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.
Ying Chen  1 ,  Ling Zhang  1 ,  Chao Yang  1 ,  Jinsong Han  1 ,  Chongqing Wang  1 ,  Canhui Zheng  1 ,  Youjun Zhou  1 ,  Jiaguo Lv  1 ,  Yunlong Song  2 ,  Ju Zhu  3
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: [email protected].
  • 3. Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. Electronic address: [email protected].
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).
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