CARBOCYCLIC NUCLEOSIDE ISOSTERES AS POTENTIAL ANTITUMOR AND ANTIVIRAL AGENTS

核苷和核苷酸是由糖部分和杂环组成的固有的柔性分子。糖基的构象柔性可以用三角表达式来描述，称为赝旋相角(P)？这包括了糖环的五个扭转角的贡献。P的优选范围定义了以北构象(P=0)和南构象(P=180)为中心的两个主要结构域，这两个构象在溶液中迅速平衡。在这些结构域中，连接糖和杂环碱基的键(糖基扭转角)采用了优先取向(syn或anti)，这对于识别和结合蛋白质是至关重要的。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度的灵活性。在过去的几年里，我们设计了一系列新的核苷，其中柔性糖部分被一个刚性碳环环(即双环[3.1.0]己烷)取代，它模仿传统核苷的南北构象。我们的第一个目标是系统地探索一系列具有构象刚性的南北底物的核苷/核苷酸结合酶，以了解首选的结合模式。我们的第二个目标是构建含有其中一些固定单位的修饰核酸，以增强或破坏分别与南方和北方糖模板相关的典型B-DNA或A-DNA构象。我们在实现这两个目标方面取得了重大进展。除了去年报道的酶，艾滋病毒逆转录酶，腺苷脱氨酶和S同型半胱氨酸腺苷水解酶，我们还增加了脱氧胞苷激酶和几个腺苷受体，如P2Y1受体。在所研究的每一种情况下，我们发现都有一个明确的偏好结合到特定的构象上。这些研究的结果已经发表或出版了。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方碱性位点的13-聚体双链强烈抑制，而含有北方碱性位点的13-聚体双链完全不活跃。这一结果有力地表明，GCGC结合域的完整B-DNA结构对于酶的识别是重要的。鉴于双环[3.1.0]己烷体系带来的合成挑战，以及对这些类似物日益增长的需求，我们最近通过一种新的卡宾插入反应成功地组装了这些分子，其中整个双环结构一步生成。艾滋病标题：用于辅助治疗艾滋病的抗疱疹和抗巨细胞病毒化合物-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 For the past several years we have designed a series of novel nucleosides where the flexible sugar moiety has been replaced by a rigid carbocyclic ring (i.e., bicyclo[3.1.0]hexane) that mimics either the North or South conformation of conventional nucleosides.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,