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

磷脂和DNA的选择性切割是至关重要的 在DNA修复过程和金属离子的作用机制中 化疗药物。一种高效金属抗癌药物的设计 抗病毒药物的体内靶点是DNA，它依赖于一种明确的 对金属-DNA识别和金属催化的理解 磷酸二酯水解法。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并被释放 通过金属催化的磷酸水解液。我们建议解决关键问题 关于金属-核苷酸分子识别性质的问题， 磷酸盐与金属的结合，并加强我们对金属的了解- Rh(III)和Rh(III)催化磷酸酯水解机理的研究 Ir(III)络合物作为模型体系。 取代-惰性过渡金属络合物(T_(1/2)>30S)的钴， Rh和Ir作为生物模型体系是非常有价值的。 对于结构和机械来说过于不稳定的活性金属 学习。Rh(III)和Ir(III)与Co(III)相比的主要优点是 如下：i)Rh(III)和Ir(III)配合物具有极强的取代- 惰性，并应使我们能够分离和表征类似的反应 相应的Co(III)的中间体 系统，ii)它们的离子大小更接近于生物相关的离子大小 镁(II)、锰(II)等离子，以及Rh(III)的核磁共振研究 复合体可以提供重要的结构和机械信息 既是通过直接观察103Rh核，也是通过与其他 系统中的细胞核。 我们建议合成、分离和表征Rh(III)和Ir(III) [MLchiPn]型络合物，其中L=磷酸盐部分。我们会研究 一、二和三磷酸配体和核苷酸(腺病、鸟苷、 胞嘧啶和尿苷一、二和三磷酸)，包括环 核苷酸。我们将阐明磷酸盐-金属配位的方式 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.