Dideoxynucleosides as Potential Anti-AIDS Drugs

基于我们从碳环核苷（Z01 BC 006174）项目中获得的关于“延迟链终止”机制的经验教训，我们实施了三条研究路线，以利用有效抗HIV抗性系活性所需的每个关键参数：1)在2'-脱氧核糖片段中引入4'-烷基可调基团；2)在2',3'-二脱氧糖部分分子的其他地方引入额外的OH基团，以允许有限的链伸长；3)在核糖片段中结合双键以实现环平坦度，这是细胞激酶有效磷酸化所必需的特性。报告强调了这三个领域的进展。1)一种含有4′-甲基的胸腺嘧啶类似物作为5′-三磷酸在体外抗HIV-RT中表现出优异的延迟链终止物特性，但不能被细胞激酶识别。该化合物仅在转染了疱疹胸苷激酶基因的细胞中表现出优异的抗hiv活性。鉴于核碱基对选择特定细胞磷酸化途径的重要性，类似的4'-甲基-2'-脱氧嘌呤类似物的合成正在进行中。2)完成了具有3′-CH2OH链的2′，3′-二脱氧腺苷类似物的合成并进行了研究。在构象方面，新链末端OH的位置允许细胞激酶识别，并为聚合酶提供有限链延伸的机会。该化合物未能显示出体外抗hiv活性，表明可能作为激酶底物失败。对5'-三磷酸类似物的研究正在进行中，以确定它是否作为延迟链终止物起作用。3)鉴于已报道的天然产物oxetanocin A的抗hiv活性，一种具有平坦氧基环的化合物，正在合成一种结合4'-CH2OH的链延伸和2',3'-双键的核糖体，以实现环的平坦性。

Based on the lessons learned from our project on carbocyclic nucleosides (Z01 BC 006174) regarding the mechanism of "delayed chain termination", three lines of investigation have been implemented to exploit each of the critical parameters necessary for efficient activity against HIV resistant lines: 1) introduction of a 4'-alkyl group of tunable bulk in a 2'-deoxyribose moiety; 2) introduction of an extra OH group elsewhere in the molecule of a 2',3'-dideoxysugar moiety to allow limited chain elongation; and 3) the incorporation of a double bond in the ribose moiety to achieve ring flatness, a property deemed essential for efficient phosphorylation by cellular kinases. Progress in these three areas is highlighted. 1) A thymidine analogue bearing a 4'-methyl group showed excellent properties as a delayed chain terminator when used in vitro against HIV-RT as the 5'-triphosphate, but failed to be recognized by cellular kinases. The compound demonstrated excellent anti-HIV activity only in cells transfected with the herpes thymidine kinase gene. In view of the importance of the nucleobase for the selection of specific cellular phosphorylation pathways, the synthesis of similar 4'-methyl-2'-deoxypurine analogues is ongoing. 2) Synthesis of a 2',3'-dideoxy adenosine analogue with a 3'-CH2OH chain was completed and studied. In conformational terms the position of the terminal OH of the new chain was to allow recognition by cellular kinases and to provide the polymerase the opportunity of limited chain elongation. This compound failed to displayed in vitro anti-HIV activity suggesting probable failure as a kinase substrate. Studies with the 5'-triphoshate analogue are in progress to determine if it operates as a delayed chain terminator. 3) In view of the reported anti-HIV activity of the natural product oxetanocin A, a compound with a flat oxetan ring, synthesis of a riboside combining a 4'-CH2OH for chain elongation and a 2',3'-double bond to achieve ring flatness is in progress.