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Synthesis, in vitro and in vivo biological evaluation of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones as new potent anticancer agents

Morigi, Rita, Locatelli, Alessandra, Leoni, Alberto, Rambaldi, Mirella, Bortolozzi, Roberta, Mattiuzzo, Elena, Ronca, Roberto, Maccarinelli, Federica, Hamel, Ernest, Bai, Ruoli, Brancale, Andrea and Viola, Giampietro 2019. Synthesis, in vitro and in vivo biological evaluation of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones as new potent anticancer agents. European Journal of Medicinal Chemistry 166 , pp. 514-530. 10.1016/j.ejmech.2019.01.049
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Abstract

A small library of 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones has been synthesized and screened according to protocols available at the National Cancer Institute (NCI). Some derivatives were potent antiproliferative agents, showing GI50 values in the nanomolar range. Remarkably, when most active compounds against leukemia cells were tested in human peripheral blood lymphocytes from healthy donors, were 100–200 times less cytotoxic. Some compounds, selected by the Biological Evaluation Committee of NCI, were examined to determine tubulin assembly inhibition. Furthermore, flow cytometric studies performed on HeLa, HT-29, and A549 cells, showed that compounds 14 and 25 caused a block in the G2/M phase. Interestingly, these derivatives induced apoptosis through the mitochondrial death pathway, causing in parallel significant activation of both caspase-3 and -9, PARP cleavage and down-regulation of the anti-apoptotic proteins Bcl-2 and Mcl-1. Finally, compound 25 was also tested in vivo in the murine BL6-B16 melanoma and E0771 breast cancer cells, causing in both cases a significant reduction in tumor volume.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: Elsevier
ISSN: 0223-5234
Date of First Compliant Deposit: 13 March 2019
Date of Acceptance: 19 January 2019
Last Modified: 29 Jun 2019 15:39
URI: http://orca.cf.ac.uk/id/eprint/120649

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