Design, synthesis and biological evaluation of N-phenyl-(2,4-dihydroxypyrimidine-5-sulfonamido)benzoyl hydrazide derivatives as thymidylate synthase (TS) inhibitors and as potential antitumor drugs.
Eur J Med Chem
; 154: 267-279, 2018 Jun 25.
Article
en En
| MEDLINE
| ID: mdl-29807332
ABSTRACT
The Inhibition of cellular nucleotide metabolism to promote apoptosis is a key principle of cancer therapy. Thymidylate synthase (TS) is a key rate-limiting enzyme in the initiation of DNA synthesis in cell. Here, we presented two types of thymidylate synthase inhibitors, and, the key pharmacological properties of these two types of thymidylate synthase inhibitor were extracted and combined to design new compounds with inhibitory activity. Therefore, two series of 42 new compounds with the common biological effect of promoting apoptosis are designed and synthesized by combination principle. Most of the compounds had good anti-proliferative activity on A549, OVCAR-3, SGC7901 and MDA-MB-231â¯cells. The IC50 of compound 10l on A549â¯cells was 1.26⯵M, which was better than that of pemetrexed (PTX, IC50â¯=â¯3.31⯵M), furthermore, the selection index of compound 10l was higher than PTX. Flow cytometry analysis showed that compound 10l (the apoptosis rate is 39.4%) could induce A549â¯cell apoptosis and effectively inhibit tumor cell proliferation. Further western blot analysis showed that compound 10l could induce intrinsic apoptosis by activating caspase-3, increasing expression of cleaved caspase-3 and reducing the ratio of bcl-2/bax. All of this makes compound 10l to be a promising compound in future animal tumor models.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Sulfonamidas
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Timidilato Sintasa
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Diseño de Fármacos
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Inhibidores Enzimáticos
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Hidrazinas
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Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2018
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
FR
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FRANCE
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FRANCIA
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FRANÇA