Beirne, Darren Fergal and Farkaš, Barbara and Donati, Chiara and Gandin, Valentina and Rozas, Isabel and Velasco-Torrijos, Trinidad and Montagner, Diego (2023) Novel design of dual-action Pt(iv) anticancer pro-drugs based on cisplatin and derivatives of the tyrosine kinase inhibitors imatinib and nilotinib. Dalton Transactions, 52 (39). pp. 14110-14122. ISSN 1477-9226

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Abstract

Tyrosine kinases (TKs) are emerging as important targets in cancer therapy and some of their inhibitors, TKIs (e.g. imatinib and nilotinib), are FDA-approved drugs that are used as selective anti-cancer therapeutics against cell lines that overexpress TKs. Many examples of metal-based complexes functionalised with TKIs are reported in the literature but very few have been functionalised with platinum. Here we report the design, a detailed computational analysis/simulation, the complete chemical characterisation and the preliminary biological evaluation of two novel Pt(IV) anticancer pro-drugs based on cisplatin tethered with a derivative of either imatinib or nilotinib in the axial position. Pt(IV) complexes are a strategic scaffold in combination therapy due to their axial ligands that can be functionalised to form dual action drugs. The activation by reduction releases the Pt(II) core and the axial ligands upon cellular internalisation. The antiproliferative activity and the TK inhibition properties of the novel adducts are analysed with a theoretical approach and confirmed in vitro with preliminary biological assays.

Item Type:	Article
Keywords:	Adducts; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cancer; Cell Line, Tumor Cisplatin - chemistry; Cisplatin - pharmacology;
Academic Unit:	Faculty of Science and Engineering > Chemistry Faculty of Science and Engineering > Research Institutes > Human Health Institute
Item ID:	18966
Identification Number:	https://doi.org/10.1039/d3dt02030d
Depositing User:	Diego Montagner
Date Deposited:	03 Oct 2024 08:35
Journal or Publication Title:	Dalton Transactions
Publisher:	Royal Society of Chemistry
Refereed:	Yes
URI:
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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