{"title":"作为潜在抗癌剂的双核金(III)配合物:一系列金(III)氧桥衍生物的结构、反应性和生物学特性","authors":"C. Gabbiani, A. Guerri, M. Cinellu, L. Messori","doi":"10.2174/1874846501003010029","DOIUrl":null,"url":null,"abstract":"Six homologous gold(III) dinuclear oxo-bridged complexes, of the type ((bipy nR )Au(µ-O) 2 Au(bipy nR ))(PF 6 ) 2 , bearing variously substituted 2,2'-bipyridine ligands (bipy nR = 2,2'-bipyridine, 4,4'-di-tert-butyl-, 6-methyl-, 6-neopentyl-, 6-o-xylyl- and 6,6'-dimethyl-2,2'-bipyridine), here called Auoxos, were prepared, characterised and recently tested as potential anticancer agents. Crystal structures were obtained for five members of the series that allowed us to perform detailed comparative analyses. Interestingly, the various Auoxos showed an acceptable stability profile in buffer solution and turned out to manifest outstanding antitumor properties in vitro. In particular, one member of this family, Auoxo6 (bipy nR = 6,6'-dimethyl-2,2'-bipyridine), produced more selective and far greater antiproliferative effects than all other tested Auoxos, qualifying itself as the best \"drug candidate\". In turn, COMPARE analysis of the cytotoxicity profiles of five Auoxos, toward an established panel of thirty-six human tumor cell lines, revealed important mechanistic differences; a number of likely biomolecular targets could thus be proposed such as HDAC and PKC. Biophysical studies revealed markedly different modes of interaction with calf thymus DNA for two representative Auoxo compounds. In addition, a peculiar reactivity with model proteins was documented on the ground of spectrophotometric and ESI MS data, most likely as the result of redox processes. In view of the several experimental evidences gathered so far, it can be stated that Auoxos constitute a novel family of promising cytotoxic gold compounds with an innovative mechanism of action that merit a more extensive pharmacological evaluation.","PeriodicalId":23072,"journal":{"name":"The Open Crystallography Journal","volume":"78 1","pages":"29-40"},"PeriodicalIF":0.0000,"publicationDate":"2010-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"2","resultStr":"{\"title\":\"Dinuclear Gold(III) Complexes as Potential Anticancer Agents: Structure, Reactivity and Biological Profile of a Series of Gold(III) Oxo-BridgedDerivatives\",\"authors\":\"C. Gabbiani, A. Guerri, M. Cinellu, L. Messori\",\"doi\":\"10.2174/1874846501003010029\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Six homologous gold(III) dinuclear oxo-bridged complexes, of the type ((bipy nR )Au(µ-O) 2 Au(bipy nR ))(PF 6 ) 2 , bearing variously substituted 2,2'-bipyridine ligands (bipy nR = 2,2'-bipyridine, 4,4'-di-tert-butyl-, 6-methyl-, 6-neopentyl-, 6-o-xylyl- and 6,6'-dimethyl-2,2'-bipyridine), here called Auoxos, were prepared, characterised and recently tested as potential anticancer agents. Crystal structures were obtained for five members of the series that allowed us to perform detailed comparative analyses. Interestingly, the various Auoxos showed an acceptable stability profile in buffer solution and turned out to manifest outstanding antitumor properties in vitro. In particular, one member of this family, Auoxo6 (bipy nR = 6,6'-dimethyl-2,2'-bipyridine), produced more selective and far greater antiproliferative effects than all other tested Auoxos, qualifying itself as the best \\\"drug candidate\\\". In turn, COMPARE analysis of the cytotoxicity profiles of five Auoxos, toward an established panel of thirty-six human tumor cell lines, revealed important mechanistic differences; a number of likely biomolecular targets could thus be proposed such as HDAC and PKC. Biophysical studies revealed markedly different modes of interaction with calf thymus DNA for two representative Auoxo compounds. In addition, a peculiar reactivity with model proteins was documented on the ground of spectrophotometric and ESI MS data, most likely as the result of redox processes. In view of the several experimental evidences gathered so far, it can be stated that Auoxos constitute a novel family of promising cytotoxic gold compounds with an innovative mechanism of action that merit a more extensive pharmacological evaluation.\",\"PeriodicalId\":23072,\"journal\":{\"name\":\"The Open Crystallography Journal\",\"volume\":\"78 1\",\"pages\":\"29-40\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2010-03-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"2\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Open Crystallography Journal\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.2174/1874846501003010029\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Open Crystallography Journal","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2174/1874846501003010029","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 2
摘要
六种金(III)双核氧桥配合物,类型为((bipy nR)Au(µ- o) 2 Au(bipy nR))(PF 6) 2,含有不同取代的2,2'-联吡啶配体(bipy nR = 2,2'-联吡啶,4,4'-二叔丁基-,6-甲基-,6-新戊基-,6-o-基-和6,6'-二甲基-2,2'-联吡啶),这里称为Auoxos,被制备,表征和最近测试为潜在的抗癌剂。获得了该系列中五个成员的晶体结构,使我们能够进行详细的比较分析。有趣的是,各种Auoxos在缓冲液中表现出可接受的稳定性,并在体外表现出出色的抗肿瘤性能。特别是,该家族的一个成员,Auoxo6 (bipy nR = 6,6'-二甲基-2,2'-联吡啶),比所有其他测试的Auoxos产生更强的选择性和更大的抗增殖作用,使其成为最佳的“候选药物”。反过来,对五种Auoxos的细胞毒性谱进行了比较分析,对36种人类肿瘤细胞系进行了研究,揭示了重要的机制差异;因此,许多可能的生物分子靶标可以被提出,如HDAC和PKC。生物物理研究表明,两种具有代表性的Auoxo化合物与小牛胸腺DNA的相互作用模式明显不同。此外,根据分光光度法和ESI MS数据,与模型蛋白的特殊反应性被记录下来,很可能是氧化还原过程的结果。鉴于目前收集到的几个实验证据,可以认为Auoxos是一个具有创新作用机制的有前景的细胞毒性金化合物的新家族,值得进行更广泛的药理学评价。
Dinuclear Gold(III) Complexes as Potential Anticancer Agents: Structure, Reactivity and Biological Profile of a Series of Gold(III) Oxo-BridgedDerivatives
Six homologous gold(III) dinuclear oxo-bridged complexes, of the type ((bipy nR )Au(µ-O) 2 Au(bipy nR ))(PF 6 ) 2 , bearing variously substituted 2,2'-bipyridine ligands (bipy nR = 2,2'-bipyridine, 4,4'-di-tert-butyl-, 6-methyl-, 6-neopentyl-, 6-o-xylyl- and 6,6'-dimethyl-2,2'-bipyridine), here called Auoxos, were prepared, characterised and recently tested as potential anticancer agents. Crystal structures were obtained for five members of the series that allowed us to perform detailed comparative analyses. Interestingly, the various Auoxos showed an acceptable stability profile in buffer solution and turned out to manifest outstanding antitumor properties in vitro. In particular, one member of this family, Auoxo6 (bipy nR = 6,6'-dimethyl-2,2'-bipyridine), produced more selective and far greater antiproliferative effects than all other tested Auoxos, qualifying itself as the best "drug candidate". In turn, COMPARE analysis of the cytotoxicity profiles of five Auoxos, toward an established panel of thirty-six human tumor cell lines, revealed important mechanistic differences; a number of likely biomolecular targets could thus be proposed such as HDAC and PKC. Biophysical studies revealed markedly different modes of interaction with calf thymus DNA for two representative Auoxo compounds. In addition, a peculiar reactivity with model proteins was documented on the ground of spectrophotometric and ESI MS data, most likely as the result of redox processes. In view of the several experimental evidences gathered so far, it can be stated that Auoxos constitute a novel family of promising cytotoxic gold compounds with an innovative mechanism of action that merit a more extensive pharmacological evaluation.