Design, synthesis, and biological evaluation of 6-Substituted Thieno[3,2-d]pyrimidine analogues as dual epidermal growth factor receptor kinase and microtubule inhibitors

Romagnoli, Romeo, Prencipe, Filippo, Oliva, Paola, Baraldi, Stefania, Baraldi, Pier Giovanni, Schiaffino Ortega, Santiago, Chayah, Mariem, Kimatrai Salvador, Maria, Lopez-Cara, Luisa Carlota, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, Ferla, Salvatore ORCID: https://orcid.org/0000-0002-5918-9237, Hamel, Ernest, Ronca, Roberto, Bortolozzi, Roberta, Mariotto, Elena, Mattiuzzo, Elena and Viola, Giampietro 2019. Design, synthesis, and biological evaluation of 6-Substituted Thieno[3,2-d]pyrimidine analogues as dual epidermal growth factor receptor kinase and microtubule inhibitors. Journal of Medicinal Chemistry 62 (3) , pp. 1274-1290. 10.1021/acs.jmedchem.8b01391

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Abstract

The clinical evidence for the success of tyrosine kinase inhibitors in combination with microtubule-targeting agents prompted us to design and develop single agents that possess both epidermal growth factor receptor (EGFR) kinase and tubulin polymerization inhibitory properties. A series of 6-aryl/heteroaryl-4-(3′,4′,5′-trimethoxyanilino)thieno[3,2-d]pyrimidine derivatives were discovered as novel dual tubulin polymerization and EGFR kinase inhibitors. The 4-(3′,4′,5′-trimethoxyanilino)-6-(p-tolyl)thieno[3,2-d]pyrimidine derivative 6g was the most potent compound of the series as an antiproliferative agent, with half-maximal inhibitory concentration (IC50) values in the single- or double-digit nanomolar range. Compound 6g bound to tubulin in the colchicine site and inhibited tubulin assembly with an IC50 value of 0.71 μM, and 6g inhibited EGFR activity with an IC50 value of 30 nM. Our data suggested that the excellent in vitro and in vivo profile of 6g may be derived from its dual inhibition of tubulin polymerization and EGFR kinase.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Publisher:	American Chemical Society
ISSN:	0022-2623
Date of First Compliant Deposit:	7 March 2019
Date of Acceptance:	11 January 2019
Last Modified:	12 Nov 2024 08:45
URI:	https://orca.cardiff.ac.uk/id/eprint/120345

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