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Antiproliferative activity of a series of cisplatin-based Pt(IV)-acetylamido/carboxylato prodrugs

Ravera, Mauro, Gabano, Elisabetta, Zanellato, Ilaria, Fregonese, Federico, Pelosi, Giorgio, Platts, James Alexis and Osella, Domenico 2016. Antiproliferative activity of a series of cisplatin-based Pt(IV)-acetylamido/carboxylato prodrugs. Dalton Transactions 45 , pp. 5300-5309. 10.1039/C5DT04905A

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Abstract

We report studies of a novel series of Pt(IV) complexes exhibiting an asymmetric combination of acetylamido and carboxylato ligands in the axial positions. We demonstrate efficient synthesis of a series of analogues, differing in alkyl chain length and hence lipophilicity, from a stable acetylamido/hydroxido complex formed by reaction of cisplatin with peroxyacetimidic acid (PAIA). NMR spectroscopy and X-ray crystallography confirm the identity of the resulting complexes, and highlight subtle differences in structure and stability of acetylamido complexes compared to equivalent acetato complexes. Reduction of acetylamido complexes, whether achieved chemically or electro-chemically, is significantly more difficult than of acetate complexes, resulting in lower antiproliferative activity for shorter-chain complexes. For those with longer chains and hence greater cell uptake, this difference is negated and acetylamido complexes are as active as acetato analogues, both exhibiting antiproliferative potency (1/IC50) against A2780 ovarian cancer cells similar to that of cisplatin.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Advanced Research Computing @ Cardiff (ARCCA)
Chemistry
Subjects: Q Science > QD Chemistry
Publisher: Royal Society of Chemistry
ISSN: 1477-9226
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 2 February 2016
Last Modified: 06 Jun 2017 15:13
URI: http://orca.cf.ac.uk/id/eprint/86539

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