A Concise Synthesis of Pyrazole Analogues of Combretastatin A1 as Potent Anti‐Tubulin Agents

Abstract

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 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.

Sydnone Cycloaddition Route to Pyrazole-Based Analogs of Combretastatin A4

“…16,20,27,28 To the best of our knowledge, there are no examples of simple (without extra substitution of the pyrazole core), pyrazole-bridged CA4 analogs reported and there has not been a systematic evaluation into the effect of substitution pattern. The pyrazole motif is an important fragment in the pharmaceutical industry and is present in a number of commercial medicines and agrichemicals.…”

Some natural sources of substances with antitumor effects

“…16,17 Neke biljne supstance su ispitivane u kom stepenu usporavaju karcionegenezu (kurkumin, rezveratrol). Antitumorsko delovanje kurkumina izolovanog iz Curcuma longa je detaljno proučavano i na kulturama ćelija i na životinjskim modelima,1 zbog čega su predloženi i unapređeni modeli sa nanočesticama kao nosačima za biljnu komponentu.…”

Synthesis, biological evaluation and 3D-QSAR studies of novel 5-phenyl-1H-pyrazol cinnamamide derivatives as novel antitubulin agents

“…[26][27][28] Besides, Pyrazole-based heterocycles play a crucial role in the arena of rigidified combretastatin analogues. [29] Lee and co-workers described a series of 3,5-diarylpyrazoles that display low cytotoxicity in tumor cell lines due to their planar conformation. [30] These previous researches encouraged us to integrate cinnamon amide with pyrazoles to screen compounds which have potent anticancer activities.…”