title: Synthesis and initial evaluation of quinoline-based inhibitors of the SH2-containing inositol 5'-phosphatase (SHIP).
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.
authors.affiliation: Department of Chemistry, Syracuse University, 1-014 Center for Science and Technology, Syracuse, NY 13244-4100, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Russo
authors.affiliation: Department of Chemistry, Syracuse University, 1-014 Center for Science and Technology, Syracuse, NY 13244-4100, USA.
authors.forename: Arijit A
authors.initials: AA
authors.lastname: Adhikari
authors.affiliation: Department of Chemistry, Syracuse University, 1-014 Center for Science and Technology, Syracuse, NY 13244-4100, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Wallach
authors.affiliation: Department of Microbiology & Immunology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Fernandes
authors.affiliation: Department of Microbiology & Immunology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
authors.forename: Amanda N
authors.initials: AN
authors.lastname: Balch
authors.affiliation: Department of Microbiology & Immunology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Kerr
authors.affiliation: Department of Chemistry, Syracuse University, 1-014 Center for Science and Technology, Syracuse, NY 13244-4100, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Chisholm
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D000072181:Inositol Polyphosphate 5-Phosphatases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D018909:src Homology Domains
chemical_list: D004791:Enzyme Inhibitors; C000612924:NSC13480; C570896:NSC305787; D011804:Quinolines; D000072181:Inositol Polyphosphate 5-Phosphatases; D000218:Adamantane
keywords: Inhibitor; Inositol; Phosphatase; Quinoline; SHIP