RESUMO
A novel series of 2,6-diamino-3-acylpyridines were designed and synthesized as cyclin-dependent kinase (CDK) inhibitors. The representative compounds 2r and 11 showed potent CDK1 and CDK2 inhibitory activities and inhibited cellular proliferation in HeLa, HCT116, and A375 tumor cells.
Assuntos
Aminopiridinas/síntese química , Aminopiridinas/farmacologia , Divisão Celular/efeitos dos fármacos , Quinases Ciclina-Dependentes/antagonistas & inibidores , Diaminas/síntese química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Diaminas/farmacologia , Células HeLa , Humanos , Modelos Moleculares , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
Benzonitrile oxides undergo 1,3-dipolar cycloaddition reactions with methyl cinnamate to produce the 5-phenyl and 4-phenyl regioisomers in approximately an 80:20 ratio. However, use of N,N-diethylcinnamide as the dipolarophile unexpectedly resulted in the formation of the 5-phenyl and 4-phenyl regioisomers in a 23:77 ratio. Studies have shown that this phenomena occurs only for tertiary cinnamides. In addition, it has been demonstrated that the phenyl group of tertiary cinnamides is not essential for the reversal of regioselectivity since crotonamides produce the same results and trends as the cinnamides. However, since acrylates and acrylamides both produce the 5-carbonyl regioisomers, it can be concluded that the beta-substituent is playing a key role for the unexpected results by possibly increasing steric interactions between the dipole and dipolarophile in the transition state. Transition state energies were calculated for the regioisomeric cycloadduct pairs derived from several crotonamides as well as methyl crotonate. These calculations indicate that steric factors are indeed responsible for the reversal of regioselectivity.
