Design and synthesis of novel quinacrine-[1,3]-thiazinan-4-one hybrids for their anti-breast cancer activity.

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.

journal_name

Eur J Med Chem

authors

Solomon VR,Pundir S,Le HT,Lee H

doi

10.1016/j.ejmech.2017.11.097

subject

Has Abstract

pub_date

2018-01-01 00:00:00

pages

1028-1038

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(17)31000-0

journal_volume

143

pub_type

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