Wang Zhimei, Fang Lei, Zhao Jian, Gou Shaohua
Research Center and School of Chemistry and Chemical Engineering, and Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
Metallomics. 2020 Mar 25;12(3):427-434. doi: 10.1039/c9mt00258h.
Sterically hindered platinum(ii) complexes have shown great advantages in overcoming platinum drug resistance. In this study, the antitumor actions of sterically hindered platinum(ii) complex 1 (cis-dichloro[(1R,2R)-N1-(2-fluorobenzyl)-1,2-diaminocyclohexane-N,N']platinum(ii), C13H19FPtCl2) were investigated by using saturation transfer difference nuclear magnetic resonance (STD NMR) and liquid chromatography-mass spectrometry (LCMS) techniques. STD NMR was applied to study the HSA (human serum albumin) binding properties, while the interactions between guanosine 5'-monophosphate (5'-GMP) and complex 1 were studied by LCMS. For HSA binding experiments, strong STD signals were observed for protons of sterically hindered parts of carrier ligands, indicating that the sterically hindered moieties of the carrier ligand could be situated inside the binding pocket of HSA. A 19F NMR experiment indicated that complex 1 could interact with HSA. Furthermore, the binding modes of complex 1 with guanosine 5'-monophosphate (5'-GMP) were studied in the absence and presence of glutathione by LCMS. According to the HPLC profiles, a mono-functional binding mode was observed for complex 1 both in the presence and in the absence of glutathione, while a bi-adduct was observed for Pt(DACH)Cl2, which may be one of the reasons for their different biological activities. Hence, this study demonstrated that the NMR method combined with the LCMS technique could provide valuable information to understand the transport and the underlying anticancer mechanisms of the platinum(ii) complex at the molecular level. Moreover, the results reported here can help to reveal the binding mechanisms of the sterically hindered platinum(ii) compounds with biomolecules, which may shed light on the design of novel platinum(ii) anticancer agents with suitable sterically hindered groups.
空间位阻铂（II）配合物在克服铂类药物耐药性方面显示出巨大优势。在本研究中，通过饱和转移差核磁共振（STD NMR）和液相色谱 - 质谱（LCMS）技术研究了空间位阻铂（II）配合物1（顺 - 二氯[（1R，2R） - N1 - （2 - 氟苄基） - 1,2 - 二氨基环己烷 - N，N']铂（II），C13H19FPtCl2）的抗肿瘤作用。STD NMR用于研究人血清白蛋白（HSA）的结合特性，而通过LCMS研究了5'-鸟苷单磷酸（5'-GMP）与配合物1之间的相互作用。对于HSA结合实验，在载体配体的空间位阻部分的质子上观察到强STD信号，表明载体配体的空间位阻部分可能位于HSA的结合口袋内。19F NMR实验表明配合物1可以与HSA相互作用。此外，通过LCMS研究了在存在和不存在谷胱甘肽的情况下配合物1与5'-鸟苷单磷酸（5'-GMP）的结合模式。根据HPLC图谱，在存在和不存在谷胱甘肽的情况下，配合物1均观察到单功能结合模式，而对于Pt（DACH）Cl2观察到双加合物，这可能是它们具有不同生物活性的原因之一。因此，本研究表明，NMR方法与LCMS技术相结合可以提供有价值的信息，以在分子水平上理解铂（II）配合物的转运和潜在的抗癌机制。此外，这里报道的结果有助于揭示空间位阻铂（II）化合物与生物分子的结合机制，这可能为设计具有合适空间位阻基团的新型铂（II）抗癌剂提供线索。
