化学
部分
黄素组
共价键
谷胱甘肽
顺铂
共轭体系
奥沙利铂
立体化学
组合化学
酶
生物化学
有机化学
癌症
医学
内科学
外科
聚合物
结直肠癌
化疗
作者
Juan Sánchez-Camacho,Sonia Tadeo-Infante,Ana C. Carrasco,Stefano Scoditti,Álvaro Martínez,Fabienne Barroso-Bujans,Emilia Sicilia,Ana M. Pizarro,Luca Salassa
标识
DOI:10.26434/chemrxiv-2023-3x80n
摘要
In situ activation of Pt(IV) to Pt(II) species is a promising strategy to control anticancer activity and overcome off-target toxicity linked to classic platinum chemotherapeutic agents. Herein, we present the design and synthesis of two new asymmetric Pt(IV) derivatives of cisplatin and oxaliplatin (1·TARF and 2·TARF, respectively) bearing a 2',3',4',5'-tetraacetylriboflavin moiety (TARF) covalently bonded. 1H and 195Pt NMR spectroscopy shows that 1·TARF and 2·TARF can be effectively activated into toxic Pt(II) species, when incubated with NADH, sodium ascorbate, and glutathione (GSH) in the dark and under light irradiation. Density functional theory studies of the dark Pt(IV)-to-Pt(II) conversion of 2·TARF indicate that the process involves first a hydride transfer from the donor to the flavin moiety of the complex, followed by electron transfer to the Pt(IV) center. When administered to MDA-MB-231 breast cancer cells pre-incubated with non-toxic amounts of ascorbate, 2·TARF displays enhanced toxicity (between one and two orders of magnitude), suggesting that generation of oxaliplatin can selectively be triggered by redox activation. Such an effect is not observed when 2 and TARF are co-administered under the same conditions, demonstrating that covalent binding of the flavin to the Pt complex is pivotal.
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