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Author Notes:

Corresponding authors: EG Van Meir, tel.: +1 404 778 5563, fax: +1 404 778 5550, email: evanmei@emory.edu; MM Goodman, tel.: +1 404 727 9366, fax: +1 404 712 5689, email: mgoodma@emory.edu.

Data analyses were performed in part through use of the Biostatistics and Bioinformatics shared Resource of the Winship Cancer Institute of Emory University.


Research Funding:

This research was supported by the National Cancer Institute Grants P50 CA 128301-01A1 Emory Molecular and Translational Imaging Research Center (EMTIC)/In vivo Cellular and Molecular Imaging Centers (ICMIC) (to Goodman, Hu, Meltzer), P50 CA 128301-01A1 Pilot Project #2 (to J.M.), the P30 CA 138292 Cancer Center grant (to the Winship Cancer Institute; W Curran, PI), R01 CA116804 and CA86335 (to E.G.V.M.), and the V Foundation, and Max Cure/Samuel Waxman cancer research foundation grants (to E.G.V.M.).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Physical Sciences
  • Biochemistry & Molecular Biology
  • Chemistry, Medicinal
  • Chemistry, Organic
  • Pharmacology & Pharmacy
  • Chemistry
  • Hypoxia inducible factor-1
  • Small molecule HIF-1 transcription factor inhibitors
  • Tumor hypoxia
  • 3,4-Dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide
  • Structure-activity relationships
  • Anti-cancer drugs
  • Brain cancer
  • VIVO

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


Journal Title:

Bioorganic and Medicinal Chemistry


Volume 20, Number 14


, Pages 4590-4597

Type of Work:

Article | Post-print: After Peer Review


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.

Copyright information:

© 2012 Elsevier Ltd. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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