Undescribed Anti-Inflammatory Thalysiaketides from Marine Sponge Clathria (Thalysias) vulpina (Lamarck, 1814).

Two undescribed polyketide-type compounds, thalysiaketide A and thalysiaketide B were isolated from a sponge of marine origin Clathria (Thalysias) vulpina (Lamarck, 1814). Thalysiaketide A exhibited significantly greater inhibitory potential against inflammatory 5-lipoxygenase (IC50 0.87 mM) and cyclooxygense-2 (IC50 0.93 mM) compared to those displayed by its thalysiaketide B analog (IC50 ≥1.05 mM). The 5-lipoxygenase inhibitory activity of thalysiaketide A was considerably superior to ibuprofen (standard, IC50 >4 mM). Higher degree of polar belongings (topological polar surface area 93.06) in conjunction with relatively lower docking parameters of thalysiaketide A with the aminoacyl residues of cyclooxygense-2 and 5-lipoxygenase (docking score -12.99 and -12.27 kcal/mol, respectively) recognized its prospective anti-inflammatory potential.

Clathriolide from marine demosponge Clathria (Thalysias) vulpina (Lamarck, 1814): previously undescribed macrocylic lactone with attenuating potential against angiotensin converting enzyme.

Angiotensin-I converting enzyme catalyses the rate-determined step of the conversion of angiotensin-I to angiotensin-II that narrows the blood vessels, and angiotensin-I converting enzyme inhibitors were recognised as important medications for hypertension-related diseases. Chemical investigation of angiotensin-I converting enzyme inhibitors from marine demospongiae Clathria (Thalysias) vulpina (family Microcionidae), resulted in a previously undescribed 22-membered macrocyclic lactone derivative, named as clathriolide. The studied compound showed potential angiotensin converting enzyme attenuation property (IC50 0.41 mM), which was comparable with the standard captopril (IC50 0.36 mM). Clathriolide revealed significantly greater antioxidant potentials against free radical species (IC50 < 1 mM) in comparison with the standard α-tocopherol (IC50 > 1.5 mM). Superior electronic characteristics (topological polar surface area > 100) coupled with relatively smaller binding energy and docking score of clathriolide with the aminoacyl residues of angiotensin-I converting enzyme (-11.5 and -12.2 kcal/mol, respectively) described its potential inhibitory property against angiotensin-I converting enzyme.

Clathriketal, a new tricyclic spiroketal compound from marine sponge Clathria prolifera attenuates serine exopeptidase dipeptidyl peptidase-IV.

An undescribed tricyclic spiroketal compound clathriketal was purified from the solvent extract of the Microcionidae sponge Clathria prolifera, and was characterised as 7-(hydroxymethyl)-13-methoxy-3,11-dimethyl-4-oxo-octahydrospiro[chromene-9,13-pyran]-11-yl propionate by spectroscopic experiments. Clathriketal exhibited significant anti-hyperglycemic property by attenuating serine protease dipeptidyl peptidase-IV (IC50 0.37 mM), and its activity was comparable with the standard diprotin A (IC50 0.31 mM). The spiroketal also exhibited significant inhibitory potentials against carbolytic enzymes α-glucosidase (IC50 0.43 mM) and α-amylase (IC50 0.41 mM). Superior antioxidant properties of clathriketal against the oxidants, 2, 2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid and 2, 2-diphenyl-1-picrylhydrazyl (IC50 ∼1.2 mM) also reinforced its promising anti-hyperglycemic activity. Considerably greater topological surface area (91.29) coupled with lesser steric parameters of clathriketal, as elucidated from the structure-activity relationship analyses could further ascribe the improved ligand-receptor interactions resulting in its prospective anti-hyperglycemic activity. Molecular docking analysis of clathriketal with dipeptidyl peptidase-IV recorded lesser binding energy (-9.63 kcal/mol), which further corroborated its prospective antihyperglycemic activity.

Erectcyanthins A-C from marine sponge Hyrtios erectus: anti-dyslipidemic agents attenuate hydroxymethylglutaryl coenzyme A reductase.

Bioactivity-steered chromatographic purification of the solvent extract of marine sponge Hyrtios erectus (Thorectidae) led to the isolation of three undescribed cyanthiwigin-type diterpenoids, erectcyanthins A-C. Erectcyanthin B exhibited comparable attenuation activity against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (IC50 0.07 mM) with that displayed by anti-dyslipidemic agent atorvastatin (IC50 0.08 mM). Comparatively greater antioxidant properties of erectcyanthin B (IC50 ∼ 0.4 mM) than that displayed by erectcyanthin A (IC50 ∼ 0.5 mM), erectcyanthin C and the standard α-tocopherol (IC50 1.5-1.7 mM) against oxidants also corroborated its promising bioactivity. Erectcyanthin B exhibited considerably greater anti-inflammatory activities (IC50 0.88-1.09 mM) than other erectcyanthin analogues in the series. The potential anti-dyslipidemic activity of erectcyanthins was linearly correlated with electronic parameter (topological polar surface area ∼ 74.6) along with balanced hydrophilic-lipophilic properties (logarithmic octanol-water partition coefficient 1.76). This study recognized the anti-dyslipidemic property of erectcyanthin B as a promising pharmaceutical lead.

Apoptotic effect of chromanone derivative, hyrtiosone A from marine demosponge Hyrtios erectus in hepatocellular carcinoma HepG2 cells.

The tumor suppressor proteins p53 and p27 exhibited a significant role in the survival of cells and regulation of cellular division and growth. In majority of the human tumors, particularly in hepatocellular carcinoma, these proteins are inactivated by mutation or deletion, and are considered to predict the pathophysiology related to liver cancer. The present study evaluated the activation of the p53 and p27 pathways as a useful therapeutic tool to attenuate hepatocellular carcinoma. Three undescribed homologous chromanone derivatives, hyrtiosones A-C were isolated from the organic extract of marine demosponge Hyrtios erectus (family Thorectidae). Preliminary bioactivity assessments found that hyrtiosone A exhibited prospective anti-inflammatory (IC50 1.02-1.86 mM) and antioxidant (IC50 0.74-0.83 mM) properties. Molecular docking analysis of the hyrtiosones using p53-murine double minute complex revealed lesser docking parameters for hyrtiosone A (binding energy -11.12 kcal mol-1, docking score -12.18 kcal mol-1) thereby attributing its greater bioactivity. Hyrtiosone A was furthermore analyzed for in vitro anticancer activity in hepatocellular carcinoma HepG2 cells. Morphological assessment of hyrtiosone A treated HepG2 cell line by acridine orange/ethidium bromide fluorescence staining revealed greater number of apoptotic cells, and was found to be comparable with the cells treated with the standard doxorubicin. Further the Annexin V-fluorescein isothiocyanate assay of hyrtiosone A treated HepG2 cell line by flow cytometry displayed greater number of early apoptotic cells (51.24%) than that exhibited by the standard (21.45%). Cell cycle distribution analysis showed that hyrtiosone A arrested the S and G2/M phase of cell cycle and upregulate the gene expression of p53 and p27 in hepatocellular carcinoma HepG2 cells.

Anti-inflammatory pregnane-type steroid derivatives clathroids A-B from the marine Microcionidae sponge Clathria (Thalysias) vulpina: Prospective duel inhibitors of pro-inflammatory cyclooxygenase-2 and 5-lipoxygenase.

Two pregnane-type of steroid derivatives characterized as 5α-pregna-3ß-methyl pent-3-enoate-12ß, 16ß diol-20-one (clathroid A) and 12ß,15ß- dihydroxypregna-4,6-diene-3,20-dione (clathroid B) were purified from the crude extract of the marine sponge, Clathria (Thalysias) vulpina (family Microcionidae) by extensive chromatographic fractionation. Spectroscopic methods including nuclear magnetic resonance spectroscopy were employed to characterize the purified clathroids A-B. The studied compounds exhibited duel inhibitory potentials against pro-inflammatory cyclooxygenase-2 and 5-lipoxygenase (median inhibitory concentration, IC50 < 1 mM), whereas the attenuation property of clathroid A against 5-lipoxygenase (IC50 0.85 mM) was greater than the standard anti-inflammatory ibuprofen (IC50 4.51 mM, p < 0.05). Greater selectivity index (anti cyclooxygense-2/anti cyclooxygense-1) of the studied clathroids (>1) than ibuprofen (0.43) attributed the greater selective attenuation properties towards pro-inflammatory inducible cyclooxygenase-2 than its constitutive isoenzyme cyclooxygenase-1. The antioxidant potentials of clathroid A against 2, 2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (IC50 0.80 mM) and diphenyl-1-picrylhydrazyl (IC50 0.83 mM) free radicals were greater than those of clathroid B (IC50 0.86-0.96 mM). Structure-activity analyses showed that the bioactivities of the clathroids were directly related to their electronic parameters coupled with permissible hydrophobic properties. Clathroid A exhibited grater electronic parameter (topological polar surface area tPSA, 83.83) than clathroid B (74.60) and ibuprofen (37.30), which were found to be in agreement with the prospective anti-inflammatory profile of clathroid A. Clathroid A exhibited higher number of hydrogen bonding interactions with 5-lipoxygenase active site and lesser docking values, such as docking score (DS -12.90 kcal mol-1) and inhibition constant (Ki 1.11 nM) than those recorded by clathroid B (DS -10.49 kcal mol-1; Ki 13.88 nM). The molecular binding properties of clathroid A with 5-lipoxidase inferred that its docking score/ binding energy were positively correlated with their in vitro bioactivie potentilas. A putative biosynthetic pathway of the studied clathroids was proposed from a pregnenolone precursor. The present study recognized the potential of clathroid A isolated from C. (Thalysias) vulpina as prospective anti-inflammatory lead that could find its use in medicinal applications.

Procerolides A-B from Microcionidae marine sponge Clathria procera: Anti-inflammatory macrocylic lactones with selective cyclooxygenase-2 attenuation properties.

Cyclooxygenase-2 has been recognized to catalyze the formation of inflammatory prostaglandins from arachidonic acid. Attenuation potential against cyclooxygenase-2 coupled with greater anti-inflammatory selectivity index were contemplated to be vital indicators to assess anti-inflammatory activities of bioactive compounds. In the present study, two undescribed fourteen-membered macrocyclic lactones, procerolide A and B were isolated to homogeneity from the organic extract of the marine sponge Clathria procera (family: Microcionidae). Procerolide B exhibited greater attenuation potential against cyclooxygenase-2 (IC50 0.89 mM) than that displayed by procerolide A, whereas 5-lipoxygenase inhibitory activity of procerolide B (IC50 1.08 mM) was significantly greater than that displayed by procerolide A (IC50 0.95 mM) and anti-inflammatory agent ibuprofen (IC50 4.50 mM). Additionally, greater anti-inflammatory selectivity index of the procerolides (~1.3) than the synthetic agent (0.43) was accounted for the selective inhibition of the compounds towards cyclooxygenase-2. Higher electronic properties (topological polar surface area of > 100) along with lesser steric properties (molar volume < 300 cm3) of the compounds compared to the standard supported their significant anti-inflammatory potential. Additionally, procerolide B exhibited comparatively lesser binding energy with aminoacyl residues of cyclooxygenase-2 (-9.82 kcal/mol) thereby recognizing its prospective therapeutic use against inflammatory pathogenesis.

Stomopnolides A-B from echinoidea sea urchin Stomopneustes variolaris: prospective natural anti-inflammatory leads attenuate pro-inflammatory 5-lipoxygenase.

Two fourteen-membered macrocyclic pyrone derivatives named as stomopnolides were identified from the organic extract of echinoidea sea urchin Stomopneustes variolaris by extensive chromatographic purification, and were characterised as methyl 10-butyl-4a-methyl-2-oxo-octahydro-2H-cyclodeca[b]pyran-8-carboxylate (stomopnolide A) and methyl 82-(4a-methyl-10-(102-methylbutyl)-2-oxo-octahydro-2H-cyclodeca[b]pyran-8-yl)acetate (stomopnolide B) by spectroscopic methods. The macrocyclic pyrone derivative bearing pyran-8-carboxylate moiety (stomopnolide A) exhibited significantly greater antioxidant properties against 2,2-diphenyl-1-picrylhydrazyl (IC50DPPH 1.43 mM) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (IC50ABTS+ 1.63 mM) free radicals than stomopnolide B (IC50 > 1.85 mM) and the commercial standard α-tocopherol (IC50 1.51 mM). Stomopnolide A exhibited potential attenuation property against pro-inflammatory 5-lipoxygenase (IC50 2.78 mM) than those exhibited by stomopnolide B (IC50 3.09 mM) and non-steroidal anti-inflammatory drug, ibuprofen (IC50 4.50 mM, p < 0.05), which signified the prospective anti-inflammatory activity of the former. The greater electronic parameters of stomopnolide A, along with greater number of hydrogen bonds and docking score obtained from the molecular docking studies attributed its potential anti-inflammatory activity.

An anti-inflammatory salmachroman from the sea urchin Salmacis bicolor: a prospective duel inhibitor of cyclooxygenase-2 and 5-lipoxygenase.

An isochroman derived polyketide, salmachroman characterized as methyl 153(11-(10-hydroxy-12-oxo-6-pent-63-en-61-yl)isochroman-10-yl)-13-oxotetrahydrofuran-15-yl was isolated from the organic extract of the Echinodermata sea urchin Salmacis bicolor (family Temnopleuridae) through chromatographic fractionation. The structure of the compound was identified by detailed spectroscopic techniques. Salmachroman demonstrated significant duel inhibition potential against pro-inflammatory enzymes, cyclooxygense-2 (IC50 1.29 mM) and 5-lipoxygenase (IC50 1.39 mM). The compound exhibited significantly greater anti-inflammatory selectivity index (1.03) than that displayed by the anti-inflammatory agent ibuprofen (0.43). The isochroman analogue exhibited greater antioxidant activities against 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (IC50 1.19 mM) and 2,2-diphenyl-1-picrylhydrazyl (IC50 1.24 mM) than the standard antioxidative agent α-tocopherol (IC50 > 1.50 mM). The binding properties of the compound with the active site of cyclooxygense-2 and 5-lipoxygenase enzymes, combined with its higher electronic parameters as attributed by the structure-activity relationship accounted for its significant anti-inflammatory properties.

Hyrtioscalaranes A and B, two new scalarane-type sesterterpenes from Hyrtios erectus with anti-inflammatory and antioxidant effects.

Two new scalarane-type sesterterpenes, hyrtioscalaranes A and B, were isolated from the organic extract of the Demosponge Hyrtios erectus through extensive chromatographic purification. Hyrtioscalarane A exhibited significantly greater attenuation property against cyclooxygense-2 (IC50 0.83 mM) than that displayed by hyrtioscalarane B (IC50 0.98 mM). The greater selectivity index of hyrtioscalaranes (> 1) than that exhibited by the commercial anti-inflammatory agent ibuprofen (0.43) further supported the higher selectivity of the former towards pro-inflammatory cyclooxygenase-2. Hyrtioscalarane A exhibited greater antioxidant activities as determined by 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (IC50 0.77 mM) and 2,2-diphenyl-1-picrylhydrazyl (IC50 0.81 mM) free radical quenching properties than those displayed by hyrtioscalarane B (IC50 > 0.83 mM) and the antioxidative agent α-tocopherol (IC50 1.51 mM). The greater binding energy (-14.32 kcal/mol) and docking score (15.22 kcal/mol) of hyrtioscalarane A at the active site of cyclooxygenase-2 along with the higher electronic parameters and balanced hydrophobicity could attribute its potential anti-inflammatory activity.

Callypyrones from marine Callyspongiidae sponge Callyspongia diffusa: antihypertensive bis-γ-pyrone polypropionates attenuate angiotensin-converting enzyme.

Angiotensin I-converting enzyme (ACE) catalyses the biosynthesis of angiotensin II, a potent blood vessel constrictor, from angiotensin I, and ACE inhibitors were recognised as medications for hypertension. Undescribed bis-γ-pyrone polypropionate compounds, callypyrones A and B were purified from the organic extract of Callyspongiidae sponge species Callyspongia diffusa by repeated chromatographic purification. Callypyrone A exhibited significantly greater attenuation potential against ACE (IC50 0.48 mM) than that displayed by callypyrone B (IC50 0.57 mM) and showed comparable activity with standard ACE inhibitor captopril (IC50 0.36 mM). Higher electronic parameters of callypyrone A (topological surface area of 108.36) combined with balanced hydrophilic-lipophilic parameter (octanol-water coefficient, log Pow 1.9), as deduced from the structure-activity relationship analyses, could further indicate the improved ligand-receptor interactions resulting in its prospective ACE inhibitory activity. In silico docking analyses of the callypyrones with ACE recorded lowest binding energy (-12.58 kcal mol-1) for callypyrone A, which further supported the antihypertensive potential of the compound.

Stomopneulactone D from long-spined sea urchin Stomopneustes variolaris: Anti-inflammatory macrocylic lactone attenuates cyclooxygenase-2 expression in lipopolysaccharide-activated macrophages.

Cyclooxygenase-2 is one of the prominent enzymes to cause an increased production of prostaglandins during inflammation and immune responses. Cyclooxygenase-2 expression is up-regulated in inflammatory conditions owing to the induction by different inflammatory stimuli including cytokines, and therefore, the expression studies of cyclooxygenase-2 in lipopolysaccharide-induced macrophage cells (RAW 264.7 cell line) could be used for screening of the compounds with anti-inflammatory potential. The present study evaluated the anti-inflammatory properties of four homologous stomopneulactones A-D, classified under the class of macrocyclic lactones isolated from the solvent extract of the long-spined sea urchin Stomopneustes variolaris (familyStomopneustidae) in the lipopolysaccharide-induced macrophages. The structures of these isolated compounds were assigned using detailed spectroscopic techniques. Stomopneulactone D bearing 5-butyl-4-hydroxy-12-oxo-1-oxa-5,9-cyclododecadienyl moiety exhibited relatively greater anti-inflammatory potentials against cyclooxygenase-2 (IC50 ~ 2 mM) and 5-lipoxygenase (IC50 2.6 mM) than those displayed by other macrocyclic lactones. The studied compounds displayed higher selectivity index values (anti-cyclooxygenase-1IC50/anti-cyclooxygenase-2IC50 > 1), which designated the selective anti-inflammatory potentials of the macrocyclic lactones against inducible inflammatory mediators than those exhibited by the anti-inflammatory agent ibuprofen (0.43). The in silico molecular modelling analyses of the stomopneulactones with cyclooxygenase-2/5-lipoxygenase enzymes recorded lowest binding energy (-7.71 and -9.60 kcal mol-1, respectively) and docking score (-8.82 and -11.12 kcal mol-1, respectively) for stomopneulactone D along with its higher electronic parameter (topological polar surface area of 72.83), which further confirmed its greater anti-inflammatory potential than other compounds in the series. Stomopneulactone D also inhibited the generation of inducible nitric oxide synthase, intracellular reactive oxygen species, along with 5-lipoxygenase and cyclooxygenase-2 in the lipopolysaccharide-stimulated macrophage cells. Additionally, the studied macrocyclic lactone decreased the mRNA expression of cyclooxygenase-2 in the inflammatory cells in dose-dependent manner, which demonstrated the therapeutic potential of stomopneulactone D in down-regulating the inflammatory pathogenesis.