Structure-activity relationship of 2,2-dimethyl-2H-chromene based arylsulfonamide analogs of 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, a novel small molecule hypoxia inducible factor-1 (HIF-1) pathway inhibitor and anti-cancer agent.
We have discovered that 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, a novel small molecule HIF-1 pathway inhibitor, can antagonize tumor growth in animal models of cancer, but the treatment necessitates its delivery in a formulation, due to poor water solubility (<15 μg/mL; pH 7.4), evidencing that the chemotype needs further exploration of its amenability to additional chemical modifications for ultimate optimization of function and pharmacology. As a first step towards this goal we investigated the structure-activity relationships of 15 lipophilic 2,2-dimethyl-2H-chromene based arylsulfonamide analogs of 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide to find out strategies of modification. A 3,4-dimethoxybenzenesulfonyl group in region 1 showed the strongest inhibition among five arylsulfonyl groups tested. The presence of propan-2-amine in region 2 conferred the strongest inhibitory effect of the compound on HIF-1 activated transcription in a reporter assay. These findings are important as they help define the structural motifs where the 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide can be chemically modified to improve its pharmacological properties towards development as a cancer therapeutic.
Department of Radiology and Imaging Sciences, Emory University CSI, Wesley Woods Health Center, 1841 Clifton Road NE, Atlanta, GA 30329, USA.
Jiyoung
J
Mun
Adnan Abdul
AA
Jabbar
Narra Sarojini
NS
Devi
Yuan
Y
Liu
Erwin G
EG
Van Meir
Mark M
MM
Goodman
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001578:Benzopyrans / Q000737:chemistry*; D045744:Cell Line, Tumor; D017930:Genes, Reporter; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D000096926:Benzenesulfonamides
D000970:Antineoplastic Agents; D001578:Benzopyrans; D051793:Hypoxia-Inducible Factor 1; D013449:Sulfonamides; C575894:3,4-dimethoxy-N-((2,2-dimethyl-2H-chromen-6-yl)methyl)-N-phenylbenzenesulfonamide; D000096926:Benzenesulfonamides