The tetranuclear Pt complex (PtL)₄ (where L²⁻ is the anion derived from para-isopropyl thiosemicarbazone) was first described in A.G. Quiroga et al., J. Med. Chem. 41, 1998, 1399–1408. (PtL)₄ manifests antiproliferative properties toward various cancer cell lines being a promising anticancer drug candidate. Yet, details of its reactivity with biomolecules have not been elucidated. To this end, we investigated the reactions of (PtL)₄ with a few model proteins, i.e. bovine pancreatic ribonuclease (RNase A), cytochrome c (Cyt c) and hen egg white lysozyme (Lysozyme), through electrospray ionization mass spectrometry and other biophysical methods. A rich reactivity of (PtL)₄ with the above-mentioned model proteins is observed, leading to the formation of numerous metallodrug-protein adducts. The tetranuclear complex breaks down and various fragments bind proteins up to high metal/protein ratios; this typically results into very complicated mass spectral patterns. However, some of the main mass peaks could be assigned in the case of the Lysozyme adduct. In addition, crystallographic data were obtained for the (PtL)₄/Lysozyme and (PtL)₄/RNase A adducts pointing at His side chains as the primary binding sites for monometallic Pt fragments. Notably, a few selected features of the interactions observed in the (PtL)₄/protein adducts were reproduced by reacting (PtL)₄ with a small molecule, i.e. N-methylimidazole. In conclusion, the present study confirms the prodrug nature of the tetraplatinum complex, clarifies one possible pathway for its activation through cluster disassembly and allows initial identification of adducts formed with a representative protein.

最初在AG Quiroga等人，J.Med.Chem.Soc。，1995，4，4中描述了四核Pt配合物（PtL）₄（其中L ^2-是衍生自对-异丙基硫代半脲的阴离子）。化学 41，1998，1399-1408。（PtL）₄对作为有希望的抗癌药物候选物的各种癌细胞系表现出抗增殖特性。然而，尚未阐明其与生物分子的反应性的细节。为此，我们研究了（PtL）₄与几种模型蛋白的反应，即牛胰核糖核酸酶（RNase A），细胞色素c（Cyt c）和鸡蛋清溶菌酶（Lysozyme），通过电喷雾电离质谱法和其他生物物理方法进行。观察到（PtL）₄与上述模型蛋白的丰富反应性，导致形成许多金属药物-蛋白质加合物。四核复合物分解，各种片段将蛋白质结合在一起，形成高金属/蛋白质比率。这通常会导致非常复杂的质谱图。但是，在溶菌酶加合物的情况下，可能会分配一些主要的质谱峰。另外，获得了（PtL）₄ /溶菌酶和（PtL）_4的晶体学数据。/ RNase A加合物指向His的侧链，作为单金属Pt片段的主要结合位点。值得注意的是，通过使（PtL）₄与小分子，即N-甲基咪唑反应，再现了在（PtL）₄ /蛋白质加合物中观察到的相互作用的一些选定特征。总而言之，本研究证实了四铂复合物的前药性质，阐明了通过簇分解激活其的一种可能途径，并允许初步鉴定与代表性蛋白质形成的加合物。