Lobatamide C: total synthesis, stereochemical assignment, preparation of simplified analogues, and V-ATPase inhibition studies

J Am Chem Soc. 2003 Jul 2;125(26):7889-901. doi: 10.1021/ja0352350.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cattle
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Macrolides / chemical synthesis*
  • Macrolides / chemistry
  • Macrolides / pharmacology*
  • Models, Molecular
  • Molecular Conformation
  • Salicylates / chemical synthesis*
  • Salicylates / chemistry
  • Salicylates / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thermodynamics
  • Vacuolar Proton-Translocating ATPases / antagonists & inhibitors*

Substances

  • Enzyme Inhibitors
  • Macrolides
  • Salicylates
  • lobatamide C
  • Vacuolar Proton-Translocating ATPases