Examining the structure-activity relationship of benzopyran-based inhibitors of the hypoxia inducible factor-1 pathway

• Type of Material: Article
• Authors: Jalisa Ferguson, Georgia State University; Zeus De Los Santos, Georgia State University; Narra Devi, Emory University; Erwin Van Meir, Emory University; Sarah Zingales, Georgia State University; Binghe Wang, Georgia State University
• Language: English
• Date: 2017-04-15
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Elsevier Ltd
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bmcl.2017.02.073
• Title of Journal or Parent Work: Bioorganic and Medicinal Chemistry Letters
• ISSN: 0960-894X
• Volume: 27
• Issue: 8
• Start Page: 1731
• End Page: 1736
• Grant/Funding Information: Financial support from the NIH (CA180805, CA116804) is gratefully acknowledged.; We also thank the GSU MBD and CDT programs for fellowships to SKZ, and a Department of Education GAANN grant (P200A120122) with Barbara Baumstark as the Principal Investigator in support of JF.
• Keywords: Physical Sciences; Hypoxia inducible factor inhibitors; HIF; Molecular docking; Life Sciences & Biomedicine; Structure-activity relationship; Chemistry; Chemistry, Medicinal; Science & Technology; Pharmacology & Pharmacy; GLIOMA GROWTH; Chemistry, Organic
• Research Categories: Biology, Neuroscience; Health Sciences, Oncology; Chemistry, General

Abstract

Many forms of solid tumor have a characteristic feature known as hypoxia, which describes a low or non-existent presence of oxygen in the cellular microenvironment. This decrease in oxygen causes activation of the hypoxia inducible factor (HIF) pathway, which activates the transcription of many genes that cause cell proliferation, metastasis, increased glycolysis and angiogenesis. Increased HIF expression has been linked with poor patient prognosis, increased malignancy, and therapeutic resistance. Previous work in our lab has identified 1 and 2 as inhibitors of the HIF pathway, specifically as disrupters of the p300-HIF-1α complex formation. A library of sulfonamide analogs has been designed and synthesized with the intent of examining the SAR of this series of compounds and improving potency and physicochemical properties as compared with lead compounds 1 and 2. At the end, we have achieved a thorough understanding of the structural features critical for future optimization work.