A Concise Synthesis of Pyrazole Analogues of CombretastatinA1 as Potent Anti-Tubulin Agents

Roberta Zaninetti, Salvatore V. Cortese, Silvio Aprile, Alberto Massarotti, Pier Luigi Canonico, Giovanni Sorba, Giorgio Grosa, Armando A. Genazzani, Tracey Pirali

Research output: Contribution to journalArticlepeer-review

Abstract

CombretastatinA1 (CA1) binds to the β-subunit at the colchicine binding site of tubulin and inhibits polymerization. As such, it is both an antitumor agent and a vascular disrupting agent. It has been shown to be at least tenfold more potent than combretastatinA4 (CA4) in terms of vascular shutdown, which correlates with its metabolism to reactive ortho-quinone species that are assumed to be directly cytotoxic in tumor cells. A series of 3,4-diarylpyrazoles were concisely synthesized, one of which, 3-methoxy-6-[4-(3,4,5-trimethoxyphenyl)-1H-pyrazol-3-yl]benzene-1,2-diol (27), proved to be a cytotoxic anti-tubulin agent with low nanomolar potency. We also report that combretastatins, including CA1, CA4, and 27, are effective against mesothelioma cell lines and therefore have significant clinical promise. Metabolism experiments demonstrate that 27 retains the ability to form ortho-quinone species, while the pyrazole ring shows high metabolic stability, suggesting that this compound might result in better pharmacokinetic profiles than CA1, with similar pharmacodynamic properties and clinical potential.

Original languageEnglish
Pages (from-to)633-643
Number of pages11
JournalChemMedChem
Volume8
Issue number4
DOIs
Publication statusPublished - Apr 2013

Keywords

  • Antitumor agents
  • Combretastatins
  • Cytotoxicity
  • Multicomponent reactions
  • Tubulin
  • Vascular disrupting agents

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