First total synthesis of phenylpyridine analogues of the antimitotic rhazinilam

J Org Chem. 2001 Apr 20;66(8):2654-61. doi: 10.1021/jo0014156.

Abstract

The first synthesis of phenylpyridine analogues of rhazinilam and evaluation of these new structures as inhibitors of microtubule disassembly by interaction with tubulin are described. The synthesis is based on such key steps as picolinic metalation, hetero-ring cross-coupling and reduction of an acetyl group to an ethyl group. Elaboration of a quaternary picolinic carbon is one of the challenges of the synthesis. Biological evaluation of compounds bearing a quaternary picolinic carbon showed interactions with tubulin similar to (-)-rhazinilam but at a lower level.

MeSH terms

  • Alkaloids / chemical synthesis*
  • Alkaloids / pharmacology*
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Humans
  • Indolizines
  • Inhibitory Concentration 50
  • Lactams
  • Microtubules / drug effects
  • Pyridines / chemical synthesis
  • Pyridines / pharmacology
  • Stereoisomerism
  • Tubulin Modulators

Substances

  • Alkaloids
  • Antineoplastic Agents
  • Indolizines
  • Lactams
  • Pyridines
  • Tubulin Modulators
  • rhazinilam