Design and in Vitro Activities of <i>N</i>-Alkyl-<i>N</i>-[(8-<i>R</i>-2,2-dimethyl-2<i>H</i>-chromen-6-yl)methyl]heteroarylsulfonamides, Novel, Small-Molecule Hypoxia Inducible Factor-1 Pathway Inhibitors and Anticancer Agents

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-<i>N</i>-[(2,2-dimethyl-2<i>H</i>-chromen-6-yl)­methyl]-<i>N</i>-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 <i>P</i>_7.4 = 3.7). Here we describe the synthesis of 12 <i>N</i>-alkyl-<i>N</i>-[(8-<i>R</i>-2,2-dimethyl-2<i>H</i>-chromen-6-yl)­methyl]­heteroarylsulfonamides, which were designed to possess optimal lipophilicities and aqueous solubilities by in silico calculations. Experimental log <i>P</i>_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 <i>N</i>-[(8-methoxy-2,2-dimethyl-2<i>H</i>-chromen-6-yl)­methyl]-<i>N</i>-(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 IC₅₀ values at or below 5 μM in our HIF-dependent reporter assay

Discovery of Tetrahydroisoquinoline-Based CXCR4 Antagonists

A de novo hit-to-lead effort involving the redesign of benzimidazole-containing antagonists of the CXCR4 receptor resulted in the discovery of a novel series of 1,2,3,4-tetrahydroisoquinoline (TIQ) analogues. In general, this series of compounds show good potencies (3–650 nM) in assays involving CXCR4 function, including both inhibition of attachment of X4 HIV-1_IIIB virus in MAGI-CCR5/CXCR4 cells and inhibition of calcium release in Chem-1 cells. Series profiling permitted the identification of TIQ-(<i>R</i>)-stereoisomer <b>15</b> as a potent and selective CXCR4 antagonist lead candidate with a promising in vitro profile. The drug-like properties of <b>15</b> were determined in ADME in vitro studies, revealing low metabolic liability potential. Further in vivo evaluations included pharmacokinetic experiments in rats and mice, where <b>15</b> was shown to have oral bioavailability (<i>F</i> = 63%) and resulted in the mobilization of white blood cells (WBCs) in a dose-dependent manner