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Design and efficient synthesis of pyrazoline and isoxazole bridged indole C-glycoside hybrids as potential anticancer agents.

ABSTRACT: C-glycosides are important class of molecules exhibit diverse biological activities and present as structural motif in many natural products. Two series of new pyrazoline and isoxazole bridged indole C-glycoside molecular hybrids (n?=?36) were efficiently synthesized starting from diverse indole 3-carboxaldehydes derived ?, ?-unsaturated ketone derivatives of ?-D-glucosyl-propan-2-one, ?-D-galactosyl-propan-2-one and ?-D-mannosyl-propan-2-one, reacting with hydrazine hydrate and hydroxyl amine hydrochloride in shorter reaction time (15?min) under microwave assisted condition. Anticancer activity of these newly synthesized pyrazoline and isoxazole bridged indoles C-glycoside hybrids were determined in details through cellular assays against MCF-7, MDA-MB-453 and MDA-MB-231 cancer cell lines. The selected library members displayed low micromolar (IC50?=?0.67-4.67?µM) and selective toxicity against breast cancer cell line (MCF-7). Whereas these compounds were nontoxic towards normal cell line (MCF-10A). Mechanistic studies showed that, active compounds inhibit COX-2 enzyme, which was also supported by molecular docking studies. These findings are expected to provide new leads towards anticancer drug discovery.

SUBMITTER: Kumari P

PROVIDER: S-EPMC7170901 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Design and efficient synthesis of pyrazoline and isoxazole bridged indole C-glycoside hybrids as potential anticancer agents.

Kumari Priti P Mishra Vishnu S VS Narayana Chintam C Khanna Ashish A Chakrabarty Anindita A Sagar Ram R

Scientific reports 20200420 1

C-glycosides are important class of molecules exhibit diverse biological activities and present as structural motif in many natural products. Two series of new pyrazoline and isoxazole bridged indole C-glycoside molecular hybrids (n = 36) were efficiently synthesized starting from diverse indole 3-carboxaldehydes derived α, β-unsaturated ketone derivatives of β-D-glucosyl-propan-2-one, β-D-galactosyl-propan-2-one and β-D-mannosyl-propan-2-one, reacting with hydrazine hydrate and hydroxyl amine h ...[more]

PMID: 32313038

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Project description:To discover anticancer drugs with novel structures and expand our research scope, pyrazoline derivatives (3a-3l) were designed and synthesized through cyclization of chalcones with thiosemicarbazide/semicarbazide in CH3COOH as a solvent. All newly synthesized pyrazoline derivatives were fully characterized using several spectroscopic experiments such as 1H, 13C NMR, FT-IR spectroscopy, and mass analysis. By HPLC, the purity of all analogs was found above 95% and both lead compounds (3a and 3h) were also validated by HRMS. Anticancer activity of synthesized pyrazoline derivatives (3a-3l) was investigated by the MTT assay against the human lung cancer cell (A549), human cervical cancer cell (HeLa), and human primary normal lung cells (HFL-1). Staurosporine (STS) was used as a standard drug. The anticancer results showed that two potent analogs 3a and 3h exhibit excellent activity against A549 (IC50 = 13.49 ± 0.17 and 22.54 ± 0.25 μM) and HeLa cells (IC50 = 17.52 ± 0.09 and 24.14 ± 0.86 μM) and low toxicity against the HFL-1 (IC50 = 114.50 ± 0.01 and 173.20 ± 10 μM). The flow cytometry was further used to confirm the anticancer activity of potent derivatives against the A549 cancer cell line. DNA binding interaction of anticancer agents 3a and 3h with Ct-DNA has been carried out by absorption, fluorescence, EtBr (dye displacement assay), circular dichroism, cyclic voltammetry and time-resolved fluorescence, which showed noncovalent binding mode of interaction. Anticancer activity of both lead compounds (3a and 3h) may be attributed to DNA binding. The evaluation of the antioxidant potential of pyrazoline analogs 3a and 3h by 2,2-diphenyl-1-picrylhydrazyl free radical showed promising antioxidant activity with IC50 values of 0.132 ± 0.012 and 0.215 ± 0.025 μg/mL, respectively. In silico molecular docking of pyrazoline derivatives was also performed using autodock vina software against the DNA hexamer with PDB ID: 1Z3F and ADMET properties to explore their best hits.

Dataset Information

Design and efficient synthesis of pyrazoline and isoxazole bridged indole C-glycoside hybrids as potential anticancer agents.

Publications

Design and efficient synthesis of pyrazoline and isoxazole bridged indole C-glycoside hybrids as potential anticancer agents.

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