Design and synthesis of novel quinacrine-[1,3]-thiazinan-4-one hybrids for their anti-breast cancer activity.
Eur J Med Chem
; 143: 1028-1038, 2018 Jan 01.
Article
en En
| MEDLINE
| ID: mdl-29232580
ABSTRACT
In an attempt to develop effective and safe anticancer agents, we designed, synthesized and examined 23 novel quinacrine (QC) derivatives by combining the 9-aminoacridine scaffold and the [1,3]thiazinan-4-ones group. Most of these hybrids showed strong anticancer activities, among which 3-(3-(6-chloro-2-methoxyacridin-9-ylamino)propyl)-2-(thiophen-2-yl)-1,3-thiazinan-4-one (25; VR151) effectively killed many different cancer cell types, including eight breast cancer cell lines with different genetic background, two prostate cancer and two lung cancer cell lines. In contrast, compound 25 is less effective against non-cancer cells, suggesting it may be less toxic to humans. Our data showed that cancer cells are arrested in S phase for a prolonged period due to the down-regulation of DNA replication, leading to eventual cell death. We have also shown that the S phase arrest may be resulted by the down-regulation of cyclin A coupled with the continued up-regulation of cyclin E, which coincide with the down-regulation of mTor-S6K and mTor-4EBP1 pathways.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Quinacrina
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Tiazinas
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Neoplasias de la Mama
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Diseño de Fármacos
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Antineoplásicos
Límite:
Female
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Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2018
Tipo del documento:
Article
Pais de publicación:
FR
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FRANCE
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FRANCIA
/
FRANÇA