Cyclometalated Iminophosphorane Gold(III) and Platinum(II) Complexes. A Highly Permeable Cationic Platinum(II) Compound with Promising Anticancer Properties

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• 作者：Malgorzata Frik ; Jacob Fern谩ndez-Gallardo ; Oscar Gonzalo ; V铆ctor Mangas-Sanjuan ; Marta Gonz谩lez-Alvarez ; Alfonso Serrano del Valle ; Chunhua Hu ; Isabel Gonz谩lez-Alvarez ; Marival Bermejo ; Isabel Marzo ; Mar铆a Contel
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：August 13, 2015
• 年：2015
• 卷：58
• 期：15
• 页码：5825-5841
• 全文大小：749K
• ISSN：1520-4804

文摘

New organometallic gold(III) and platinum(II) complexes containing iminophosphorane ligands are described. Most of them are more cytotoxic to a number of human cancer cell lines than cisplatin. Cationic Pt(II) derivatives 4 and 5, which differ only in the anion, Hg₂Cl₆^{2鈥?/sup> or PF₆鈥?/sup> respectively, display almost identical IC₅₀ values in the sub-micromolar range (25鈥?35-fold more active than cisplatin on these cell lines). The gold compounds induced mainly caspase-independent cell death, as previously reported for related cycloaurated compounds containing IM ligands. Cycloplatinated compounds 3, 4, and 5 can also activate alternative caspase-independent mechanisms of death. However, at short incubation times cell death seems to be mainly caspase dependent, suggesting that the main mechanism of cell death for these compounds is apoptosis. Mercury-free compound 5 does not interact with plasmid (pBR322) DNA or with calf thymus DNA. Permeability studies of 5 by two different assays, in vitro Caco-2 monolayers and a rat perfusion model, have revealed a high permeability profile for this compound (comparable to that of metoprolol or caffeine) and an estimated oral fraction absorbed of 100%, which potentially makes it a good candidate for oral administration.}