Synthesis and initial evaluation of quinoline-based inhibitors of the SH2-containing inositol 5′-phosphatase (SHIP)

Christopher M. Russo, Arijit A. Adhikari, Daniel R. Wallach, Sandra Fernandes, Amanda N. Balch, William G. Kerr, John D. Chisholm

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Recently, inhibition of the SH2-containing inositol 5′-phosphatase 1 (SHIP1) has become an attractive strategy for facilitating engraftment of MHC-I mismatched bone marrow grafts, increasing the number of adult stem cells in vivo, and inducing mobilization of hematopoietic stem cells. Utilizing high-throughput screening, two quinoline small molecules (NSC13480 and NSC305787) that inhibit SHIP1 enzymatic activity were discovered. New syntheses of these inhibitors have been developed which verified the relative stereochemistry of these structures. Utilizing this synthetic route, some analogs of these quinolines have been prepared and tested for their ability to inhibit SHIP. These structure activity studies determined that an amine tethered to the quinoline core is required for SHIP inhibition. SHIP inhibition may explain the antitumor effects of similar quinoline amino alcohols and provides an impetus for further synthetic studies in this class of compounds.

Original languageEnglish (US)
Pages (from-to)5344-5348
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume25
Issue number22
DOIs
StatePublished - Nov 15 2015

Keywords

  • Inhibitor
  • Inositol
  • Phosphatase
  • Quinoline
  • SHIP

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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