Design, synthesis and biological activity of N5-substituted tetrahydropteroate analogs as non-classical antifolates against cobalamin-dependent methionine synthase and potential anticancer agents.
Eur J Med Chem
; 190: 112113, 2020 Mar 15.
Article
en En
| MEDLINE
| ID: mdl-32058237
ABSTRACT
Cobalamin-dependent methionine synthase (MetH) is involved in the process of tumor cell growth and survival. In this study, a novel series of N5-electrophilic substituted tetrahydropteroate analogs without glutamate residue were designed as non-classical antifolates and evaluated for their inhibitory activities against MetH. In addition, the cytotoxicity of target compounds was evaluated in human tumor cell lines. With N5-chloracetyl as the optimum group, further structure research on the benzene substituent and on the 2,4-diamino group was also performed. Compound 6c, with IC50 value of 12.1 µM against MetH and 0.16-6.12 µM against five cancer cells, acted as competitive inhibitor of MetH. Flow cytometry studies indicated that compound 6c arrested HL-60 cells in the G1-phase and then inducted late apoptosis. The molecular docking further explained the structure-activity relationship.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Pterinas
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5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa
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Inhibidores Enzimáticos
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Antagonistas del Ácido Fólico
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Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2020
Tipo del documento:
Article
País de afiliación:
China