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

• 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
• ISSN: 0366-6352; 1336-9075; 2585-7290
• DOI: 10.1007/s11696-024-03508-0

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