][33]; neviotives A (56) [54[34][35][36][37],55,56,57], B (57) [53][33], C (58) [55][35], and D (59) [57][37]; sipholenols A (60) [7[21][11][38][35][36][37][39][40][41][42],8,25,55,56,57,58,59,60,61], B (61) [61][42], C (62) [61][42], D (63) [61][42], E (64) [61][42], F (65) [53][33], G (66) [53][33], H (67) [53][33], I (68) [59][40], J (69) [52][32], K (70) [52][32], L (71) [55][35], L (72) [8[11][32][36],52,56], M (73) [52][32], N (74) [57][37], and O (75) [57][37]; sipholenones A (76) [7[21][11][38][35][36][39][40][41][42],8,25,55,56,58,59,60,61], B (77) [61][42], C (78) [61][42], D (79) [53][33], and E (80) [52][32]; sipholenosides A (81) [53][33] and B (82) [53][33]; siphonellinol (83) [62][43] and siphonellinols B (84) [53][33], C (85) [59][40], C-23-hydroperoxide (86) [52][32], D (87) [52[32][37],57], and E (88) [52][32]. The extracts studied were: EtOAc (54, 60, 69, 70, 72, 73, 76, 80, and 86–88), EtOAc/MeOH 1:1 (55, 57, 65–67, 79, 81–82, and 84), petroleum ether (60–64, 76–78, and 83), chloroform (56), CH2Cl2/MeOH 1:1 (56, 58, 60, 71, 72, and 76), MeOH (60, 68, 76, and 85), EtOH (56, 59, 60, 74–76, and 87) and EtOH 70% (56, 60, 72, and 76) extracts. Molecules 63 and 67 present elucidating 1H NMR data, and the other metabolites are fully characterized by both 1H and 13C NMR. Sipholane triterpenoids have distinct structures (Figure 2 ), which are composed of monocyclic and polycyclic rings, unsaturation, epoxy oxygen, ether, alcohol, and carbonyls.
Fifteen sterols were isolated from Callyspongia species: 24S-24-methyl-cholestane-3β,5α,6β,25-tetraol-25-mono acetate (89), 24S-24-methyl chelestane-3β,5α,6β,12β,25-pentaol-25-O-acetate (90), 24S-24-methyl cholest-25-ene-3β,5α,6β,12β-tetrol (91), 24S-24-methyl cholestane-3β,6β,25-triol-25-O-acetate (92), 24S-24-methyl cholestane-3β,6β,8β,25-tetraol-25-O-acetate (93) and 24S-24-methylcholesterol (94), 5α-cholestanone (95), callysterol (96 and 97) or ergosta-5,11-dien-3β-ol (97), cholestenone (98), Stigmasta-4,22-dien-3,6-dione (99), stigmasterone (100), gelliusterol E (101), β-sitosterol (102), siphonocholin (103), and ergosta-5,24(28)-dien-3β-ol (104). The obtainment of these metabolites is associated with the following extracts: 89–94 to MeOH extract from Callyspongia fibrosa [23][24]; 95, 96 [7][21], 98–100 [7][21], and 103 [63,64][44][45] to EtOH extract from Callyspongia siphonella; 97 [19][46] and 104 [8][11] to MeOH/CH2Cl2 1:1 extract from Callyspongia siphonella and, 101, and 102 to MeOH/CH2Cl2 1:1 extract from Callyspongia implexa [28][2]. Compounds 89–94, 97, and 101 were elucidated by 1H and 13C NMR, while remaining compounds of this set do not present NMR data, but are compared with information from other studies. These compounds are four-ring sterols (Figure 2), with 89–103 being formed by three six-membered rings and one of five, while in 104 a four six-membered ring system is present.

2.3. Alkaloids

Several alkaloids were isolated and properly characterized from Callyspongia species. The bromopyrrole alkaloids 2-bromoaldisine (105), callyspongisines A (106), B (107), C (108), and D (109) and hymenialdisine (110) were obtained from the hydroalcoholic extract from Callyspongia sp. [65][47]. The bicyclic structures of compounds 105–110 were elucidated by 1H and 13C NMR and are formed by a seven-membered cyclic amide and a pyrrole attached to a bromine atom (Figure 3).
Marinedrugs 19 00663 g003a 550Marinedrugs 19 00663 g003b 550
Figure 3. Structures of alkaloids isolated from Callyspongia species.
Some alkaloids were obtained from EtOH 95% extract of Callyspongia sp.: callyimine A (111) [18][48], callylactam A (112) [18][48], clathryimine B (113) [18][48], 3-(2-(1H-indol-3-yl)-2-oxoethyl)-5,6-dihydropyridin-2(1H)-one (114) [18][48], 3-(2-(4-hydroxyphenyl)-2-oxoethyl)-5,6-dihydropyridin-2(1H)-one (115) [18][48], (1R,3R)-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid (116a) [66][49], (1R,3S)-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid (116b) [66][49], C2-α-D-mannosylpyranosyl-tryptophan (117) [66][49], Ethyl 2-(1H-indol-3-yl) acetate (118) [67][50], and the indol derivative 1H-indole-3-carbaldehyde (119) [67][50] (Figure 3). Molecules 111 and 113 are structurally similar due to the presence of aromatic rings and nitrogen as a heteroatom, while 112 and 115 are only differentiated by the presence of a hydroxyl group in 115; and the structures 114 and 116a-119 are formed by an indol heterocycle. Metabolites 111–119 not present NMR data, but compare with information from others studies.
The isomers 5-bromo trisindoline (120) and 6-bromo trisindoline (121) were isolated from the ethanolic extract of Callyspongia siphonella [7][21], and they are differentiated by the position of bromine in the aromatic ring of the indole unit of the molecules. In addition, from Callyspongia sp. were isolated the untenines A (122), B (123), and C (124), from the methanolic extract [68][51], and niphatoxin C (125), from the mixture of CH2Cl2/MeOH 4:1 and MeOH extracts [69][52]. The 122–125 structures have the pyridine group in the molecule. Metabolites 120–125 (Figure 3) were determined by 1H and 13C NMR.
Studies of some sponges Callyspongia sp. resulted in the isolation of Callysponine (126), cyclo-(S-Pro-R-Tyr) (127), cyclo-(S-Pro-R-Val) (128), cyclo-(S-Pro-R-Ala) (129), cyclo-(S-Pro-R-Leu) (130), callysponine A (131), cyclo-(Gly-Pro) (132), cyclo-(Ile-Pro) (133), cyclo-(Pro-Pro) (134), cyclo-(Thr-Pro) (135), cyclo-(R-Pro-6-hydroxyl-R-Ile) (136), cyclo-(R-Pro-R-Phe) (137), cyclo-(R-Tyr-R-Phe) (138), cyclo-(S-Pro-S-Phe) (139), Staphyloamide A (140), dysamide A (141), callyspongidipeptide A (142), cyclo-((S)-Pro-(R)-Ile) (143), seco-((S)-Pro-(R)-Val) (144), (3R)-methylazacyclodecane (145), and callyazepin (146) (Figure 3). The analyzed metabolites were obtained from the following extracts: EtOH for 126–130 [70][53] and 141 [6][54], EtOH 95% for 129 and 130 [66,71][49][55], 136–140 [66][49] and 142–144 [71][55], EtOH/H2O 9:1 for 131–135 [72[56][57][58][59][60][61][62][63],73,74,75,76,77,78,79], and MeOH + CH2Cl2 for 145 and 146 [5][64]. Only 126, 130, 131, 136, 141, 142, and 144–146 present 1H and 13C NMR data. The structures of 138, 141, 144, and 145 are monocyclic, while 126–137, 139, 140, 142, 143, and 146 are bicyclic.

3. Biological Aspects of Metabolites Isolated in Callyspongia species

3.1. Polyacetylenes

The aikupikanynes E (5) and F (6) from Callyspongia sp. showed moderate activity (with IC50 values of 5 and 10 μg/mL) against the cancer cell lines studied [27][1]. Other polyacetylenes obtained from Callyspongia truncata showed a potent metamorphosis-inducing activity in the ascidian Halocynthia roretzi larvae (with ED100 values of 0.13–1.3 μg/mL) for 9, 11, 15, and 32–38, and antifouling activity against the barnacle Balanus amphitrite larvae (with ED50 values of 0.24–4.5 μg/mL) for 15 and 32–38 [29][4]. In addition, the inhibitory effect of the fertilization of starfish gametes of 32 and 33 in concentrations of 6.3 and 50 μM, respectively, [42][18].
Three polyacetylene diols were isolated from Callyspongia sp. and have driving Th1 polarization and antiproliferative effect against HL-60 (IC50 values: 6.5 μg/mL for 13,14 and 2.8 μg/mL for 15) and HCT-15 (IC50 values: 21 μg/mL for 13, 22 μg/mL for 14 and 34 μg/mL for 15) [31][6]. 13, 15 and 18 exhibited strong inhibitory activity against gastric H,K-ATPase (IC50 1.0 × 10−5 M) [32,96][7][65]. The 16a and 16b isomers are weakly cytotoxic, with IC50 values of 0.47 for 16a natural, 1.5 (± 0.29) for 16a synthetic, 0.11 for 16b natural and 0.35 (± 0.13) for 16b synthetic against TR-LE and 1.8 (± 5.0) for 16a and 5.3 (± 1.1) for 16b synthetics against HeLa [35][10]. Other activities have been attributed to siphonodiol (15): medium antibacterial effect against S. aureus (MIC 12.5 μg/mL) and S. pyrogenes C-203 (MIC 6.2 μg/mL), and weak antifungal activity against T. asteroids (MIC 25.0 μg/mL) [33,96][8][65].
The metabolites 17 and 23 from Callyspongia siphonella proved to be weakly cytotoxic active against HCT-116. In addition, 17 and 26 were found to be weak cytotoxic against cells of MCF-7 with IC50 values of 65.7 and 73.6 μM, respectively, while 23 (IC50: 11.7 μM) presented greater activities [36][12].
The compound (3R,4E,28Z)-hentriacont-4,28-diene-1,23,30-triyn-3-ol (19) has been reported to be cytotoxic against the NBT-II cell line at concentrations of 5 and 10 μg/mL [37][13]. The metabolites 20–22 and 26 are moderately cytotoxic against the P388 cell lines (IC50 values in μg/mL: 2.2 for 20, 22, and 26 and 10.0 for 21) and HeLa (IC50 values in μg/mL: 4.5 for 20, 10.0 for 21, 3.9 for 22, and 5.1 for 26) [38][14]. Cytotoxic compounds 26–30 also have moderate activity against HeLa (IC50 values 23.9–26.5 μM), MCF-7 (IC50 values 54.9–69.2 μM), and A549 (IC50 values 58.5–63.4 μM) cell lines [40][16]. In vitro cytotoxicity activities of compounds 24 and 25 were evaluated and verified to fight MOLT-4 cell lines (IC50 values: 1.9 μM for both), K-562 (IC50 values 5.6–6.1 μM), and HCT 116 (IC50 values 5.4–7.0 μM), only 24 against T-47D (IC50 value: 8.9 μM) and 25 against MDA-MB-231 (IC50 value: 9.9 μM) [39][15].
Two interesting compounds were isolated from Callyspongia truncata, the Callysponginol sulfate A (31), which was found to inhibit MT1-MMP with an IC50 of 15.0 μg/mL [41][17], and Callyspongynic Acid (44), a α-glucosidase inhibitor with an IC50 of 0.25 μg/mL [44][22]. The glycerolipid Batyl alcohol 46 showed biofilm inhibition capacity for Alteromona macleodii, Ochrobactrum pseudogrignonense, Vibrio harveyi, and Staphylococcus aureus at 0.5 and 0.025 mg/mL [97][66]. The polyacetylenic amide callyspongamide A (47) was shown to be moderately cytotoxic against HeLa (IC50 of 4.1 μg/mL) [46][25].

3.2. Terpenoids and Steroids

The metabolites 60, 72, 76, and 104, from Callyspongia siphonella, proved to be weakly cytotoxic active against HCT-116, but 60, 72, and 76 were found to have moderate activity (at the respective IC50 values of 14.8 ± 2.33, 19.8 ± 3.78, and 95.8 ± 1.34 μM) [8][11]. In addition, 60 presented high cytotocix activity against cells of MCF-7 with IC50 values of 8.8 μM [36][12]. The effects on Reversing P-gp-Mediated MDR to colchicine involving the KB-3-1 cell lines were also tested (IC50 values in μM: 5.6 ± 0.5 for 54, 4.8 ± 0.1 for 60, 5.1 ± 0.3 for 72, 4.7 ± 0.3 for 73, 4.7 ± 0.4 for 80, 4.2 ± 0.1 for 87 and 4.6 ± 0.6 for 88) and KB-C2 (IC50 values in μM: 390 ± 40 for 54, 140 ± 30 for 60, 150 ± 10 for 72, 780 ± 60 for 73, 62 ± 11 for 80, 180 ± 10 for 87 and 560 ± 50 for 88) [52][32].
The isocopalanol (49) showed inhibition ability for the PANC-1 cell line with an IC50 of 0.1 μg/mL [50][29]. akaterpin (50) has been proven to inhibit PI-PLC (IC50 of 0.5 μg/mL) and neural sphingomyelinase (IC50 of 30 μg/mL) [51][30]. The sulfated meroterpenoids 51–53 are inhibitors of L-APRT at IC50 of 0.7, 0.7 and 1.05 μM, respectively, [11][31].
The metabolites 56, 58, 60, and 71 showed activity against PC-3 (IC50 7.9 ± 0.12–71.2 ± 0.34 μM) and A549 (IC50 8.9 ± 0.01–87.2 ± 1.34 μM) cell lines, with compound 60 being the most active [55][35]. The cell lines MCF-7 (IC50 3.0 ± 0.4–19.2 ± 0.6 μM) and HepG-2 (IC50 2.8 ± 0.4–18.7 ± 0.9 μM) were tested for 56, 60, 71, and 76, and 76 had the most significant effect [56][36] (also obtained MCF-7 IC50 values of 1.162 for 60 and 0.9 μM for 76 [58][39]). In the same study, antiviral activity against HAV-10 was also weak for 56 and 71 (which also showed weak effectiveness against HSV-1) and moderate for 60 [56][36] (60 is an inhibitor of P-gp too) [98][67]. In addition, the antimicrobial activities of 56 and 71 were measured , in which 56 obtained the greater result (12.7 ± 0.58–17.2 ± 0.58 mm) and 71 obtained a moderate one against gram positive bacteria only (12.3 ± 0.72–14.5 ± 0.72 mm) [56][36]. Compounds 56 and 59 also strongly inhibit RANKL-induced osteoclastogenesis with IC50 values of 32.8 and 12.8 μM, respectively, [57][37].
Sipholenol A (60) and sipholenone A (76) exhibited antiproliferative activity against +SA mouse mammary epithelial cells. While compound 76 was found to be a potential inhibitor (IC50 20–30 μM), 60 had lower activity (IC50 70 μM) [58][39]. Substances 60 and 76, in addition to 85, showed Reversal effects for KB-C2 [59][40], and 76 had both anti-angiogenic activity in CAM assay (0.026 μM per pellet) [58][39] and antibacterial activity [56][36]. In another study, substances 89–92 were associated with moderate antimalarial activity against Plasmodium falciparum [23][24], in which 89 showed the best result. Callysterol (97) showed an anti-inflammatory effect [19][46] and cholestenone (98) had an anti-metastatic effect on lung adenocarcinoma [98,99][67][68]. Gelliusterol E (101) inhibited the formation and growth of chlamydial trachomatis (IC50 value 2.3 μM) [28][2], and siphonocholin (103) inhibited the production of violacein, being an Anti-QS and Anti-biofilm compound [63][44]. β-Sitosterol (102) was found to exhibit anthelminthic [100][69], antimutagenic (at 0.5 mg/kg inhibited the mutagenicity of tetracycline) [100][69], angiogenic [101][70], antibacterial [102[71][72][73],103,104], antifungal against Fusarium spp. [104][73], antidiabetic [102[71][74],105], analgesic [100,106][69][75], antipyretic [107][76], anti-inflammatory [100[69][75][76][77][78][79][80][81][82][83],106,107,108,109,110,111,112,113,114], cytotoxic [108[77][78][79][80][81][82][83],109,110,111,112,113,114], hypocholesterolemic [115][84], and immunomodulatory activities [116][85].

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