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 Inhib

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• 作者：Jiyoung Mun ; Adnan Abdul Jabbar ; Narra Sarojini Devi ; Shaoman Yin ; Yingzhe Wang ; Chalet Tan ; Deborah Culver ; James P. Snyder ; Erwin G. Van Meir ; Mark M. Goodman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：August 9, 2012
• 年：2012
• 卷：55
• 期：15
• 页码：6738-6750
• 全文大小：444K
• 年卷期：v.55,no.15(August 9, 2012)
• ISSN：1520-4804

文摘

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 渭M 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鈥?.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 渭M, e.g., a solubility improvement of 9000-fold. The pharmacological optimization had limited impact on drug efficacy as the compounds retained IC₅₀ values at or below 5 渭M in our HIF-dependent reporter assay.