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It has been shown to be at least tenfold more potent than combretastatin\u2005A4 (CA4) in terms of vascular shutdown, which correlates with its metabolism to reactive <jats:italic>ortho<\/jats:italic>\u2010quinone species that are assumed to be directly cytotoxic in tumor cells. A series of 3,4\u2010diarylpyrazoles were concisely synthesized, one of which, 3\u2010methoxy\u20106\u2010[4\u2010(3,4,5\u2010trimethoxyphenyl)\u20101<jats:italic>H<\/jats:italic>\u2010pyrazol\u20103\u2010yl]benzene\u20101,2\u2010diol (<jats:bold>27<\/jats:bold>), proved to be a cytotoxic anti\u2010tubulin agent with low nanomolar potency. We also report that combretastatins, including CA1, CA4, and <jats:bold>27<\/jats:bold>, are effective against mesothelioma cell lines and therefore have significant clinical promise. Metabolism experiments demonstrate that <jats:bold>27<\/jats:bold> retains the ability to form <jats:italic>ortho<\/jats:italic>\u2010quinone 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.<\/jats:p>","DOI":"10.1002\/cmdc.201200561","type":"journal-article","created":{"date-parts":[[2013,2,21]],"date-time":"2013-02-21T17:13:02Z","timestamp":1361466782000},"page":"633-643","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["A Concise Synthesis of Pyrazole Analogues of Combretastatin\u2005A1 as Potent Anti\u2010Tubulin Agents"],"prefix":"10.1002","volume":"8","author":[{"given":"Roberta","family":"Zaninetti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore V.","family":"Cortese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvio","family":"Aprile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Massarotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pier Luigi","family":"Canonico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Sorba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Grosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armando A.","family":"Genazzani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracey","family":"Pirali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,2,21]]},"reference":[{"key":"e_1_2_6_1_2","unstructured":"\u00a0"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-0642-03"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.20299"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1628"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.24975"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01954881"},{"key":"e_1_2_6_7_2","unstructured":"\u00a0"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2613.2009.00651.x"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3253"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00443a031"},{"key":"e_1_2_6_11_2","unstructured":"\u00a0"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1517\/13543784.13.9.1171"},{"key":"e_1_2_6_13_2","unstructured":"http:\/\/www.clinicaltrials.govNCT00507429 NCT00653939 NCT00113438 NCT00060242 NCT00395434."},{"key":"e_1_2_6_14_2","unstructured":"\u00a0"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-2414"},{"key":"e_1_2_6_16_2","unstructured":"http:\/\/www.clinicaltrials.govNCT0097210 NCT00960557."},{"key":"e_1_2_6_17_2","unstructured":"\u00a0"},{"key":"e_1_2_6_18_2","first-page":"1453","volume":"22","author":"Hill S. 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