Dideoxynucleosides as Potential Anti-AIDS Drugs

基于我们碳环核苷项目的经验教训（Z 01 BC 006174）关于“延迟链终止”的机制，已经进行了三条研究路线以利用针对HIV抗性系的有效活性所必需的每个关键参数：1）在2 ′-脱氧核糖部分中引入可调体积的4 ′-烷基; 2）在2 '，3'-双脱氧糖部分的分子中的其它地方引入额外的OH基团以允许有限的链延长;和3）在核糖部分中掺入双键以实现环平坦性，这是被认为对于细胞激酶的有效磷酸化是必需的性质。报告突出强调了这三个领域的进展。1)带有4 '-甲基的胸苷类似物在体外作为5'-三磷酸抗HIV-RT时显示出作为延迟链终止剂的优异性质，但未能被细胞激酶识别。该化合物仅在用疱疹胸苷激酶基因转染的细胞中表现出优异的抗HIV活性。鉴于核碱基对于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)合成了一种含3 ′-CH_2 OH链的2 ′，3 ′-双脱氧腺苷类似物。在构象方面，新链的末端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，表明可能不能作为激酶底物。目前正在对5 '-triphoshate类似物进行研究，以确定其是否作为延迟链终止剂发挥作用。3)鉴于天然产物氧杂环丁烷A（一种具有扁平氧杂环丁烷环的化合物）的抗HIV活性的报道，结合用于链延长的4 '-CH 2 OH和用于实现环扁平的2'，3 '-双键的核苷的合成正在进行中。

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.