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

磷脂和DNA的选择性裂解是至关重要的 在DNA修复过程和金属的作用机制中， 化疗剂。 有效金属抗癌药物的设计 抗病毒药物，其体内靶点是DNA，依赖于一个明确的 理解金属-DNA识别和金属催化的 磷酸二酯水解 此外，很大一部分能源 生命系统的货币储存在磷酸二酯键中， 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-核苷酸分子识别的性质的问题， 磷酸盐-金属结合，并提高我们对金属的理解- 通过使用Rh（III）催化的磷酸酯水解机理， Ir（III）配合物作为模型体系。 Co的取代惰性过渡金属络合物（t1/2大于30 s）， Rh和Ir作为生物学的模型系统是非常有价值的。 对于结构和机械来说太不稳定的活性金属 问题研究 Rh（III）和Ir（III）相对于Co（III）的主要优点是 Rh（III）和Ir（III）配合物是非常取代的- 它是惰性的，应该可以让我们分离和表征类似的反应 已提出的相应Co（III）的中间体 系统，ii）它们的离子大小更接近生物相关的 离子如Mg（II）和Mn（II），和iii）Rh（III）的NMR研究 复合物可以提供重要的结构和机理信息 通过直接观察103 Rh核和与其他核的耦合， 系统中的原子核。 我们计划合成、分离和表征Rh（III）和Ir（III） [MLchiPn]型复合物，其中L=磷酸部分。 我们将研究 单、二和三磷酸配体和核苷酸（腺病，鸟苷， 胞嘧啶和尿苷单磷酸、二磷酸和三磷酸），包括环 个核苷酸 我们将阐明磷酸盐-金属配位的模式 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.