Synthesis of new transglycosidically tethered 5'-nucleotides constrained to a highly biologically relevant profile.
Synthesis of new transglycosidically tethered 5'-nucleotides constrained to a highly biologically relevant profile.
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合成新的转糖苷连接的 5-核苷酸，具有高度生物学相关性。
DOI：
10.1021/jo0110045
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Thomas,DavidW
中科院分区：
文献类型：
--
作者：
Groziak,MichaelP;Thomas,DavidW
已经开发了用于将5 '-核苷酸限制为高度生物学相关构象的新基序。尿苷5 '-单磷酸和2'-脱氧尿苷5 '-单磷酸的5'，6-氧亚甲基转糖苷连接形式（分别为1和2）是从它们各自的天然核苷前体沿着制备各种5 '-核苷酸基化合物的连接形式的一般路线在10−11个步骤中合成的。在这两种途径中，储存稳定的6-羟甲基嘧啶核苷5 '-甲醛是关键中间体。它在非质子条件下以环状半缩醛形式以类似碳水化合物的方式存在。磷酸化的环状半缩醛1和2被分离为5 '-非对映异构体的二元混合物，其主要不同之处在于磷酸基团相对于碳水化合物的轨迹。1H NMR结果表明，1和2在室温D2 O溶液中至少能稳定水解2个月。在1和2中部署的氧亚甲基转糖苷系链保留了所有天然的5 '核苷酸分子识别位点，同时将框架限制为低能抗糖基构象和延长的磷酸盐配置。这提供了一个空间存在，接近蛋白质数据库中描述的蛋白质结合的5 '-核苷酸配体的近四分之三。系链具有低的结构和电子影响，占据很少被蛋白质穿透的空间区域（在呋喃环的β-面上），并且应该像在基于嘧啶的框架上一样容易地容纳在基于嘌呤的5 '-核苷酸框架上。由于其独特的和有吸引力的功能，这种新的基序的构象限制的5 '-核苷酸，预计将是有用的，用于生产探针的结构/功能关系，并在评估构象结合的要求，酶和受体位点有其天然的5'-核苷酸为基础的配体。
A new motif for restricting 5‘-nucleotides to highly biologically relevant conformations has been developed. The 5‘,6-oxomethylene transglycosidically tethered versions of uridine 5‘-monophosphate and 2‘-deoxyuridine 5‘-monophosphate (1and2, respectively) were synthesized in 10−11 steps from their respective natural nucleoside precursors along routes general to the preparation of tethered versions of a wide variety of 5‘-nucleotide-based compounds. In both routes, a shelf-stable 6-hydroxymethyl pyrimidine nucleoside 5‘-carboxaldehyde is the key intermediate. It exists in a carbohydrate-like fashion in a cyclic hemiacetal form under aprotic conditions. The phosphorylated cyclic hemiacetals1and2were isolated as binary mixtures of 5‘-diastereomers differing principally in the trajectory of the phosphate group with respect to the carbohydrate. By1H NMR, both1and2were demonstrated to be stable to hydrolysis at ambient temperature in D2O solution for at least 2 months. The oxomethylene transglycosidic tether as deployed in1and2leaves all of the native 5‘-nucleotide molecular recognition sites intact while it restricts the framework to a low-energy anti glycosyl conformation and an extended phosphate disposition. This provides a spatial presence that approximates nearly three-quarters of the protein-bound 5‘-nucleotide ligands described in the Protein Data Bank. The tether has a low structural and electronic impact, occupies a region of space (over the β-face of the furan ring) seldom penetrated by proteins, and should be accommodated as readily on purine-based 5‘-nucleotide frameworks as on pyrimidine-based ones. Because of its unique and attractive features, this new motif for the conformational restriction of 5‘-nucleotides is expected to be useful for producing probes of structure/function relationships and in assessing the conformational binding requirements that enzymes and receptor sites have for their natural 5‘-nucleotide-based ligands.