INERT TRANSITION METAL/NUCLEOTIDE INTERACTIONS--MODELS FOR BIOLOGICAL PROCESSES

磷脂和 DNA 的选择性切割至关重要 在 DNA 修复过程和金属作用机制中 化疗剂。 有效金属抗癌药物的设计 抗病毒药物的体内靶标是DNA，依赖于明确的 了解金属-DNA 识别和金属催化 磷酸二酯水解。 此外，很大一部分能量 生命系统的货币存储在磷酸二酯债券中并释放 通过金属催化的磷酸盐水解。 我们建议解决关键问题 关于金属核苷酸分子识别本质的问题， 磷酸盐-金属结合并增强我们对金属-的理解 使用Rh(III)和催化磷酸酯水解机制 Ir(III) 配合物作为模型系统。 Co的取代惰性过渡金属配合物（t1/2大于30s）， Rh 和 Ir 作为生物学模型系统非常有价值 对于结构和机械而言太不稳定的活性金属 研究。 Rh(III) 和 Ir(III) 相对于 Co(III) 的主要优点是 以下： i) Rh(III) 和 Ir(III) 络合物是高度取代的- 惰性，应该允许我们分离和表征反应的类似物 已提议用于相应 Co(III) 的中间体 系统，ii) 它们的离子尺寸更接近生物学相关的离子尺寸 Mg(II) 和 Mn(II) 等离子，以及 iii) Rh(III) 的 NMR 研究 配合物可以提供重要的结构和机械信息 通过直接观察 103Rh 核和通过与其他核的耦合 系统中的原子核。 我们建议合成、分离和表征 Rh(III) 和 Ir(III) [MLchiPn] 类型的复合物，其中 L=磷酸盐部分。 我们将学习 单磷酸、二磷酸和三磷酸配体和核苷酸（腺苷、鸟苷、 胞嘧啶和尿苷单磷酸、二磷酸和三磷酸），包括环状 核苷酸。 我们将阐明磷酸盐-金属配位模式 并将分离和表征磷酸盐中的关键中间体 水解反应。

The selective cleavage of phospholipids and DNA is of critical importance in the DNA repair processes and in the mechanism of action of metallo- chemotherapeutic agents. The design of effective metallo-anticancer and antiviral drugs, whose in vivo target is DNA, depends on a clear understanding of the metal-DNA recognition and of metal-catalyzed phosphodiester hydrolysis. In addition, a large part of the energy currency of living systems is stored in phosphodiester bonds and released through metal-catalyzed phosphate hydrolysis. We propose to address key questions on the nature of metal-nucleotide molecular recognition, phosphate-metal binding and to enhance our understanding of the metal- catalyzed phosphate ester hydrolysis mechanisms by using Rh(III) and Ir(III) complexes as model systems. Substitution-inert transition metal complexes (t1/2 more than 30s) of Co, Rh, and Ir are extremely valuable as model systems for the biologically active metals which are too labile for structural and mechanistic studies. Key advantages of Rh(III) and Ir(III) over Co(III) are the following: i) Rh(III) and Ir(III) complexes are extremely substitution- inert and should allow us to isolate and characterize analogs of reaction intermediates which have been proposed for the corresponding Co(III) systems, ii) their ion size is closer to that of biologically relevant ions such as Mg(II) and Mn(II), and iii) NMR studies of Rh(III) complexes can provide important structural and mechanistic information both by direct observation of the 103Rh nucleus and by coupling to other nuclei in the system. We propose to synthesize, isolate and characterize Rh(III) and Ir(III) complexes of the type [MLchiPn] where L=phosphate moiety. We will study mono-, di, and triphosphate ligands and nucleotides (adenosis, guanosine, cytosine and uridine mono-, di- and triphosphates), including cyclic nucleotides. We will elucidate the mode of phosphate-metal coordination and will isolate and characterize key intermediates in the phosphate hydrolysis reaction.