Anticancer Agents: Does a Phosphonium Behave Like a Gold(I) Phosphine Complex? Let a 鈥淪mart鈥?Probe Answer!
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- 作者：Moussa Ali ; Lucile Dondaine ; Anais Adolle ; Carla Sampaio ; Florian Chotard ; Philippe Richard ; Franck Denat ; Ali Bettaieb ; Pierre Le Gendre ; V茅ronique Laurens ; Christine Goze ; Catherine Paul ; Ewen Bodio
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：June 11, 2015
- 年：2015
- 卷：58
- 期：11
- 页码：4521-4528
- 全文大小：352K
- ISSN：1520-4804
文摘
Gold phosphine complexes, such as auranofin, have been recognized for decades as antirheumatic agents. Clinical trials are now underway to validate their use in anticancer or anti-HIV treatments. However, their mechanisms of action remain unclear. A challenging question is whether the gold phosphine complex is a prodrug that is administered in an inactive precursor form or rather that the gold atom remains attached to the phosphine ligand during treatment. In this study, we present two novel gold complexes, which we compared to auranofin and to their phosphonium analogue. The chosen ligand is a phosphine-based smart probe, whose strong fluorescence depends on the presence of the gold atom. The in vitro biological action of the gold complexes and the phosphonium derivative were investigated, and a preliminary in vivo study in healthy zebrafish larvae allowed us to evaluate gold complex biodistribution and toxicity. The different analyses carried out showed that these gold complexes were stable and behaved differently from phosphonium and auranofin, both in vitro and in vivo. Two-photon microscopy experiments demonstrated that the cellular targets of these gold complexes are not the same as those of the phosphonium analogue. Moreover, despite similar IC50 values in some cancer cell lines, gold complexes displayed a low toxicity in vivo, in contrast to the phosphonium salt. They are therefore suitable for future in vivo investigations.