A Concise Synthesis of Pyrazole Analogues of Combretastatin A1 as Potent Anti‐Tubulin Agents. Issue 4 (21st February 2013)

• Record Type: Journal Article
• Authors: Zaninetti, Roberta; Cortese, Salvatore V.; Aprile, Silvio; Massarotti, Alberto; Canonico, Pier Luigi; Sorba, Giovanni; Grosa, Giorgio; Genazzani, Armando A.; Pirali, Tracey
• Is Part Of: ChemMedChem. Volume 8:Issue 4(2013:Apr.)
• Page Start: 633
• Page End: 643
• Publication Date: 2013-02-21
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201200561
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Combretastatin A1 (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 combretastatin A4 (CA4) in terms of vascular shutdown, which correlates with its metabolism to reactive <italic>ortho</italic>‐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)‐1<italic>H</italic>‐pyrazol‐3‐yl]benzene‐1, 2‐diol (<bold>27</bold>), proved to be a cytotoxic anti‐tubulin agent with low nanomolar potency. We also report that combretastatins, including CA1, CA4, and <bold>27</bold>, are effective against mesothelioma cell lines and therefore have significant clinical promise. Metabolism experiments demonstrate that <bold>27</bold> retains the ability to form <italic>ortho</italic>‐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.</p> </abstract>