A facile synthesis of diaryl pyrroles led to the discovery of potent colchicine site antimitotic agents

Romagnoli, Romeo, Oliva, Paola, Salvador, Maria Kimatrai, Manfredini, Stefano, Padroni, Chiara, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, Ferla, Salvatore, Hamel, Ernest, Ronca, Roberto, Maccarinelli, Federica, Rruga, Fatlum, Mariotto, Elena, Viola, Giampietro and Bortolozzi, Roberta 2021. A facile synthesis of diaryl pyrroles led to the discovery of potent colchicine site antimitotic agents. European Journal of Medicinal Chemistry 214 , 113229. 10.1016/j.ejmech.2021.113229

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Abstract

Three different series of cis-restricted analogues of combretastatin A-4 (CA-4), corresponding to thirty-nine molecules that contained a pyrrole nucleus interposed between the two aryl rings, were prepared by a palladium-mediated coupling approach and evaluated for their antiproliferative activity against six human cancer cell lines. In the two series of 1,2-diaryl pyrrole derivatives, results suggested that the presence of the 3′,4′,5′-trimethoxyphenyl moiety at the N-1 position of the pyrrole ring was more favorable for antiproliferative activity. In the series of 3,4-diarylpyrrole analogues, three compounds (11i-k) exhibited maximal antiproliferative activity, showing excellent antiproliferative activity against the CA-4 resistant HT-29 cells. Inhibition of tubulin polymerization of selected 1,2 pyrrole derivatives (9a, 9c, 9o and 10a) was similar to that observed with CA-4, while the isomeric 3,4-pyrrole analogues 11i-k were generally from 1.5- to 2-fold more active than CA-4. Compounds 11j and 11k were the only compounds that showed activity as inhibitors of colchicine binding comparable to that CA-4. Compound 11j had biological properties consistent with its intracellular target being tubulin. This compound was able to block the cell cycle in metaphase and to induce significant apoptosis at a concentration of 25 nM, following the mitochondrial pathway, with low toxicity for normal cells. More importantly, compound 11j exerted activity in vivo superior to that of CA-4P, being able to significantly reduce tumor growth in a syngeneic murine tumor model even at the lower dose tested (5.0 mg/kg).

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Publisher:	Elsevier
ISSN:	0223-5234
Date of First Compliant Deposit:	15 February 2021
Date of Acceptance:	24 January 2021
Last Modified:	05 Jan 2024 08:42
URI:	https://orca.cardiff.ac.uk/id/eprint/138549

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