CARBOCYCLIC NUCLEOSIDE ISOSTERES AS POTENTIAL ANTITUMOR AND ANTIVIRAL AGENTS

核苷和核苷酸本质上是由糖段和杂环组成的柔性分子。糖部分的构象灵活性可以用三角函数的数学表达式来描述。称为伪旋转相角(P)？这包含了糖环的五个扭转角的贡献。P的首选范围确定了两个主要结构域，以北构象（P = 0）和南构象（P = 180）为中心，它们在溶液中迅速平衡。在这些结构域中，连接糖和杂环碱的键（糖基扭角）采用优先取向（顺或反），这对于识别和结合蛋白质至关重要。解释核苷和核苷酸的结构-活性相关性的主要障碍之一是这种高水平的灵活性。在过去的几年里，我们设计了一系列新的核苷，其中柔性糖部分被刚性碳环（即双环[3.1.0]己烷）取代，模仿传统核苷的北或南构象。我们的第一个目标是系统地探索一系列核苷/核苷酸结合酶与一系列构象刚性的北底物和南底物，以了解首选的结合模式。我们的第二个目标是构建含有这些固定单元的修饰核酸，以加强或破坏分别与南糖模板和北糖模板相关的典型B-或A-DNA构象。我们在这两个目标方面都取得了重大进展。除了去年报道的酶，hiv逆转录酶，腺苷脱氨酶和s -腺苷同型半胱氨酸水解酶，我们还增加了脱氧胞苷激酶和一些腺苷受体，如P2Y1受体。在研究的每一个案例中，我们发现有一个明确的偏好结合到一个特定的构象。这些研究的结果已经发表或出版。其次，我们合成了第一个含有构象刚性核苷或糖（基本位点）的DNA，以探索DNA结合酶的偏好。例如，DNA甲基转移酶被含有刚性南基位的13聚双链强烈抑制，而含有北基位的13聚双链则完全无活性。这一结果强烈表明，完整的GCGC结合域的B-DNA结构对于酶识别是重要的。鉴于双环[3.1.0]己烷体系带来的合成挑战，以及对大量此类类似物的需求不断增加，我们最近通过一种新的碳插入反应成功地组装了这些分子，该反应一步生成了整个双环结构。AIDS题目：用于辅助治疗AIDS的抗疱疹和抗hcmv化合物——碳环核苷、化疗、DNA结合、分子模型、核酸化学、

Nucleosides and nucleotides are inherently flexible molecules comprised of a sugar moiety and a heterocyclic ring. The conformational flexibility of the sugar moiety can be mathematically described as a trigonometric expression ?known as pseudorotational phase angle (P)? that encompasses the contribution of the five torsion angles of the sugar ring. The preferred ranges of P define two main domains centered around a North conformation (P = 0) and a South conformation (P = 180) which equilibrate rapidly in solution. In each of these domains the bond linking the sugar to the heterocyclic base (glycosyl torsion angle) adopts a preferred orientation (syn or anti) which is critical for recognition and binding to proteins. One of the main obstacles in interpreting structure-activity correlations in nucleosides and nucleotides is this high level of flexibility. For the past several years we have designed a series of novel nucleosides where the flexible sugar moiety has been replaced by a rigid carbocyclic ring (i.e., bicyclo[3.1.0]hexane) that mimics either the North or South conformation of conventional nucleosides. Our first objective is to systematically probe a series of nucleoside/nucleotide binding enzymes with sets of conformationally rigid North and South substrates to learn about the preferred mode of binding. Our second objective is to construct modified nucleic acids that incorporate some of these fixed units to either reinforce or disrupt the typical B- or A-DNA conformations that are associated, respectively, with South and North sugar templates. We have made significant progress towards both of these goals. In addition to the enzymes reported last year, HIV-reverse transcriptase, adenosine deaminase and S-adenosylhomocysteine hydrolase, we have added deoxycytidine kinase and several adenosine receptors like the P2Y1 receptor. In each of the cases studied, we find that there is a definitive preference to bind to a particular conformer. The results from these studies have been published or in press. Secondly, we have synthesized the first DNAs containing either conformationally rigid nucleosides or sugars (abasic sites) to probe the preference of DNA binding enzymes. For example, DNA methyltransferase is strongly inhibited by a 13-mer duplex containing a rigid South abasic site, whereas the 13-mer duplex containing the North abasic site was totally inactive. This result strongly suggests that an intact B-DNA structure of the GCGC binding domain is important for enzyme recognition. In view of the synthetic challenge presented by the bicyclo[3.1.0]hexane system, and the increasing demand for large quantities of these analogues, we have recently succeeded in assembling these molecules by a novel carbene insertion reaction where the entire bicyclic structure is generated in one step.AIDS title: Antiherpetic and Anti-HCMV Compounds for the Adjuvant Treatment of AIDS - carbocyclic nucleosides, chemotherapy, DNA binding, molecular models, nucleic acid chemistry,