Synthesis and antitumor activity evaluation of PI3K inhibitors containing 3-substituted quinazolin-4(3H)-one moiety

Hao Zhang; Min-Hang Xin; Xiao-Xiao Xie; Shuai Mao; Sai-Jie Zuo; She-Min Lu; San-Qi Zhang

doi:10.1016/j.bmc.2015.11.027

Synthesis and antitumor activity evaluation of PI3K inhibitors containing 3-substituted quinazolin-4(3H)-one moiety

Bioorg Med Chem. 2015 Dec 15;23(24):7765-76. doi: 10.1016/j.bmc.2015.11.027. Epub 2015 Nov 22.

Authors

Hao Zhang¹, Min-Hang Xin¹, Xiao-Xiao Xie¹, Shuai Mao¹, Sai-Jie Zuo¹, She-Min Lu², San-Qi Zhang³

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
² Department of Genetics and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
³ Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China. Electronic address: [email protected].

PMID: 26652969
DOI: 10.1016/j.bmc.2015.11.027

Abstract

In present study, a series of N-(2-methoxy-5-(3-substituted quinazolin-4(3H)-one-6-yl)-pyridin-3-yl)phenylsulfonamide were synthesized. Their antiproliferative activities in vitro were evaluated via MTT assay against HCT116 and MCF-7 cancer cell lines. The SAR of title compounds was discussed. The compounds (S)-C5 and (S)-C8 displayed potent inhibitory activity against PI3Ks and mTOR, especially against PI3Kα. In addition, compound (S)-C5 can efficaciously inhibit tumor growth in a mice S-180 model. These findings suggest that our designed compounds can serve as potent PI3K inhibitors and effective anticancer agents.

Keywords: Antitumor activity; PI3K inhibitor; Quinazolin-4(3H)-ones; Synthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / therapeutic use*
Cell Line, Tumor
Class I Phosphatidylinositol 3-Kinases
Humans
Mice
Models, Molecular
Neoplasms / drug therapy*
Neoplasms / metabolism
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / therapeutic use
Quinazolinones / chemical synthesis
Quinazolinones / chemistry*
Quinazolinones / therapeutic use*
TOR Serine-Threonine Kinases / antagonists & inhibitors
TOR Serine-Threonine Kinases / metabolism

Substances

Antineoplastic Agents
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Quinazolinones
4-hydroxyquinazoline
Class I Phosphatidylinositol 3-Kinases
PIK3CA protein, human
TOR Serine-Threonine Kinases