title: Synthesis and Cytotoxicity Evaluation of C4- and C5-Modified Analogues of the α,β-Unsaturated Lactone of Pironetin.
abstract: Pironetin is a natural product with potent antiproliferative activity that forms a covalent adduct with α-tubulin via conjugate addition into the natural product's α,β-unsaturated lactone. Although pironetin's α,β-unsaturated lactone is involved in its binding to tubulin, the structure-activity relationship at different positions of the lactone have not been thoroughly evaluated. For a systematic evaluation of the structure-activity relationships at the C4 and C5 positions of the α,β-unsaturated lactone of pironetin, twelve analogues of the natural product were prepared by total synthesis. Modifying the stereochemistry at the C4 and/or C5 positions of the α,β-unsaturated lactone of pironetin resulted in loss of antiproliferative activity in OVCAR5 ovarian cancer cells. While changing the C4 ethyl substituent with groups such as methyl, propyl, cyclopropyl, and isobutyl were tolerated, groups with larger steric properties such as an isopropyl and benzyl groups were not.
authors.affiliation: Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, 717 Delaware Street, SE, Minneapolis, MN, 55414, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Huang
authors.affiliation: Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, 717 Delaware Street, SE, Minneapolis, MN, 55414, USA.
authors.forename: Henry L
authors.initials: HL
authors.lastname: Wong
authors.affiliation: Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, 717 Delaware Street, SE, Minneapolis, MN, 55414, USA.
authors.forename: Gunda I
authors.identifier: 0000-0002-8900-9460
authors.initials: GI
authors.lastname: Georg
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007783:Lactones / Q000737:chemistry*; D011485:Protein Binding; D011753:Pyrones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D007783:Lactones; D011753:Pyrones; D014404:Tubulin; D050257:Tubulin Modulators; C088446:pironetin
keywords: antitumor agents; natural products; tubulin binding agents; α,β-unsaturated lactones; α-tubulin