title: N'-Alkylaminosulfonyl Analogues of 6-Fluorobenzylideneindolinones with Desirable Physicochemical Profiles and Potent Growth Inhibitory Activities on Hepatocellular Carcinoma.
abstract: 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.
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543 (Republic of Singapore).
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543 (Republic of Singapore).
authors.forename: Tianming
authors.initials: T
authors.lastname: Yang
authors.affiliation: National Cancer Centre, 11 Hospital Drive, Singapore 169610 (Republic of Singapore).
authors.forename: Amudha
authors.initials: A
authors.lastname: Deivasigamani
authors.affiliation: Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Singapore 117597 (Republic of Singapore).
authors.forename: Muthu K
authors.initials: MK
authors.lastname: Shanmugam
authors.affiliation: National Cancer Centre, 11 Hospital Drive, Singapore 169610 (Republic of Singapore).
authors.forename: Kam-Man
authors.initials: KM
authors.lastname: Hui
authors.affiliation: Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Singapore 117597 (Republic of Singapore).
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543 (Republic of Singapore). phagoml@nus.edu.sg.
authors.forename: Mei-Lin
authors.initials: ML
authors.lastname: Go
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D060326:Chemistry Techniques, Synthetic; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: C000608412:6-fluoro-3-(3'-N-propylaminosulfonylbenzylidene)-1,3-dihydroindol-2-one; D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C581292:ERBB3 protein, human; C496371:FGFR4 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D020893:Receptor, ErbB-3; D051499:Receptor, Fibroblast Growth Factor, Type 4
keywords: antitumor agents; benzylideneindolinones; drug-like properties; multi-target kinase inhibitors