Dinuclear Ruthenium Complexes for Cancer Treatment

描述（由申请人提供）：基于Pt（II）的药物在人类癌症化疗中的广泛成功引起了对另一种过渡金属Ru（II）作为抗癌剂的潜力的兴趣[3]。许多DMA结合的阳离子双核Ru（II）多吡啶基络合物已经以外消旋形式制备，并且在培养的恶性细胞系以及在同基因原位小鼠黑素瘤模型中的初步研究显示出有希望的抗肿瘤活性。据推测，这些Ru（II）配合物中的一些可以开发成有效的抗癌剂，并且Ru（II）配合物的抗肿瘤活性可以基于特定的、可调的结构特征来预测。我们建议在以下三个具体目标的研究中验证我们的假设：1。确定Ru（II）配合物在培养的人恶性细胞以及上皮细胞中的抗肿瘤活性。这些研究将解决这样的假设，即这些Ru（II）络合物中的一些将对一系列组织学类型的人类癌症表现出抗肿瘤活性。2.确定Ru（II）配合物的结构-毒性关系。这些研究将解决具有17 A桥的类似物对小鼠不会有急性毒性而具有12 A桥的类似物有毒性的假设。他们还将解决的假设，绝对手性的复合物可以影响毒性的水平，因为不同的能力的两种对映异构体抑制乙酰胆碱酯酶活性。3.确定Ru（II）配合物的结构-活性关系。这些研究将解决具有长的氧化还原活性桥连配体的络合物在嵌入、氧化还原活性和抗肿瘤活性方面上级较短的非氧化还原活性桥的假设。这些研究也将解决的假设，光学解决（对映体纯）复合物将表现出不同的DNA结合能力，因此表现出不同的DNA结合活性。过渡金属，特别是Pt（II）在人类化疗中的使用已经导致许多癌症患者的预后的显著改善。另一种金属Ru（II）具有类似的性质，并且正在探索其在化疗中的潜力。初步结果是有希望的。

DESCRIPTION (provided by applicant): The broad success of Pt(ll) based drugs in human cancer chemotherapy, has led to interest in the potential for another transition metal, Ru (II), as an antineoplastic agent [3]. A number of DMA-binding, cationic dinuclear Ru(ll) polypyridyl complexes have been prepared in racemic form, and preliminary studies in cultured malignant cell lines as well as in isogenic, orthotopic mouse melanoma model show promising antineoplastic activity. It is hypothesized that some of these Ru(ll) complexes can be developed into effective anticancer agents, and that the antitumor activity of Ru(ll) complexes can be predicted on the basis of specific, tunable structural features. We propose to test our hypothesis in studies with these three specific aims: 1. Defining the antineoplastic activity of Ru(ll) complexes in cultured human malignant cells as well as with epithelial cells. These studies will address the hypothesis that some of these Ru(ll) complexes will exhibit antineoplastic activity against an array of histological types of human cancers. 2. Determining the structure-toxicity relationships for Ru(ll) complexes. These studies will address the hypothesis that analogs with 17 A bridges will not be acutely toxic to mice whereas those with the 12 A bridges will be toxic. They will also address the hypothesis that the absolute chirality of the complex can affect the level of toxicity because of the differing ability of the two enantiomers to inhibit acetylcholinesterase activity. 3. Determining the structure-activity relationships for Ru(ll) complexes. These studies will address the hypothesis that the complexes with long, redox-active bridging ligands will be superior to the shorter, non- redox active bridges for intercalation, redox activity, and anti-tumor activity. These studies will also address the hypothesis that optically resolved (enantiopure) complexes will exhibit different DNA binding abilities and therefore exhibit different antineoplastic activity. The use of transition metals, in particular Pt(ll), in human chemotherapy has led to dramatic improvements in the prognosis for a great many cancer patients. Another metal, Ru(ll), has similar properties and is being explored for its potential in chemotherapy. Preliminary results are promising.