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Design, Synthesis, anticancer evaluation and in silico studies of 2,4,6-trimethoxychalcone derivatives.

ABSTRACT: Chalcone, a common chemical scaffold of many naturally occurring compounds, has been widely used as an effective template for drug discovery due to its broad biological activities. In this study, a series of chalcone derivatives were designed and synthesized based on the hybridization of 1-(2,4,6-trimethoxyphenyl)butan-1-one with chalcone. Interestingly, most of the target compounds exhibited inhibitory effect of tumor cells in vitro. Especially, (E)-3-(5-bromopyridin-2-yl)-1-(2,4,6-trimethoxyphenyl)prop-2-en-1-one (B3) revealed over 10-fold potency than 5-fluorocrail against the Hela and MCF-7 cells with IC₅₀ values of 3.204 and 3.849 μM respectively. Moreover, B3 displayed low toxicity on normal cells. Further experiments indicated that B3 effectively inhibited the proliferation and migration of tumor cells, and promoted their apoptosis. The calculation and prediction of ADME showed that the target compounds may have good pharmacokinetic properties and oral bioavailability. Reverse molecular docking suggested that the possible target of B3 is CDK1. Taken together, these results suggested that B3 appears to be a promising candidate that merits further attention in the development of anticancer drugs.

SUBMITTER: Li T

PROVIDER: S-EPMC9845116 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Design, Synthesis, anticancer evaluation and in silico studies of 2,4,6-trimethoxychalcone derivatives.

Li Tong T Li Weiwei W Yang Xianjing X Chen Gong G Jin Xiaobao X Chen Weiqiang W Ye Lianbao L

Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society 20221116 1

Chalcone, a common chemical scaffold of many naturally occurring compounds, has been widely used as an effective template for drug discovery due to its broad biological activities. In this study, a series of chalcone derivatives were designed and synthesized based on the hybridization of 1-(2,4,6-trimethoxyphenyl)butan-1-one with chalcone. Interestingly, most of the target compounds exhibited inhibitory effect of tumor cells in vitro. Especially, (E)-3-(5-bromopyridin-2-yl)-1-(2,4,6-trimethoxyph ...[more]

PMID: 36685294

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Project description:Curcumin, a widely utilized flavor and coloring agent in food, has been shown to demonstrate powerful antioxidant, antitumor promoting and anti-inflammatory properties in vitro and in vivo. In the present work, synthesis of new heterocyclic derivatives based on Curcumin was studied. Compound 3 was synthesized via the reaction of furochromone carbaldehyde (1) with Curcumin (2) using pipredine as catalyst. Also, novel, 4,9-dimethoxy-5H-furo [3, 2-g] chromen-5-one derivatives 4a?d, 6a?d, 7, 8a?d, 9 and 10 were synthesized by the reactions of furochromone carbaldehyde (1) with different reagents (namely: appropriate amine 3a?d, appropriate hydrazine 5a?d, hydroxylamine hydrochloride, urea/thiourea, malononitrile, malononitrile with hydrazine hydrate). The structure of the synthesized products had been confirmed from their spectroscopic data (IR, ¹H-NMR, 13C-NMR and mass spectra). In the present investigation, the newly synthesized products were screened using the MTT colorimetric assay for their in vitro inhibition capacity in two human cancer cell lines (hepatocellular carcinoma (HEPG2) and breast cancer (MCF-7) as well as the normal cell line (human normal melanocyte, HFB4) in comparison to the known anticancer drugs: 5-flurouracil and doxorubicin. The anticancer activity results indicated that the synthesized products 4c and 8b showed growth inhibition activity against HEPG2 cell line and synthesized products 4b and 8a showed growth inhibition activity against MCF-7, but with varying intensities in comparison to the known anticancer drugs, 5-flurouracil and doxorubicin. Cyclin dependent kinase 2 (CDK2), a major cell cycle protein, was identified as a potential molecular target of Curcumin. Furthermore, Curcumin induced G1 cell cycle arrest, which is regulated by CDK2 in cancer cells. Therefore, we used molecular modelling to study in silico the possible inhibitory effect of CDK2 by Curcumin derivatives as a possible mechanism of these compounds as anticancer agents. The molecular docking study revealed that compounds 4b, 8a and 8b were the most effective compounds in inhibiting CDk2, and, this result was in agreement with cytotoxicity assay.

Dataset Information

Design, Synthesis, anticancer evaluation and in silico studies of 2,4,6-trimethoxychalcone derivatives.

Publications

Design, Synthesis, anticancer evaluation and in silico studies of 2,4,6-trimethoxychalcone derivatives.

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