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首页> 外文期刊>Chemistry: A European journal >Diazido mixed-amine platinum(IV) anticancer complexes activatable by visible-light form novel DNA adducts
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Diazido mixed-amine platinum(IV) anticancer complexes activatable by visible-light form novel DNA adducts

机译：可被可见光激活的二氮杂混合胺铂（IV）抗癌复合物形成新型DNA加合物

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摘要

Platinum diam(m)ine complexes, such as cisplatin, are successful anticancer drugs, but suffer from problems of resistance and side-effects. Photoactivatable Pt~(IV) prodrugs offer the potential of targeted drug release and new mechanisms of action. We report the synthesis, X-ray crystallographic and spectroscopic properties of photoactivatable diazido complexes trans,trans,trans-[Pt(N_3)_2(OH) _2(MA)(Py)] (1; MA=methylamine, Py=pyridine) and trans,trans,trans- [Pt(N_3)_2(OH)_2(MA)(Tz)] (2; Tz=thiazole), and interpret their photophysical properties by TD-DFT modelling. The orientation of the azido groups is highly dependent on H bonding and crystal packing, as shown by polymorphs 1 p and 1 q. Complexes 1 and 2 are stable in the dark towards hydrolysis and glutathione reduction, but undergo rapid photoreduction with UVA or blue light with minimal amine photodissociation. They are over an order of magnitude more potent towards HaCaT keratinocytes, A2780 ovarian, and OE19 oesophageal carcinoma cells than cisplatin and show particular potency towards cisplatin-resistant human ovarian cancer cells (A2780cis). Analysis of binding to calf-thymus (CT), plasmids, oligonucleotide DNA and individual nucleotides reveals that photoactivated 1 and 2 form both mono- and bifunctional DNA lesions, with preference for G and C, similar to transplatin, but with significantly larger unwinding angles and a higher percentage of interstrand cross-links, with evidence for DNA strand cross-linking further supported by a comet assay. DNA lesions of 1 and 2 on a 50 bp duplex were not recognised by HMGB1 protein, in contrast to cisplatin-type lesions. The photo-induced platination reactions of DNA by 1 and 2 show similarities with the products of the dark reactions of the Pt~(II) compounds trans-[PtCl _2(MA)(Py)] (5) and trans-[PtCl_2(MA)(Tz)] (6). Following photoactivation, complex 2 reacted most rapidly with CT DNA, followed by 1, whereas the dark reactions of 5 and 6 with DNA were comparatively slow. Complexes 1 and 2 can therefore give rapid potent photocytotoxicity and novel DNA lesions in cancer cells, with no activity in the absence of irradiation. A photo-finish: New photoactivatable Pt~(IV) prodrugs, as shown in figure, have been developed, which when activated with visible light show high potency towards a number of cell lines, including the cisplatin-resistant cancer cell line A2780cis. The photo-induced platination of DNA by these complexes showed significant differences from the lesions produced by cisplatin, which may help to explain their high activity in the cisplatin-resistant cell line.
机译：铂金（m）ine络合物（例如顺铂）是成功的抗癌药物，但存在耐药性和副作用的问题。可光活化的Pt〜（IV）前药具有靶向释放药物和新作用机制的潜力。我们报告了可光活化的重氮叠氮配合物反式，反式，反式-[Pt（N_3）_2（OH）_2（MA）（Py）]的合成，X射线晶体学和光谱性质（1; MA =甲胺，Py =吡啶）和反式，反式，反式-[Pt（N_3）_2（OH）_2（MA）（Tz）]（2; Tz =噻唑），并通过TD-DFT建模解释其光物理性质。叠氮基的取向高度依赖于H键和晶体堆积，如多晶型物1p和1q所示。配合物1和2在黑暗中对水解和谷胱甘肽还原都是稳定的，但是在UVA或蓝光的作用下，胺光解离最少，可进行快速光还原。它们对HaCaT角质形成细胞，A2780卵巢和OE19食管癌细胞的作用比顺铂强一个数量级，并且对顺铂耐药的人卵巢癌细胞（A2780cis）表现出特殊的作用。分析与小牛胸腺（CT），质粒，寡核苷酸DNA和单个核苷酸的结合后发现，光活化的1和2形成单功能和双功能DNA损伤，优先选择G和C，与跨铂相似，但展开角度大得多以及更高百分比的链间交联，彗星试验进一步证明了DNA链交联的证据。与顺铂型病变相反，HMGB1蛋白无法识别50 bp双链体上1和2的DNA病变。 DNA的1和2光诱导的平台化反应与Pt〜（II）化合物反式-[PtCl _2（MA）（Py）]（5）和反式-[PtCl_2（ MA）（Tz）]（6）。光活化后，复合物2与CT DNA的反应最快，其次是1，而5和6与DNA的暗反应相对较慢。因此，复合物1和2可以在癌细胞中产生快速有效的光细胞毒性和新的DNA损伤，在没有照射的情况下没有活性。照相光洗剂：如图所示，已经开发出了新的可光激活的Pt〜（IV）前药，当用可见光激活时，它对许多细胞系（包括对顺铂耐药的癌细胞系A2780cis）显示出高效力。这些复合物对DNA的光诱导镀铂与顺铂产生的损伤显示出显着差异，这可能有助于解释它们在顺铂耐药细胞系中的高活性。

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