TY - JOUR

T1 - Aminocarbonylation of 2-(N-substituted) 5-iodobenzoates: synthesis of glyoxylamido-anthranilates, their cytotoxicity and molecular modeling study

AU - Cheremnykh, Kirill P.

AU - Baev, Dmitry S.

AU - Nacharova, Elizaveta A.

AU - Pokrovskii, Mikhail A.

AU - Savelyev, Victor A.

AU - Meshkova, Yulia V.

AU - Marenina, Mariya K.

AU - Tolstikova, Tatyana G.

AU - Pokrovskii, Andrey G.

AU - Shults, Elvira E.

N1 - This work was supported from the Russian Science Foundation, Grant Number: 23-73-00077.

PY - 2024/6

Y1 - 2024/6

N2 - 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: (Figure presented.)

AB - 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: (Figure presented.)

KW - Aminocarbonylation reaction

KW - Anthranilic acid

KW - Cytotoxicity

KW - Molecular docking

KW - Palladium catalyst

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85192818484&origin=inward&txGid=17e20c9c099dbad3c05f604a44ef7910

UR - https://www.mendeley.com/catalogue/94938ec5-e83d-3b00-ba96-1263f9f97859/

U2 - 10.1007/s11696-024-03508-0

DO - 10.1007/s11696-024-03508-0

M3 - Article

VL - 78

SP - 5639

EP - 5656

JO - Chemical Papers

JF - Chemical Papers

SN - 0366-6352

IS - 9

ER -