Synthesis and structure-activity relationships of nonaromatic taxoids: effects of alkyl and alkenyl ester groups on cytotoxicity

J Med Chem. 1997 Jan 31;40(3):279-85. doi: 10.1021/jm9606711.

Abstract

Several new nonaromatic taxoids are synthesized by means of the beta-lactam synthon method. These include taxoids modified with 3-methylbut-2-enoate, 3-methylbutanoate, and cyclohexanecarboxylate groups in place of the benzoate at the C-2 position. In addition, taxoids with 2-methylprop-1-enyl, 2-methylpropyl, (E)-prop-1-enyl, and cyclohexyl groups at the C-3' position are also prepared in combination with the modifications at C-2. The alkyl and alkenyl ester groups at C-2 displayed pronounced effects on the in vitro cytotoxicity. Two of the fully aliphatic taxoids possess similar or stronger activity than paclitaxel and docetaxel. It is clear that the 2-benzoate does not play a unique role, and replacement with the appropriate alkyl and alkenyl groups provides taxoids with equivalent or superior activity.

Publication types

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

MeSH terms

  • Antineoplastic Agents, Phytogenic / chemical synthesis*
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Breast Neoplasms / drug therapy
  • Docetaxel
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Esters
  • Female
  • Humans
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Structure
  • Ovarian Neoplasms / drug therapy
  • Paclitaxel / analogs & derivatives*
  • Paclitaxel / chemical synthesis
  • Paclitaxel / chemistry
  • Paclitaxel / pharmacology
  • Structure-Activity Relationship
  • Taxoids*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents, Phytogenic
  • Esters
  • Taxoids
  • Docetaxel
  • Paclitaxel