Ma Ziqi, Zhang Jishuai, Lin Jiafan, Li Wenbing, Wu Xiaoqin, Wang Fuyi, Zhao Yao, Wu Kui
Key Laboratory of Hubei Province for Coal Conversion and New Carbon Materials; School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, P. R. China.
Beijing National Laboratory for Molecular Sciences; National Centre for Mass Spectrometry in Beijing; CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China.
Dalton Trans. 2023 Feb 28;52(9):2786-2798. doi: 10.1039/d2dt03924a.
CpG and its cytosine-methylated counterpart (CpG) are a unique reversible pair of sequences in regulating the expression of genes epigenetically. As DNA is the potential target of Pt-based anticancer metallodrugs, herein, we comparatively investigate the interactions of 5'-CpG and 5'-CpG with a photoactivatable anticancer Pt(IV) prodrug, ,,-[Pt(N)(OH)(py)] (1; py = pyridine), to explore the effects of methylation on the platination and ROS-induced oxidation of the CpG motif. Mono-platinated dinucleotides were demonstrated by ESI-MS to be the main products for both 5'-CpG and 5'-CpG with the bound Pt moiety as [Pt(N)(py)] generated by the photodecomposition of complex 1 under irradiation with blue light, accompanied by the formation of less abundant di-platinated adducts. G-N7 and C-N3/C-N3 were shown to be the major and minor platination sites, respectively, with G-N1 as the third and weakest platination site, in particular, in di-platinated products. Moreover, platinated dinucleotides associated with guanine and/or cytosine oxidation were also observed. Apart from 8-oxo-guanine (G) and -formylamidoiminohydantoin (RedSp) reported previously, novel oxidation adducts 5-guanidinohydantoin (Gh) derived from guanine and 1-carbamoyl-4,5-dihydroxy-2-oxoimidazolidine (ImidCyt) derived from cytosine in CpG, and diimino imidazole (DIz) and 2,5-diaminoimidazol-4-one (imidazolone, Iz) derived from guanine and ImidCyt derived from C in CpG were proposed according to MS information. These results showed that methylation exerted little effects on the platination modes of CpG, but triggered distinct oxidation pathways of CpG, perhaps causing discriminated DNA damage to CpG-rich genes. This work provides novel insights into the role of the anticancer photoactivatable Pt(IV) prodrug through damaging the epigenetically modified DNA sequences.
CpG及其胞嘧啶甲基化对应物（CpG）是在基因表观遗传调控中一对独特的可逆序列。由于DNA是铂类抗癌金属药物的潜在靶点，在此，我们比较研究了5'-CpG和5'-CpG与一种光活化抗癌铂（IV）前药，,-[Pt(N)(OH)(py)]（1；py =吡啶）的相互作用，以探讨甲基化对CpG基序的铂化作用以及活性氧诱导的氧化作用的影响。电喷雾电离质谱（ESI-MS）表明，单铂化二核苷酸是5'-CpG和5'-CpG的主要产物，结合的铂部分为蓝光照射下配合物1光分解产生的[Pt(N)(py)]，同时伴有较少丰度的双铂化加合物的形成。结果表明，G-N7和C-N3/C-N3分别是主要和次要的铂化位点，G-N1是第三个且最弱的铂化位点，特别是在双铂化产物中。此外，还观察到与鸟嘌呤和/或胞嘧啶氧化相关的铂化二核苷酸。除了先前报道的8-氧代鸟嘌呤（G）和-甲酰氨基亚氨基乙内酰脲（RedSp）外，根据质谱信息，还提出了源自CpG中鸟嘌呤的新型氧化加合物5-胍基乙内酰脲（Gh）、源自胞嘧啶的1-氨基甲酰基-4,5-二羟基-2-氧代咪唑烷（ImidCyt），以及源自CpG中鸟嘌呤和源自C的ImidCyt的二亚氨基咪唑（DIz）和2,5-二氨基咪唑-4-酮（咪唑酮，Iz）。这些结果表明，甲基化对CpG的铂化模式影响很小，但引发了CpG不同的氧化途径，可能导致对富含CpG基因的差异性DNA损伤。这项工作通过破坏表观遗传修饰的DNA序列，为抗癌光活化铂（IV）前药的作用提供了新的见解。
