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Discovery of novel quinoline-based mTOR inhibitors via introducing intra-molecular hydrogen bonding scaffold (iMHBS): The design, synthesis and biological evaluation.

Abstract：

:A series of quinoline derivatives featuring the novelty of introducing intra-molecular hydrogen bonding scaffold (iMHBS) were designed, synthesized and biologically evaluated for their mTOR inhibitory activity, as well as anti-proliferative efficacies against HCT-116, PC-3 and MCF-7 cell lines. As a result, six compounds exhibited significant inhibition against mTOR with IC50 values below 35nM. Compound 15a, the most potent mTOR inhibitor reported herein (IC50=14nM), also displayed the most favorable cellular activities, with the IC50 values of 0.46, 0.61 and 0.24μM against HCT-116, PC-3 and MCF-7, respectively. Besides, several compounds in this series were identified to be selective over class I PI3Ks. Further western blot analysis of 16b, a representative compound in this series, highlighted their advantage in surmounting the S6K/IRS1/PI3K negative feedback loop upon dual inhibition of mTORC1 and mTORC2. In addition to the remarkable activity, 15a demonstrated acceptable stability in simulated gastric fluid (SGF), simulated intestinal fluid (SIF) and liver microsome, thereby being valuable for extensive in vivo investigation.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Ma X,Lv X,Qiu N,Yang B,He Q,Hu Y

doi

10.1016/j.bmc.2015.11.003

subject

Has Abstract

pub_date

2015-12-15 00:00:00

pages

7585-96

issue

24

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(15)30128-0

journal_volume

23

pub_type

杂志文章

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