title: Synthesis and Biological Evaluation of Lactimidomycin and Its Analogues.
abstract: The studies culminating in the total synthesis of the glutarimide-containing eukaryote translation elongation inhibitor lactimidomycin are described. The optimized synthetic route features a Zn(II)-mediated intramolecular Horner-Wadsworth-Emmons (HWE) reaction resulting in a highly stereoselective formation of the strained 12-membered macrolactone of lactimidomycin on a 423 mg scale. The presence of the E,Z-diene functionality was found to be key for effective macrocyclizations as a complete removal of these unsaturation units resulted in exclusive formation of the dimer rather than monocyclic enoate. The synthetic route features a late-stage installation of the glutarimide functionality via an asymmetric catalytic Mukaiyama aldol reaction, which allows for a quick generation of lactimidomycin homolog 55 containing two additional carbons in the glutarimide side chain. Similar to lactimidomycin, this analog was found to possess cytotoxicity against MDA-MB-231 breast cancer cells (GI50 =1-3 μM) using in vitro 2D and 3D assays. Although lactimidomycin was found to be the most potent compound in terms of anticancer activity, 55 as well as truncated analogues 50-52 lacking the glutarimide side-chain were found to be significantly less toxic against human mammary epithelial cells.
authors.affiliation: Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, MI 48109-1055 (USA).
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Larsen
authors.affiliation: Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, MI 48109-1055 (USA).
authors.forename: Zhankui
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Medicinal Chemistry Department, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1065 (USA).
authors.forename: Eric
authors.initials: E
authors.lastname: Lachacz
authors.affiliation: Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, MI 48109-1055 (USA).
authors.forename: Yaroslav
authors.initials: Y
authors.lastname: Khomutnyk
authors.affiliation: Medicinal Chemistry Department, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1065 (USA). soellner@umich.edu.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Soellner
authors.affiliation: Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, MI 48109-1055 (USA). nagorny@umich.edu.
authors.forename: Pavel
authors.initials: P
authors.lastname: Nagorny
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001685:Biological Factors; D002465:Cell Movement / Q000187:drug effects*; D003500:Cyclization; D006801:Humans; D007783:Lactones / Q000737:chemistry*; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010881:Piperidones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D015032:Zinc / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D001685:Biological Factors; D007783:Lactones; D018942:Macrolides; D010881:Piperidones; C077633:lactimidomycin; D015032:Zinc; C007864:glutarimide
keywords: anticancer activity; biological evaluation; lactimidomycin; macrocyclization; total synthesis