ArticleJournal of medicinal chemistry2012
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.
Article in Journal of medicinal chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 53 citations in OpenAlex.
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- Hypoxia-induced signaling in the cardiovascular system: pathogenesis and therapeutic targets.Signal transduction and targeted therapy · 2023Review
- Glioblastoma: Current Status, Emerging Targets, and Recent Advances.Journal of medicinal chemistry · 2022Review
- Enantioselective one-pot synthesis of 4RSC advances · 2020Article
- Design, synthesis, ADME prediction and pharmacological evaluation of novel benzimidazole-1,2,3-triazole-sulfonamide hybrids as antimicrobial and antiproliferative agents.Chemistry Central journal · 2018Article
- Purifying Properly Folded Cysteine-rich, Zinc Finger Containing Recombinant Proteins for Structural Drug Targeting Studies: the CH1 Domain of p300 as a Case Example.Bio-protocol · 2017Article
- Biology of advanced uveal melanoma and next steps for clinical therapeutics.Pigment cell & melanoma research · 2015Review
- Synthesis and Biological Investigation of some Novel Sulfonamide and Amide Derivatives Containing Coumarin Moieties.Iranian journal of pharmaceutical research : IJPR · 2014Article
- Hypoxia inducible factor pathway inhibitors as anticancer therapeutics.Future medicinal chemistry · 2013Review
- Arylsulfonamide KCN1 inhibits in vivo glioma growth and interferes with HIF signaling by disrupting HIF-1α interaction with cofactors p300/CBP.Clinical cancer research : an official journal of the American Association for Cancer Research · 2012Article
- Binding Model for the Interaction of Anticancer Arylsulfonamides with the p300 Transcription Cofactor.ACS medicinal chemistry letters · 2012Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
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.
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