In-vitro and in-silico evaluations of heterocyclic-containing diarylpentanoids as Bcl-2 inhibitors against LoVo colorectal cancer cells

In the present study, we investigated the in-vitro anti-cancer potential of six diarylpentanoids against a panel of BRAF- and KRAS-mutated colorectal cancer cell lines including T84, SW620, LoVo, HT29, NCI-H508, RKO, and LS411N cells. Structure-activity relationship study suggested that the insertions of tetrahydro-4H-thiopyran-4-one and brominated phenyl moieties are essential for better cytotoxicity. Among the evaluated analogs, 2e has been identified as the lead compound due to its low IC50 values of approximately 1 µM across all cancer cell lines and high chemotherapeutic index of 7.1. Anti-proliferative studies on LoVo cells showed that 2e could inhibit cell proliferation and colony formations by inducing G2/M cell cycle arrest. Subsequent cell apoptosis assay confirmed that 2e is a Bcl-2 inhibitor that could induce intrinsic cell apoptosis by creating a cellular redox imbalance through its direct inhibition on the Bcl-2 protein. Further molecular docking studies revealed that the bromophenyl moieties of 2e could interact with the Bcl-2 surface pocket through hydrophobic interaction, while the tetrahydro-4H-thiopyran-4-one fragment could form additional Pi-sulfur and Pi-alkyl interactions in the same binding site. In all, the present results suggest that 2e could be a potent lead that deserves further modification and investigation in the development of a new Bcl-2 inhibitor

In vitro and in silico evaluations of diarylpentanoid series as a-glucosidase inhibitor

A series of thirty-four diarylpentanoids derivatives were synthesized and evaluated for their α-glucosidase inhibitory activity. Eleven compounds (19, 20, 21, 24, 27, 28, 29, 31, 32, 33 and 34) were found to significantly inhibit α-glucosidase in which compounds 28, 31 and 32 demonstrated the highest activity with IC50 values ranging from 14.1 to 15.1 µM. Structure-activity comparison shows that multiple hydroxy groups are essential for α-glucosidase inhibitory activity. Meanwhile, 3,4-dihydroxyphenyl and furanyl moieties were found to be crucial in improving α-glucosidase inhibition. Molecular docking analyses further confirmed the critical role of both 3,4-dihydroxyphenyl and furanyl moieties as they bound to α-glucosidase active site in different mode. Overall result suggests that diarylpentanoids with both five membered heterocyclic ring and polyhydroxyphenyl moiety could be a new lead design in the search of novel α-glucosidase inhibitor

Comparative study of the antioxidant activities of some lipase-catayzed alkyl dihydrocaffeates synthesized in ionic liquid

The solubility limitations of phenolic acids in many lipidic environments are now greatly improved by their enzymatic esterification in ionic liquids (ILs). Herein, four different ILs were tested for the esterification of dihydrocaffeic acid with hexanol and the best IL was selected for the synthesis of four other n-alkyl esters with different chain-lengths. The effect of alkyl chain length on the anti-oxidative properties of the resulted purified esters was investigated using β-carotene bleaching (BCB) and free radical scavenging method DPPH and compared with butylated hydroxytoluene (BHT) as reference compound. All four esters (methyl, hexyl, dodecyl and octadecyl dihydrocaffeates) exhibited relatively strong radical scavenging abilities. The scavenging activity of the test compounds was in the following order: methyl ester>hexyl ester⩾dodecyl ester>octadecyl ester>BHT while the order for the BCB anti-oxidative activity was; BHT>octadecyl ester>dodecyl ester>hexyl ester>methyl ester

Antinociceptive activity of 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol in mice

A novel compound from diarylpentanoids analogues, 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol, was evaluated on its antinociceptive activity in mice through acetic acid-induced abdominal constriction test. Antinociception of 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol was indicated by the reduction in the mean of the number of abdominal constrictions in the test groups compared to the control group. Acetylsalicylic acid (ASA, 100 mg/kg) was used as reference drugs while control group only received vehicle (5% DMSO: 5% Tween 20: 90% Distilled water) that used to dissolve the compound. The mice that received intraperitoneal injections of 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol at 0.1, 0.3, 1.0 and 3.0 mg/kg showed 48.34%, 60.79%, 90.07% and 98.54% of inhibition respectively. Acetic acid injection in mice peritoneal cavity can promote the release of many inflammatory mediators such as prostaglandin, bradykinin, substance P, TNF-α, IL-1β, IL-8 and other mediator, which will then stimulate primary afferent neurons to enhance the release of aspartate and glutamate. Hence, the result obtained from this chemical model of nociception suggests that the antinociceptive activity of 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol may be linked partly to the inhibition of the inflammatory mediators

α‐Glucosidase inhibitory and antioxidant activities of different ipomoea aquatica cultivars and LC–MS/MS profiling of the active cultivar

The present study was designed to investigate the effect of Ipomoea aquatica extracted using water and methanol at various concentrations on the total phenolics, antioxidant capacity, and a-glucosidase inhibitory activities. Three I. aquatica cultivars were used in this study including the upland type with narrow leaves (K-11), low-land aquatic types with broader shaped leaves (K-25), and bamboo-shaped leaves (K-88). The results revealed that 70% methanol extract of K-11 showed higher total phenolic content and a-glucosidase inhibitory and antioxidant activities than the other two cultivars. The phytochemical constituents in the active extract K-11 were analyzed by means of liquid chromatography coupled with diode array detection and electrospray tandem mass spectroscopy. Eighteen compounds were detected of which 13 were tentatively identified as quercetin-3-O-sophoroside, quercetin-3-O-glucoside, quercetin-3,7-di-O-glucoside, nomilinic acid glucoside, 4,5-di-O-caffeoylquinic acid, 3,5-di-O-caffeoylquinic acid, luteolin-7-glucoside and 3,4,5-tricaffeolquinic acid, fatty acid together with quercetin, and tricaffeoylquinic acid derivatives

Chemical constituents and biological activities of South East Asia marine sponges: a review

The ocean has an exceptional resource with various groups of natural products that are potentially useful for biomedical and other applications. Marine sponges have prominent characteristic natural products with high diversity. They produce many vital therapeutic metabolites with prominent biological activities. Marine invertebrates and microbial communities are the primary producers of such metabolites. Among the richest sources of these metabolites, class Demospongiae and the order Haplosclerida and genus Xestopongiae from family Petrosiidae are of interest. This review summarizes the research that has been conducted on two classes, eight orders, twelve families and fourteen genera of marine sponges available in the South East Asia region, covering the literature of the last 20 years. Ninety-five metabolites including alkaloids, sterols, terpenoids, quinones isolated from marine sponges collected in South East Asia along with their bioactivities especially cytotoxicity and antibacterial activities were reported in this review. Chemistry and biology are highly involved in studying marine sponges. Thus, tight collaboration is needed for understanding their taxonomy aspects. This review will outline chemistry and biological aspects, challenge, limitation, new idea and a clear future perspective on the discovery of new drugs from South East Asia's marine sponges

Phytochemical and bioactivity alterations of Curcuma species harvested at different growth stages by NMR-based metabolomics

Curcuma species is a popular traditional folk medicine in India and Southeast Asia. This study aims to profile the metabolites in four Curcuma species, including C. zedoaria, C. xanthorrhiza, C. aeruginosa and C. mangga at three developmental stages (seven, eight and nine months old) using nuclear magnetic resonance (NMR)-based metabolomics. Principal component analysis (PCA) showed that there are metabolites changes due to the month of harvest in each of the four species. A large quantity of curcumin and demethoxycurcumin contributed to the separation of C. xanthorrhiza, whereas the diterpenoids, such as curcumanggoside, (E)-labda-8(17),12-diene15,16-dial, calcaratarin A and zerumin B were responsible for the discrimination of C. mangga. Eight-month-old C. xanthorrhiza exhibited the highest nitric oxide (NO) inhibitory activity, while nine-month-old C. mangga exhibited the highest α-glucosidase inhibitory activity. The correlation among the bioactivities and phytochemical constituents was determined using partial least square (PLS) analysis. Curcumin, demethoxycurcumin, germacrone, zedoarol and xanthorrhizol were correlated with the NO inhibitory activity in C. xanthorrhiza, whereas curcumanggoside, labda-8(17),12-diene-15,16-dial and zerumin B were correlated with the α-glucosidase inhibitory activity in C. mangga. From the phytochemical markers and metabolic changes among growth stages of C. xanthorrhiza and C. mangga, the biosynthetic pathway was proposed to show the metabolites that might contribute to their health benefits

Phytochemical diversity of Clinacanthus nutans extracts and their bioactivity correlations elucidated by NMR based metabolomics

Clinacanthus nutans is a medicinal herb and a traditional remedy for herpes viral infection, cancer, and diabetes mellitus. Despite its popular use, there is limited information on the chemical constituents and their relationship with the bioactivities of the herb. The choice of drying and extraction methods will greatly influence the metabolite profile and the bioactivities of an herbal extract. In order to maximize retention of the original chemical profile of the herb and quality assurance, optimization of processing methods is needed. Using nuclear magnetic resonance (NMR) based metabolomics approach, we have carried out a discriminative analysis of the metabolite profiles of the leaves and stems of the herb when different drying (air, oven, and freeze) and extraction (soaking and sonication) methods were used and correlated the metabolite profiles with the total phenolic content (TPC), antioxidant and α-glucosidase inhibitory activities. Identification of primary and secondary metabolites was performed using 1D- and 2D-NMR techniques as well as ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS). Results showed that the leaf extracts, which were richer in phenolic compounds and terpenoids, showed significantly higher bioactivities compared to the stem extracts. Several newly reported compounds in the herb, identified using tandem mass spectrometry, included gendarucin A, a gendarucin A isomer, 3,3-di-O-methylellagic acid, ascorbic acid, and two isomeric oxoprolinates. From the NMR metabolomics analysis, the PLS biplot model indicated that the presence of some phenolics compounds, terpenoids, and sulfur-containing glucosides in the oven and air dried leaf extracts are the main components responsible for the antioxidant and α-glucosidase inhibitory activities. This study has provided additional information on the chemistry and biology of the herb that may be useful in future development phytomedicinal preparations of C. nutans

Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA

The search of novel mPGES-1 inhibitors has recently intensified probably due to the superior safety in comparison to existing anti-inflammatory drugs. Although two mPGES-1 inhibitors have entered clinical trials, none has yet reached the market. In this study, we performed modifications guided by 3D-QSAR CoMFA on 2, which is an unsymmetrical curcumin derivative with low binding affinity towards mPGES-1. To counter the PAINS properties predicted for 2, the diketone linker was replaced with a pyrazole ring. On the other hand, both prenyl and carboxylate ester groups were introduced to improve the activity. When tested in vitro, 11 suppressed PGE2 biosynthesis in activated macrophages and showed promising human mPGES-1 inhibition in microsomes of interleukin-1β-stimulated A549 cells. Altogether, 11 has been identified as a potential mPGES-1 inhibitor and could be a promising lead for a novel class of mPGES-1 inhibitors