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Inhibition of mitosis and microtubule function through direct tubulin binding by a novel antiproliferative naphthopyran LY290181.

Abstract
The mechanism of action of a novel antiproliferative compound LY290181 [2-amino-4-(3-pyridyl)-4H-naphtho(1,2-b)pyran-3-carbonitrile] was characterized. LY290181 is a potent inhibitor of cell proliferation, producing 50% inhibition of vascular smooth muscle, endothelial, Chinese hamster ovary, HeLa, and human erythroleukemia cells at concentrations of 8-40 nM. Cell cycle analysis showed that LY290181 caused accumulation of smooth muscle cells at the G2/M phase and induced mitotic arrest in Chinese hamster ovary cells and HeLa cells. At low concentrations (3-30 nM), LY290181 blocked transition of cells from metaphase to anaphase and disrupted mitotic spindle organization. At high concentrations (>/=100 nM), LY290181 produced a concentration-dependent loss of cytoplasmic and spindle microtubules. LY290181 inhibited the polymerization of purified bovine brain microtubule protein into microtubules, and it depolymerized preformed microtubules. Using tubulin-1-anilino-8-naphthalene sulfonate complex fluorescence, we have shown that LY290181 directly interacted with tubulin in a unique manner. These studies show that LY290181 induces cell growth arrest in prometaphase/metaphase, and tubulin appears to be its molecular target.
AuthorsD L Wood, D Panda, T R Wiernicki, L Wilson, M A Jordan, J P Singh
JournalMolecular pharmacology (Mol Pharmacol) Vol. 52 Issue 3 Pg. 437-44 (Sep 1997) ISSN: 0026-895X [Print] United States
PMID9281606 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antineoplastic Agents
  • Growth Inhibitors
  • LY 290181
  • Naphthalenes
  • Pyrans
  • Tubulin
Topics
  • Animals
  • Antineoplastic Agents (metabolism, pharmacology)
  • Binding Sites
  • CHO Cells (cytology, drug effects, metabolism)
  • Cattle
  • Cell Division (drug effects)
  • Cells, Cultured
  • Cricetinae
  • G2 Phase (drug effects)
  • Growth Inhibitors (metabolism, pharmacology)
  • Humans
  • Interphase (drug effects)
  • Metaphase (drug effects)
  • Microtubules (drug effects, physiology)
  • Mitosis (drug effects)
  • Muscle, Smooth, Vascular (cytology, drug effects, metabolism)
  • Naphthalenes (metabolism, pharmacology)
  • Pyrans (metabolism, pharmacology)
  • Rabbits
  • Tubulin (metabolism)

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