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TETHERED NUCLEOTIDE BIOMEDICAL PROBES

束缚核苷酸生物医学探针

基本信息

批准号：
2875495
负责人：
MICHAEL GROZIAK
金额：
$ 10万
依托单位：
SRI INTERNATIONAL
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-09-30 至 2000-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2875495
关键词：
X ray crystallography chemical structure function chemical synthesis conformation nuclear magnetic resonance spectroscopy nucleic acid probes nucleotide analog stereochemistry

项目摘要

Well-designed analogs of the naturally occurring ribo- and deoxyribonucleotides that are conformationally restricted by a transglycosidic tether would be valuable as biochemical, pharmacological, and biomedical probes and would have wide use in such fields of study as endonucleases, topoisomerases, ribozymes, oligonucleotide interstrand recognition, and many types of DNA and RNA structure-function relationships. However, the elements of their design must meet stringent criteria: (1) minimal structural disturbance caused by presence of the tether, (2) preservation of every natural hydrogen- bond donating/accepting molecular recognition site, (3) accessibility to both pyrimidine-and purine-based analogs, (4) conformational restriction of the glycosidic bond in the most commonly found bioactive anti form to retain the potential of A.T and C.G Watson-Crick-style base-pairing interactions, and (5) retention of all carbohydrate oxygen functionalities to allow potential incorporation into DNA or RNA oligonucleotide strands. The work will involve design, synthesis, and characterization of two new classes of nucleotide analogs that meet all of these criteria: (Class I) transglycosidically tethered ribo- and 2'-deoxyribonucleotide analogs derivable from 6-substituted pyrimidine and 8-substituted purine nucleosides and (Class II) transglycosidically tethered 2'- deoxyribonucleotide mimics derivable from 6-substituted pyrimidine and 8-substituted purine arabinofuranosides. The primary goal will be synthesis of the target Class I and II nucleotides in sufficient quantity for full structural characterization and for in-house and collaborative enzymatic, structural, and biological assays. Aspects of connectivity, stereoisomerism, and conformation in solution will be determined using high-field NMR spectroscopy; those in the solid state will be established by X-ray crystallography. Di-and triphosphates will be prepared, as will dinucleotides and related phosphoramidites. The Class I design will be modified to include structural features that may precipitate the irreversible inactivation of certain phosphodiester bond-hydrolyzing enzymes. Molecular modeling will be used to compare targets with natural counterparts, to analyze oligomers that will contain targets, and to evaluate potential interactions with enzymes of biomedical importance. All promising materials will be evaluated for antitumor, antiviral and biocidal potential.

天然存在的核糖和核糖核酸的精心设计的类似物脱氧核糖核苷酸，其在构象上受转糖苷系链作为生物化学，药理学和生物医学探针，并将广泛用于这种核酸内切酶、拓扑异构酶、核酶寡核苷酸链间识别，以及许多类型的DNA和RNA 结构-功能关系。然而，它们的设计元素必须符合严格的标准：（1）最小的结构干扰所造成的由于系绳的存在，（2）保存每一个天然氢- 供/受键分子识别位点，（3）可及性与嘧啶和嘌呤类似物，（4）构象限制糖苷键在最常见的生物活性反形式，以保留A.T和C.G沃森-克里克式的潜力碱基配对相互作用，和（5）保留所有碳水化合物氧允许潜在掺入DNA或RNA的功能寡核苷酸链。这项工作将涉及两种新的满足所有这些标准的核苷酸类似物的类别：（类别 I）转糖苷键连的核糖和2 '-脱氧核糖核苷酸类似物衍生自6-取代嘧啶和8-取代嘌呤核苷和（II类）转糖苷连接的2 '- 衍生自6-取代嘧啶的脱氧核糖核苷酸模拟物， 8-取代的嘌呤阿拉伯呋喃糖苷。主要目标将是以足够的量合成靶I类和II类核苷酸，全面结构表征和内部和协同的酶、结构和生物测定。方面溶液中的连接性、立体异构性和构象将是使用高场NMR光谱测定;那些在固态将通过X射线晶体学建立。二磷酸盐和三磷酸盐将如二核苷酸和相关的亚磷酰胺。的 I类设计将被修改，以包括可能使某些磷酸二酯不可逆地失活键水解酶分子建模将用于比较目标与天然对应物，以分析寡聚体，包含目标，并评估与酶的潜在相互作用，生物医学的重要性所有有希望的材料将被评估，抗肿瘤、抗病毒和杀菌潜力。