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Aminocarbonylation of 2-(N-substituted) 5-iodobenzoates: synthesis of glyoxylamido-anthranilates, their cytotoxicity and molecular modeling study

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Abstract

The aminocarbonylation of ethyl 2-substituted 5-iodobenzoate has been investigated in the presence of a series of amine nucleophiles, providing an efficient synthetic route for producing various 5-carboxamide and 5-glyoxylamide derivatives of 2-(N-substituted) ethylbenzoates. It was shown, after detailed optimization study, that the formation of amides and α-ketoamides is strongly influenced by the reaction conditions. Performing the reactions of ethyl 2-substituted 5-iodobenzoate with nitrogen nucleophiles at 1 atm of carbon monoxide pressure in the presence of [Pd(η3-C3H5)(μ-Cl)]2 as a palladium source and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) as the base, the corresponding 2-ketocarboxamides were formed as major products (up to 60%). We have characterized the cytotoxicity (MTT test) and SAR of a new class of 2-(N-substituted) ethylbenzoate 5-amides and 5-(α-keto)amides. 5-Glyoxylamido derivatives 9a,b, 14a,d exhibited remarkably good cytotoxic potential on MCF-7 and T98G cancer cell lines. In addition, all the synthesized compounds were found to be non-toxic against normal cells (DF-2). The readily available nitrogen substituted 5-glyoxylamido-2-(N-acetylamino)ethylbenzoates 14a,d may serve as lead molecules for the future research regarding the identification of new anticancer agents. These novel compounds were confirmed to be cyclin-dependent kinase 6 and 9 (CDK6 and 9) inhibitors through in silico molecular modeling studies for the mode of action.

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Acknowledgements

We thank the Multi-Access Chemical Research Center SB RAS for spectral and analytical measurements.

Funding

This work was supported from the Russian Science Foundation, Grant Number: 23-73-00077.

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KPC: synthesis, analysis, writing; DSB: docking studies, analysis, writing; EAN: synthesis, analysis; MAP, YBM and MKM: cytotoxicity studies; VAS: synthesis, analysis, review; TGT, AGP: review and editing; EES: writing—review and editing, supervision.

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Correspondence to Elvira E. Shults.

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The work is not applicable for both human and/or animal studies.

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Cheremnykh, K.P., Baev, D.S., Nacharova, E.A. et al. Aminocarbonylation of 2-(N-substituted) 5-iodobenzoates: synthesis of glyoxylamido-anthranilates, their cytotoxicity and molecular modeling study. Chem. Pap. (2024). https://doi.org/10.1007/s11696-024-03508-0

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