ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

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

Kirill P. Cheremnykh, Dmitry S. Baev, Elizaveta A. Nacharova, Mikhail A. Pokrovskii, Victor A. Savelyev, Yulia V. Meshkova, Mariya K. Marenina, Tatyana G. Tolstikova, Andrey G. Pokrovskii, and Elvira E. Shults

Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation

E-mail: schultz@nioch.nsc.ru

Received: 24 October 2023  Accepted: 6 May 2024

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.

Graphical abstract

Keywords: Anthranilic acid; Palladium catalyst; Aminocarbonylation reaction; Cytotoxicity; Molecular docking

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-024-03508-0

Chemical Papers 78 (9) 5639–5656 (2024)