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N ′‐Alkylaminosulfonyl Analogues of 6‐Fluorobenzylideneindolinones with Desirable Physicochemical Profiles and Potent Growth Inhibitory Activities on Hepatocellular Carcinoma
Author(s) -
Chen Xiao,
Yang Tianming,
Deivasigamani Amudha,
Shanmugam Muthu K.,
Hui KamMan,
Sethi Gautam,
Go MeiLin
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500235
Subject(s) - hepatocellular carcinoma , inhibitory postsynaptic potential , chemistry , cancer research , carcinoma , biochemistry , pharmacology , biology , endocrinology , genetics
The benzylideneindolinone 6‐chloro‐3‐(3′‐trifluoromethylbenzylidene)‐1,3‐dihydroindol‐2‐one ( 4 ) was reported to exhibit potent and selective growth inhibitory effects on hepatocellular carcinoma (HCC). Corroborative evidence supported multi‐receptor tyrosine kinase (RTK) inhibition as a possible mode of action. However, the poor physicochemical properties of 4 limited its furtherance as a lead compound. In this study, the modification of 4 was investigated with the aim of improving its potency and physicochemical profile. The 6‐fluorobenzylideneindolinone 3‐12 bearing a 3′‐ N ‐propylaminosulfonyl substituent was found to be a promising substitute. Compound 3‐12 [6‐fluoro‐3‐(3′‐ N ‐propylaminosulfonylbenzylidene)‐1,3‐dihydroindol‐2‐one] was found to be tenfold more soluble than 4 and to have sub‐micromolar growth inhibitory activities on HCC cells. It is apoptogenic and inhibits the phosphorylation of several RTKs in HuH7, of which the inhibition of FGFR4 and HER3 are prominent. Compound 3‐12 decreased the tumor load in a physiologically relevant orthotopic HCC xenograft murine model. Structure–activity relationships support pivotal roles for the fluoro and N ′‐propylaminosulfonyl moieties in enhancing cell‐based activity and moderating the physicochemical profile (solubility, permeability) of 3‐12 .