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

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 det...

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Bibliographic Details
Published in:	Chemical papers Vol. 78; no. 9; pp. 5639 - 5656
Main Authors:	Cheremnykh, Kirill P., Baev, Dmitry S., Nacharova, Elizaveta A., Pokrovskii, Mikhail A., Savelyev, Victor A., Meshkova, Yulia V., Marenina, Mariya K., Tolstikova, Tatyana G., Pokrovskii, Andrey G., Shults, Elvira E.
Format:	Journal Article
Language:	English
Published:	Cham Springer International Publishing 01-06-2024
Subjects:	Biochemistry Biotechnology Chemistry Chemistry and Materials Science Chemistry/Food Science Industrial Chemistry/Chemical Engineering Materials Science Medicinal Chemistry Original Paper Cytotoxicity Aminocarbonylation reaction Palladium catalyst Anthranilic acid Molecular docking
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Summary:	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(η 3 -C 3 H 5 )(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. Graphical abstract
ISSN:	0366-6352 1336-9075 2585-7290
DOI:	10.1007/s11696-024-03508-0