CONFORMATIONAL STUDIES OF NEW ANTITUMOR AGENTS

药物分子的构象与其结构密切相关 功能。这项研究将确定对药物的潜在限制 实验性抗肿瘤药物噻唑呋喃和环丙沙星的构象 硒氮呋喃。 噻唑呋喃(Tf)和硒(SF)是一种新的C-糖基 目前正在进行临床试验的核苷。在体内，Tf和Tf SF并入辅因子NAD的类似物中。这些 NAD类似物作为一磷酸肌苷的抑制剂 脱氢酶，细胞毒性的推定原因。结晶体 Tf和Sf的结构显示出不寻常的紧密接触 碱(S或硒)和呋喃糖环氧中的杂原子， 这表明这些药物的构象和/或它们的 NAD类似物在溶液中可能受到限制。如果是这样的话 对药物结合和活性的重要影响。 计算结果表明，杂原子-氧 相互作用在一定程度上是静电作用。因此，两者之间的相关性 杂环电荷和糖基键构象将是 在一系列新的碱基取代的噻唑类类似物中进行了研究。 和硒氮呋喃。结晶学、计算和核磁共振 将采用各种技术。结晶学数据库综述 显示分子内紧密连接的化合物将是 以进一步确定 杂原子-氧相互作用。核磁共振实验采用一种 各种质子和异核技术将检查 的母体化合物和NAD类似物的构象 解决方案。酶抑制和建模研究将调查 NAD类似物与其他脱氢酶和 结合能力与糖基键变化的相关性 构象。

The conformation of a drug molecule is initimately related to its function. This research will identify potential constraints on drug conformation in the experimental antitumor agents tiazofurin and selenazofurin. Tiazofurin (TF) and selenazofurin (SF) are new C-glycosyl nucleosides currently undergoing clinical trials. In vivo, TF and SF are incorporated into analogues of the cofactor NAD. These NAD analogues act as inhibitors of inosine monophosphate dehydrogenase, the putative cause of cytotoxicity. Crystal structures of TF and SF show unusual close contacts between the heteroatom in the base (S or Se) and the furanose ring oxygen, suggesting that the conformations of these agents and/or their NAD analogues may be restricted in solution. This would have important implications for drug binding and activity. Computational results suggest that the heteroatom-oxygen interaction is in part electrostatic. Thus, the correlation between heterocycle charge and glycosyl bond conformation will be examined in a series of new base-substituted analogues of tiazo- and selenazofurin. Crystallographic, computational and NMR techniques will be employed. A crystallographic data base survey of compounds showing close intramolecular contracts will be performed in order to further identify the origins of the heteroatom-oxygen interaction. NMR experiments employing a variety of proton and heteronuclear techniques will examine the conformation of the parent compounds and the NAD analogues in solution. Enzyme inhibition and modeling studies will investigate binding of the NAD analogues to other dehydrogenases and correlate binding ability with changes in glycosyl bond conformation.