Classification of Marine Natural Products - Chemistry and Bioactivity

Enthusiasm of the scientific community towards the discovery of new drug leads from marine habitats is unquenchable. Marine natural products have been recognized as a source of highly desirable chemodiversity to support drug discovery and pharmacology applications by the diverse chemical features and the wide range of biological activities possessed by them. According to the latest review by Blunt et a,l., 1378 new compounds were isolated from marine organisms in 2014 compared with 332 in 1984 (Blunt et al., 2016; Faulkner, 1994). Marine flora and fauna play a momentous role as a foundation of new molecular entity. Over 5 million species of the world in about 30 different phyla reside in the oceans. Because of the diversities of marine organism and habitats, marine natural products enfold a wide variety of chemical classes, including Terpenes, Shikimates, Polyketides, Acetogenins, Peptides, and Alkaloids of varying structures and multitude of compounds of mixed biosynthesis. These natural products are secondary metabolites and enhance survival fitness and may serve as chemical weapons used against bacteria, fungi, viruses and small or large animals. A good number of the natural products of interest to the pharmaceutical industry are secondary metabolites and several such compounds, derived from marine organisms, have been in clinical trials as experimental drugs. Over the past 50 years, numerous novel compounds have been isolated from marine flora and fauna having biological activities such as antibacterial, antiviral, antitumor, antiparasitic, anticoagulants, antimicrobial, antiinflammatory and cardiovascular compounds

Photoprotective sulfated mannogalactan from heterotrophic Bacillus velezensis blocks UV-A mediated matrix metalloproteinase expression and nuclear DNA damage in human dermal fibroblast

Prolonged exposure of human dermal fibroblasts (HDF) to ultraviolet (UV) radiation triggers the production of reactive oxygen species by upregulating the expression of matrix metalloproteinases (MMPs), causing type-I collagen degradation and photoaging. A sulfated (1 → 3)/(1 → 4) mannogalactan exopolysaccharide (BVP-2) characterized as [→3)-α-Galp-{(1 → 4)-α-6-O-SO3-Manp}-(1 → 3)-α-6-O-SO3-Galp-(1→] was isolated from seaweed-associated heterotrophic bacterium Bacillus velezensis MTCC13097. Whole genome analysis of B. velezensis MTCC13097 (Accession number JAKYLL000000000) revealed saccharine biosynthetic gene clusters for exopolysaccharide production. BVP-2 administered cells showed noteworthy reduction in mitochondrial superoxide (∼85 %, p < 0.05) and ROS production (62 %) than those exhibited by UV-A irradiated HDF cells. Oxidative imbalance in HDF cells (after UV-A exposure) was recovered with BVP-2 treatment by significantly downregulating nitric oxide (NO) production (98.6 μM/mL, 1.9-fold) and DNA damage (⁓67 %) in comparison with UV-A induced cells (191.8 μM/mL and 98.7 %, respectively). UV-irradiated HDF cells showed a ∼30-50 % downregulation in the expression of MMPs (1, 2, and 9) following treatment with BVP-2. Considerable amount of sulfation (18 %) along with (1 → 3)/(1 → 4) glycosidic linkages in BVP-2 could be pivotal factors for down-regulation of the intracellular MMP-1, which was further supported by molecular docking and structure-activity studies. The (1 → 3)/(1 → 4)-linked bacterial exopolysaccharide (BVP-2) might be used as prospective natural lead to attenuate and mitigate UV-A-induced photoaging

Spirornatas A-C from brown alga Turbinaria ornata: Anti-hypertensive spiroketals attenuate angiotensin-I converting enzyme

Bioactive compounds with angiotensin-I converting enzyme attenuation potential are deemed as therapeutic agents for hypertension owing to their capacity to suppress the conversion of angiotensin-I into the vasoconstrictor angiotensin-II. In an aim to develop natural angiotensin-I converting enzyme (ACE-I) inhibitors from marine algae, three 6, 6-spiroketals, spirornatas A-C were isolated from the organic extract of the spiny brown marine macroalga Turbinaria ornata (Turner) (family Sargassaceae). Spirornata A exhibited comparatively greater ACE-I attenuation potential (IC50 4.5 μM) than those displayed by other studied spiroketals (IC50 4.7–4.9μM), and its activity was comparable to the ACE inhibitory agent captopril (IC50 4.3 μM). Greater antioxidant properties of spirornata A against oxidants (IC50 1.1–1.3 mM) also substantiated its potential attenuation property against ACE-I. Structure-activity correlation studies showed that electronic properties (topological polar surface area, 71) and balanced hydrophilic-lipophilic parameters (partition coefficient of logarithmic octanolwater ~3.2) of spirornata A appeared to play pivotal roles in the inhibition of the targeted enzyme. Predicted drug-likeness and other physicochemical parameters appeared to attribute to the acceptable oral bioavailability of spiroketal derivatives. Additionally, the least binding energy of spirornata A with ACE-I (− 10.5 kcal/mol) coupled with the maximum number of hydrogen-bonding interactions with allosteric sites of the zinc-dependent dicarboxypeptidyl peptidase could recognize its potential therapeutic application against hypertensive diseases

Turbinafuranone A–C, new 2-furanone analogues from marine macroalga Turbinaria ornata as prospective anti-hyperglycemic agents attenuate tyrosine phosphatase-1B

Chemical investigation of Phaeophytan marine macroalga Turbinaria ornata (family Sargassaceae) resulted in the characterization of three 2-furanone analogues, which were characterized as 6, 7-dihydroxy-8-methyl-3-(5′-methyloct-4′- en-1′-yl)-hexahydrocyclooct-1-en-[1, 2-c]furan-11-one (turbinafuranone A), 4-hydroxy-3-isopropyl-7, 8-dimethyl-6- (pentan-2′-acetate)-hexahydrocycloocta-1-en-[1, 2-c]furan-11-one (turbinafuranone B), and 6-acetoxy-8-ethyl-5-methoxy�3-(2′-methylhex-4′-en-1′-yl)-pentahydrocycloocta-1, 7-dien-[1, 2-c]furan-11-one (turbinafuranone C). Inhibitory property of turbinafuranone B against tyrosine phosphatase-1B was significantly greater (IC50 2.42 mM) than standard agent sodium metavanadate (IC50 2.52 mM). Greater electronic properties along with molecular docking experiments corroborated the attenuation property of turbinafuranone B against protein tyrosine phosphatase-1B, by exhibiting minimum binding energy of −11.80 kcal/mol compared to other studied analogues. The results demonstrated that the undescribed turbinafuranone B might be used as prospective natural anti-hyperglycemic lead to alleviate the likelihood of higher postprandial blood glucose levels

Immunomodulatory effect of sulfated galactofucan from marine macroalga Turbinaria conoides

Sulfated polysaccharides are effective immunostimulating agents by activating several intracellular signaling pathways. A sulfated (1 → 3)/(1 → 4)-linked galactofucan TCP-3 with promising immunomodulatory effects was purified from a marine macroalga Turbinaria conoides. The immune-enhancing potential of TCP-3 (100–400 mg/kg BW) was evaluated on cyclophosphamide-induced immunosuppressed animals by increasing bone marrow cellularity (10–13 cells/femur/mL x 106), α-esterase activity (1200–1700 number of positive cells/4000 BMC), interferon-γ (1.31–1.49 pg/mL), interleukin-2 (3.49–3.99 pg/mL) secretion, and WBC count (> 3000 cells/cu mm). The proliferation of lymphocytes for in vitro and in vivo conditions was enhanced by administering TCP-3 besides regulating the secretion of pro-inflammatory cytokines (interleukin-6/1β/12, tumor necrosis factor-α, transforming growth factor-β), and an inducible isoform of nitric oxide synthase. A promising reduction of viral copy formation was observed by administering TCP-3 ( 5 × 107 number)

Anti-inflammatory xenicane-type diterpenoid from the intertidal brown seaweed Sargassum ilicifolium

Chemical analysis of the organic extract from intertidal brown seaweed Sargassum ilicifolium (family Sargassaceae) characterised an undescribed xenicane-type diterpenoid sargilicixenicane, elucidated as 3-(17-hydroxy-14-methylhept-13-en-10-yl)-6-methylhexahydro-1H-cyclonona[c]furan-4,19-diyl diacetate (compound 1). The studied compound exhibited prospective free radical quenching potential (IC50 1.2-1.4 mM) in comparison with commercial antioxidant (α-tocopherol, IC50 > 1.40 mM). Attenuation property of sargilicixenicane against pro-inflammatory enzyme, 5-lipoxygenase (IC50 4.70 mM) was comparable with that displayed by the non-steroidal anti-inflammatory agent ibuprofen (IC50 4.51 mM). Greater selectivity index displayed by the studied xenicane-type diterpenoid (1.42) than that exhibited by ibuprofen (0.44) recognised the selective attenuation potential of the former against the inducible cyclooxygenase-2 and 5-lipoxygenase enzymes. Higher electronic parameters (topological polar surface area, 82.06) and balanced hydrophobic-hydrophilic property (octanol-water partition coefficient 2.94) coupled with docking score (-11.17 kcal mol−1) and lower binding energy (-9.61 kcal mol−1) with the active site of 5-lipoxygenase supported the significant anti-inflammatory properties of the studied xenicane-type diterpenoid

Conoidecyclics A-C from marine macroalga Turbinaria conoides: Newly described natural macrolides with prospective bioactive properties

Intertidal marine brown alga Turbinaria conoides (J.Agardh) Kützing (family Sargassaceae) is considered as one of the largely abundant species, available in the coastal zones of the Indian subcontinent. Bioactivity-guided chromatographic fractionation of the organic extract of T. conoides resulted in three previously undescribed macrocyclic lactone homologues, named as conoidecyclics A-C. Conoidecyclic A displayed greater attenuation potential against cyclooxygenase-2 (IC50 1.75 mM) and 5-lipoxygenase (IC50 4.24 mM) in comparison with other analogues. Conoidecyclic A exhibited higher attenuation potential against 5-lipoxygenase than that displayed by an anti-inflammatory agent, ibuprofen (IC50 4.51 mM). The higher selectivity index of conoidecyclic A (1.79) recognized its selective attenuation potential against the inducible cyclooxygenase-2 enzyme. Inhibition potential of conoidecyclic A against angiotensin converting enzyme-I (IC50 1.23 mM) and protein tyrosine phosphatase-1B (IC50 1.39 mM) were non-competitive, as deduced by kinetic studies. In-silico molecular modeling study of conoidecyclic A with the allosteric sites of the targeted enzymes exhibited least binding energy of -14.51 to -11.27 kcal mol-1 compared to those exhibited by other studied macrolide homologues. Reaction kinetic studies of conoidecyclic A coupled with lesser apparent Vmax inferred that it could efficiently bind with the allosteric site of targeted enzymes in a non-competitive manner to diminish the reaction velocity resulting in enzyme inhibition. Drug-likeness and predictive pharmacokinetic parameters of conoidecyclic A exhibited an acceptable oral bioavailability. These reports inferred that conoidecyclic A encompassing pentacosa macrocyclic moiety could be a promising therapeutic lead to inhibit the enzymes related to the development and progression of pathological conditions leading to inflammation, hypertension and type-2 diabetes

Apoptotic effect of sulfated galactofucan from marine macroalga Turbinaria ornata on hepatocellular and ductal carcinoma cells

Tumor protein or cellular tumor antigen p53, is considered a critical transcriptional regulation factor, which can suppress the growth of tumor cells by activating other functional genes. The current study appraised the p53 activation pathways, which could be used as an alternative therapeutic strategy for the treatment of hepatocellular and ductal carcinoma. Algal polysaccharides have been used as emerging sources of bioactive natural pharmacophores. A sulfated galactofucan characterized as [→1)-O-4-sulfonato-α-fucopyranose-(3 → 1)-α-fucopyranose-(3→] as the main branch with [→1)-6-O-acetyl-β-galactopyranose-(4→] as side chain isolated from marine macroalga Turbinaria ornata exhibited prospective apoptosis on HepG2 (hepatocellular carcinoma) and MCF7 (ductal carcinoma) cells. Annexin V-fluorescein isothiocyanate-propidium iodide study displayed higher early apoptosis in MCF7 and HepG2 cell lines (56 and 24.2%, respectively) treated with TOP-3 (at IC50 concentration) than those administered with standard camptothecin. Upregulation of the p53 gene expression was perceived in TOP-3 treated HepG2 and MCF7 cells

First report of substituted 2H-pyranoids from brown seaweed Turbinaria conoides with antioxidant and anti-inflammatory activities

The organic extract of Turbinaria conoides, a brown seaweed harvested from the Gulf of Manner region of Indian peninsular was chromatographically fractionated to yield three substituted 2H-pyranoids, namely methyl-21-yl-[50, 60- dihydro-50-yl-{54-(4-hydroxybenzoyl)- oxy-(52-methylbutyl)}-30-methyl-2H-pyran]-21-methyl butanoate (1), 11-[(30, 60-dihydro-40-methyl-20-oxo-2H-pyran-30-yl)methyl]-10- methylhexyl benzoate (2), and [6-ethyl-3,4-dimethyl-(tetrahydro-20, 20, 60-trimethyl-2H-pyran-30-yl)-2,5-cycloheptadiene]-1-propanoate (3). The compounds 1 and 2 bearing 2H-pyranyl-4-hydroxybenzoyl and 2H-pyranyl-10-methylhexylbenzoate moieties exhibited potential antioxidant activities (IC50 0.54-0.69mg mL�1) as commercial antioxidant (a-tocopherol IC50 0.63-0.73mg mL�1). Likewise, potential bioactivity of the 2H-pyran derivative, 1 against 5-lipoxygenase (IC50 � 1mg mL�1) along with higher index of selectivity (COX-1 inhibitoryIC50/COX-2 inhibitoryIC50 1.88) indicated their selective antiinflammatory properties against inducible inflammatory mediators than that displayed by commercially available non-steroidal antiinflammatory drug (ibuprofen, 0.44). Structure activity relationship analysis of the studied compounds showed that the antioxidative and anti-inflammatory properties were directly proportional to their electronic properties. The previously undescribed 2H-pyranoids might constitute as potential antioxidative and anti-inflammatory pharmacophores for medicinal applications

Polygalacto-fucopyranose biopolymer structured nanoparticle conjugate attenuates glucocorticoid-induced osteoporosis: An in vivo studyarachidonate 5-lipoxygenase

Naturally occurring polysaccharide-structured nanoparticles have developed as promising materials for treatment of bone health disorders. Silver nanoparticle (ST-AgNP) structured from sulfated polygalacto-fucopyranose comprising of recurring structural entities of 2-SO3-α-(1 → 3)-fucopyranose and 6-O-acetyl-β-(1 → 4)-galactopyranose isolated from marine macroalga Sargassum tenerrimum demonstrated potential activities associated with osteogenesi