title: Lobatamide C: total synthesis, stereochemical assignment, preparation of simplified analogues, and V-ATPase inhibition studies.
abstract: The total synthesis and stereochemical assignment of the potent antitumor macrolide lobatamide C, as well as synthesis of simplified lobatamide analogues, is reported. Cu(I)-mediated enamide formation methodology has been developed to prepare the highly unsaturated enamide side chain of the natural product and analogues. A key fragment coupling employs base-mediated esterification of a beta-hydroxy acid and a salicylate cyanomethyl ester. Three additional stereoisomers of lobatamide C have been prepared using related synthetic routes. The stereochemistry at C8, C11, and C15 of lobatamide C was assigned by comparison of stereoisomers and X-ray analysis of a crystalline derivative. Synthetic lobatamide C, stereoisomers, and simplified analogues have been evaluated for inhibition of bovine chromaffin granule membrane V-ATPase. The salicylate phenol, enamide NH, and ortho-substitution of the salicylate ester have been shown to be important for V-ATPase inhibitory activity.
authors.affiliation: Department of Chemistry and Center for Chemical Methodology and Library Development, Boston University, 590 Commonwealth Avenue, Boston, MA 02215, USA.
authors.forename: Ruichao
authors.initials: R
authors.lastname: Shen
authors.forename: Cheng Ting
authors.initials: CT
authors.lastname: Lin
authors.forename: Emma Jean
authors.initials: EJ
authors.lastname: Bowman
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Bowman
authors.forename: John A
authors.initials: JA
authors.lastname: Porco
mesh_terms: D000818:Animals; D002417:Cattle; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D012459:Salicylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D018942:Macrolides; D012459:Salicylates; C460781:lobatamide C; D025262:Vacuolar Proton-Translocating ATPases