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 (HIF-1) pathway inhibitors and anti-cancer agents

• Authors: Jiyoung Mun, Emory University; Adnan Abdul Jabbar, Emory University; Narra Sarojini Devi, Emory University; Shaoman Yin, Emory University; Yingzhe Wang, Mercer University College of Pharmacy; Chalet Tan, Mercer University College of Pharmacy; Deborah Culver, Emory University; James P Snyder, Emory University; Erwin Van Meir, Emory University; Mark M. Goodman, Emory University
• Journal Title: Journal of Medicinal Chemistry
• Volume: Volume 55, Number 15
• Publisher: American Chemical Society | 2012-08-09, Pages 6738-6750
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1021/jm300752n
• Subjects: Health Sciences, Radiology; Health Sciences, Oncology; Biology, Neuroscience
• Keywords: drug discovery; HIF pathway inhibitors; anticancer drug; Hypoxia Inducible Factor; N-alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides; a HRE-mediated luciferase assay; HIF-1α western blotting assay; logP7.4; drug aqueous solubility; sulforhodamine B (SRB) cytotoxicity assay; clonogenic cytotoxicity assay; glioma; brain tumor

Abstract

The Hypoxia Inducible Factor (HIF) pathway is an attractive target for cancer as it controls tumor adaptation to growth under hypoxia and mediates chemo- 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; logP7.4: 3.7). Here we describe the synthesis of twelve 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 logP7.4 values of 8 of the 12 new analogs ranged from 1.2 ∼ 3.1. Aqueous solubilities of 3 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 ∼9,000-fold. The pharmacological optimization had minimal impact on drug efficacy as the compounds retained IC50 values at or below 5 μM in our HIF-dependent reporter assay.