Discovery of benzenesulfonamide derivatives as potent PI3K/mTOR dual inhibitors with in vivo efficacies against hepatocellular carcinoma. Issue 5 (1st March 2016)

• Record Type: Journal Article
• Authors: Chen, Ying; Zhang, Ling; Yang, Chao; Han, Jinsong; Wang, Chongqing; Zheng, Canhui; Zhou, Youjun; Lv, Jiaguo; Song, Yunlong; Zhu, Ju
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 5(2016)
• Page Start: 957
• Page End: 966
• Publication Date: 2016-03-01
• Subjects: BBRINJUWZRLWKK-UHFFFAOYSA-N; AKT protein kinase B -- CREB cAMP response element binding protein -- FoxO Forkhead box O -- GI50 drug concentration yielding 50% growth inhibition -- HCC hepatocellular carcinoma -- IC50 drug concentration yielding 50% inhibition -- MTT 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- PI3K phosphoinositide 3-kinase -- mTOR mammalian target of rapamycin -- PIP2 phosphatidylinositol 4, 5-bisphosphate -- PIP3 phosphatidylinositol 3, 4, 5-trisphosphate; Phosphoinositide 3-kinase (PI3K) -- Dual inhibitors -- Hepatocellular carcinoma -- Benzenesulfonamide derivatives -- Antitumor -- Mammalian target of rapamycin (mTOR); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.01.008
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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. Compound7k (NSC781406) was identified as a highly potent dual inhibitor, which exhibited potent tumor growth inhibition in the hepatocellular carcinoma BEL-7404 xenograft model. Compound7k may be a potential therapeutic drug candidate for HCC.