title: Design and in vitro activities of N-alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides, novel, small-molecule hypoxia inducible factor-1 pathway inhibitors and anticancer agents.
abstract: The hypoxia inducible factor (HIF) pathway is an attractive target for cancer, as it controls tumor adaptation to growth under hypoxia and mediates chemotherapy and radiation resistance. We previously discovered 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide as a novel, small-molecule HIF-1 pathway inhibitor in a high-throughput cell-based assay, but its in vivo delivery is hampered by poor aqueous solubility (0.009 μM in water; log P(7.4) = 3.7). Here we describe the synthesis of 12 N-alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides, which were designed to possess optimal lipophilicities and aqueous solubilities by in silico calculations. Experimental log P(7.4) values of 8 of the 12 new analogs ranged from 1.2-3.1. Aqueous solubilities of three analogs were measured, among which the most soluble N-[(8-methoxy-2,2-dimethyl-2H-chromen-6-yl)methyl]-N-(propan-2-yl)pyridine-2-sulfonamide had an aqueous solubility of 80 μM, e.g., a solubility improvement of ∼9000-fold. The pharmacological optimization had limited impact on drug efficacy as the compounds retained IC(50) values at or below 5 μM in our HIF-dependent reporter assay.
authors: Department of Radiology and Imaging Sciences, Emory University CSI , Wesley Woods Health Center, 1841 Clifton Road, NE, Atlanta, Georgia 30329, United States.
authors: Jiyoung
authors: J
authors: Mun
authors: Adnan Abdul
authors: AA
authors: Jabbar
authors: Narra Sarojini
authors: NS
authors: Devi
authors: Shaoman
authors: S
authors: Yin
authors: Yingzhe
authors: Y
authors: Wang
authors: Chalet
authors: C
authors: Tan
authors: Deborah
authors: D
authors: Culver
authors: James P
authors: JP
authors: Snyder
authors: Erwin G
authors: EG
authors: Van Meir
authors: Mark M
authors: MM
authors: Goodman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D015398:Signal Transduction; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001578:Benzopyrans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D013449:Sulfonamides