Sridevi Gorle

Novel 2-(1-(substitutedbenzyl)-1H-tetrazol-5-yl)-3-phenylacrylonitrile derivatives: synthesis, in vitro antitumor activity and computational studies

This work describes the two-step synthesis of new series of 2-(1-(substitutedbenzyl)-1H-tetrazol-5-yl)-3-phenylacrylonitrile derivatives (6a–k) starting from substituted benzyl halides (5a–k) and 3-phenyl-2-(1H-tetrazol-5-yl)acrylonitrile (4). Initially, compound 4 was synthesized using benzaldehyde, malononitrile and sodium azide. All the synthesized compounds were obtained in good yields and were characterized using 1H NMR, 13C NMR, FTIR and HRMS spectral data. The new compounds (6a–k) were evaluated for their potential in vitro antitumor activity against four human cancer cell lines (MCF-7, CaCO2, HeLa and SkBr3) by MTT assay. The most potent compounds 6b, 6h and 6j show good activity (IC50 values) relative to 5-fluorouracil, with potential to be antitumor agents. Compounds 6a, 6c, 6g, 6f and 6k showed moderate activity. The best performing three compounds (6b, 6h and 6j) were evaluated for in silico analysis on the PharmMapper web server, and the human mitogen-activated protein kinase 1 (MEK-1) enzyme was recognized as the main target protein. MEK-1 inhibition by these compounds was further confirmed by the docking study to corroborate the target.Graphical Abstract

Novel serum-tolerant lipoplexes target the folate receptor efficiently

Gene transfer using non-viral vectors is a promising approach for the safe delivery of nucleic acid therapeutics. In this study, we investigate a lipid-based system for targeted gene delivery to malignant cells overexpressing the folate receptor (FR). Cationic liposomes were formulated with and without the targeting ligand folate conjugated to distearoylphosphatidyl ethanolamine polyethylene glycol 2000 (DSPE-PEG2000), the novel cytofectin 3β[N(N(1),N(1)-dimethlaminopropylsuccinamidoethane)-carbamoyl]cholesterol (SGO4), which contains a 13atom, 15Å spacer element, and the helper lipid, dioleoylphosphatidylethanolamine (DOPE). Physicochemical parameters of the liposomes and lipoplexes were obtained by zeta sizing, zeta potential measurement and cryo-TEM. DNA-binding and protection capabilities of liposomes were confirmed by gel retardation assays, EtBr intercalation and nuclease protection assays. The complexes were assessed in an in vitro system for their effect on cell viability using the MTT assay, and gene transfection activity using the luciferase assay in three cell lines; HEK293 (FR-negative), HeLa (FR(+)-positive), KB (FR(++)-positive). Low cytotoxicities were observed in all cell lines, while transgene activity promoted by folate-tagged lipoplexes in FR-positive lines was tenfold greater than that by untargeted constructs and cell entry by folate complexes was demonstrably by FR mediation. These liposome formulations have the design capacity for in vivo application and may therefore be promising candidates for further development.

SYNTHESIS AND ANTIOXIDANT EVALUATION OF NOVEL PHENOTHIAZINE LINKED SUBSTITUTEDBENZYLIDENEAMINO-1,2,4-TRIAZOLE DERIVATIVES

ABSTRACT A series of novel 5-((10 H -phenothiazin-10yl)methyl)-4-(substitutedbenzylideneamino)-4 H -1,2,4-triazole-3-thiol derivatives (6a-i) have been synthesized from compound (1) through a multi-step reaction. The key intermediate (5) afforded a series of title compounds (6a–i) on condensation with various suitable aldehydes in the presence of H 2 SO 4 . The structures of novel compounds were characterized based on their elemental analysis, IR, 1 H-NMR, 13 C-NMR and MS spectral data. All these novel compounds were screened for their in vitro antioxidant activity by employing nitric oxide, hydrogen peroxide, and DPPH radical scavenging assays. The compounds 6d, 6e and 6i demonstrated potent antioxidant activity as these contain the electron-releasing groups. Keywords: Synthesis, Anti-oxidant activity, 1,2,4-Triazole, Phenothiazines. INTRODUCTION The heterocyclic compounds chemistry continues to be an emerging field in the organic and pharmaceutical chemistry 1 . Heterocyclic compounds are present in various drugs, several natural products, some vitamins, biomolecules, and biologically active compounds such as anti-inflammatory, antitumour, antimalarial, antidepressant, anti-HIV, antibiotic and antimicrobial agents etc

Synthesis, Molecular Docking Study and in vitro Anticancer Activity of Tetrazole Linked Benzochromene Derivatives.

BACKGROUND Globally, cancer is regarded as one of the biggest health concern in humans and animals and is one of the most terrifying diseases. Therefore, there is a necessity for the discovery, development and improvement of novel antitumor drug molecules which could efficiently prevent proliferative pathways and clonal expansion of cells. Heterocyclic compounds like benzochromene play a key role in the development of current pharmaceuticals, natural resources, agriculture products, analytical reagents and dyes. Therefore, anticancer drugs show increased resistance, it is essential to designing the novel structured heterocyclic moieties to create potential anticancer agents with promising biological applications. OBJECTIVE To synthesis a novel 1-(substitutedphenyl)-2-(1H-tetrazol-5-yl)-1H-benzo[f]chromene-3-amine derivatives for in vitro antitumour activity. METHOD The reaction of 3-amino-1-(substitutedphenyl)-1H-benzo[f]chromene-2-carbonitrile with sodium azide, ammonium chloride in dimethyl formamide solvent under reflux condition for 4 h afforded products (3a-k). The synthesized molecules were subjected to possible potential anti-tumour activity in vitro in four human cancer cell lines (MCF-7, Caco-2, HeLa and SKBR-3), and one human non-cancer cell line (HEK293), using the MTT cell viability assay. RESULTS A novel series of products (3a-k) were synthesized with good yield and were identified with 1H NMR, 15N NMR, 13C NMR, FT-IR and HR-MS spectrum. The most potent compounds 3d, 3e, and 3f possessing the greatest cytotoxicity activity with IC50 values slightly higher (15-33 μM) than that of 5-Fluorouracil (10-17 μM), indicating their potential to be antitumor agents. The 3a, 3b, 3c, 3h, 3i and 3j compounds showed moderate activity. Additionally, a molecular docking analysis was conducted to predict the multi-drug resistance modulator behavior of synthesized compounds in the ATP binding site of P-glycoprotein. CONCLUSIONS We synthesized and designated eleven novel derivatives of tetrazole linked benzochromenes (3a-k) and evaluated their anti-cancer activity. Additionally, the results from the docking studies were found to be in good agreement with the results from computational profiling.