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首页> 外文期刊>Dalton transactions: An international journal of inorganic chemistry >Cobalt complexes with tripodal ligands: implications for the design of drug chaperones
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Cobalt complexes with tripodal ligands: implications for the design of drug chaperones

机译：具有三脚架配体的钴配合物：对药物伴侣设计的影响

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Extensive research is currently being conducted into metal complexes that can selectively deliver cytotoxins to hypoxic regions in tumours. The development of pharmacologically suitable agents requires an understanding of appropriate ligand-metal systems for chaperoning cytotoxins. In this study, cobalt complexes with tripodal tren (tris-(2-aminoethyl)amine) and tpa (tris-(2-pyridylmethyl)amine) ligands were prepared with ancillary hydroxamic acid, β-diketone and catechol ligands and several parameters, including: pKa, reduction potential and cytotoxicity were investigated. Fluorescence studies demonstrated that only tpa complexes with β-diketones showed any reduction by ascorbate in situ and similarly, cellular cytotoxicity results demonstrated that ligation to cobalt masked the cytotoxicity of the ancillary groups in all complexes except the tpa diketone derivative [Co(naac)tpa](C104) (naac = 1-methyl-3-(2-naphthyl)-propane-1,3-dione). Additionally, it was shown that the hydroxamic acid complexes could be isolated in both the hydroxamate and hydroximate form and the pKa values (5.3-8.5) reveal that the reversible protonation/deprotonation of the complexes occurs at physiologically relevant pHs. These results have clear implications for the future design of prodrugs using cobalt moieties as chaperones, providing a basis for the design of cobalt complexes that are both more readily reduced and more readily taken up by cells in hypoxic and acidic environments.
机译：目前正在对可将细胞毒素选择性地递送至肿瘤低氧区域的金属络合物进行广泛的研究。药理学上合适的试剂的开发需要了解用于伴侣蛋白的合适的配体-金属系统。在这项研究中，用辅助异羟肟酸，β-二酮和邻苯二酚配体制备了具有三脚架tr（三（2-氨基乙基）胺）和tpa（三-（2-吡啶甲基甲基）胺）配位体的钴配合物，并包括以下几个参数： ：研究了pKa，还原电位和细胞毒性。荧光研究表明，只有带有β-二酮的tpa配合物显示出原位抗坏血酸的还原作用，并且类似地，细胞毒性结果表明，钴的连接掩盖了除tpa二酮衍生物[Co（naac）tpa以外的所有配合物的辅助基团的细胞毒性。 ]（C104）（naac ＝ 1-甲基-3-（2-萘基）丙烷-1,3-二酮）。另外，表明异羟肟酸复合物可以异羟肟酸酯和异羟肟酸酯形式分离，并且pKa值（5.3-8.5）揭示了该复合物的可逆质子化/去质子化发生在生理学相关的pH下。这些结果对于使用钴部分作为分子伴侣的前药的未来设计具有明显的意义，这为设计钴复合物提供了基础，钴复合物在低氧和酸性环境中更容易还原，也更容易被细胞吸收。

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