Synthesis of novel macrocyclic docetaxel analogues. Influence of their macrocyclic ring size on tubulin activity

J Med Chem. 2003 Aug 14;46(17):3623-30. doi: 10.1021/jm030770w.

Abstract

This work describes the synthesis of a series of novel macrocyclic taxoids 3 and 3(H) designed to mimic the docetaxel solid-state ("nonpolar") conformation. These compounds, bearing 18-, 20-, 21-, and 22-membered rings connecting the C-2 OH and C-3' NH moieties, were constructed by ring-closing olefin metathesis of the taxoid-omega,omega'-dienes 4. Biological evaluation of these new taxoids showed that activity is dependent on the ring size, and only the 22-membered ring taxoid 3d exhibits significant tubulin binding. Synthesis of the open-chain analogues 7 and 7(H) and comparison of their biological activities with macrocyclic taxoids show that the carbon tether between C-2 OH and C-3' NH does not hamper tubulin binding. Computational studies of the conformational behavior of the macrocyclic taxoids 3 indicate that the 18-, 20-, and 21-membered-ring 3a-c adopt mainly conformations that are not recognized by tubulin. The most active taxoid 3d appears to adopt a conformation that is between the "nonpolar" and T-shaped forms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Docetaxel
  • Drug Screening Assays, Antitumor
  • Humans
  • KB Cells
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Conformation
  • Paclitaxel / analogs & derivatives*
  • Paclitaxel / chemical synthesis*
  • Paclitaxel / chemistry
  • Paclitaxel / pharmacology
  • Solutions
  • Structure-Activity Relationship
  • Taxoids*
  • Tubulin / chemistry*

Substances

  • Antineoplastic Agents
  • Solutions
  • Taxoids
  • Tubulin
  • Docetaxel
  • Paclitaxel