Discovery of benzenesulfonamide derivatives as potent PI3K/mTOR dual inhibitors with in vivo efficacies against hepatocellular carcinoma

Ying Chen; Ling Zhang; Chao Yang; Jinsong Han; Chongqing Wang; Canhui Zheng; Youjun Zhou; Jiaguo Lv; Yunlong Song; Ju Zhu

doi:10.1016/j.bmc.2016.01.008

Discovery of benzenesulfonamide derivatives as potent PI3K/mTOR dual inhibitors with in vivo efficacies against hepatocellular carcinoma

Bioorg Med Chem. 2016 Mar 1;24(5):957-66. doi: 10.1016/j.bmc.2016.01.008. Epub 2016 Jan 6.

Authors

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
² Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. Electronic address: ylsong@smmu.edu.cn.
³ Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. Electronic address: zhuju@smmu.edu.cn.

PMID: 26819001
DOI: 10.1016/j.bmc.2016.01.008

Abstract

The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is related to cellular activities. Abnormalities of this signaling pathway were discovered in various cancers, including hepatocellular carcinoma (HCC). The PI3K/mTOR dual inhibitors were proposed to have enhanced antitumor efficacies by targeting multiple points of the signaling pathway. We synthesized a series of propynyl-substituted benzenesulfonamide derivatives as PI3K/mTOR dual inhibitors. Compound 7k (NSC781406) was identified as a highly potent dual inhibitor, which exhibited potent tumor growth inhibition in the hepatocellular carcinoma BEL-7404 xenograft model. Compound 7k may be a potential therapeutic drug candidate for HCC.

Keywords: Antitumor; Benzenesulfonamide derivatives; Dual inhibitors; Hepatocellular carcinoma; Mammalian target of rapamycin (mTOR); Phosphoinositide 3-kinase (PI3K).

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use*
Benzenesulfonamides
Carcinoma, Hepatocellular / drug therapy*
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology
Cell Line, Tumor
Humans
Liver / drug effects
Liver / metabolism
Liver / pathology
Liver Neoplasms / drug therapy*
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Male
Mice, Inbred BALB C
Mice, Nude
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use*
Proto-Oncogene Proteins c-akt / antagonists & inhibitors
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction / drug effects
Sulfonamides / chemistry
Sulfonamides / pharmacology
Sulfonamides / therapeutic use*
TOR Serine-Threonine Kinases / antagonists & inhibitors*
TOR Serine-Threonine Kinases / metabolism

Substances

Antineoplastic Agents
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Sulfonamides
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases