AN IMPROVED SYNTHESIS OF OLIGODEOXYRIBONUCLEOSIDE PHOSPHOROTHIOATES

一段时间以来，已知反义硫代磷酸互补物是一种抗肿瘤药物。 对HIV-1 rev基因的信使RNA抑制了细胞病变， 病毒在慢性感染的H9细胞中的作用。 的可用性 因此，这些寡核苷酸类似物对于生物医学至关重要。 调查事务所 我们实验室最近报道了使用3 H-1，2-苯并二硫杂环戊烯-3- 一种1，1-二氧化物作为硫转移试剂， 寡脱氧核苷硫代磷酸酯。 推进 硫转移试剂Judith B的可及性。里根和 P.I.已经扩大规模并改进了试剂的制备。 这 程序已发表在有机制备和程序 国际化. 寡核苷硫代磷酸酯本身对核酸酶具有抗性 因此难以表征。 一种方法来轻松 对糖苷硫代磷酸酯的表征将是 通过氧化脱硫将它们转化为天然寡核苷酸。 我们的实验室投入了大量的精力来筛选各种 用于糖苷固相转化的氧化剂 硫代磷酸三酯转化为相应的磷酸三酯。 它 已经发现，0.05M的单过氧邻苯二甲酸在 冰醋酸是理想的脱硫剂， 硫代磷酸酯低聚物。 然而，这种试剂引起了 胞嘧啶环的修饰。 寻找新的氧化剂， 硫代磷酸酯低聚物的脱硫被放弃。 此外，硫代磷酸酯低聚物转化为 氨基磷酸酯寡核苷酸，另一类抗核酸酶 寡核苷酸，但尚未导致试剂 能够进行干净和快速的转换。

It is known for some time that antisense phosphorothioate complementary to the messenger RNA of the HIV-1 rev gene inhibited the cytopathic effect of the virus in chronically infected H9 cells. The availability of these oligonucleotide analogues is thus critical for biomedical investigations. Our laboratory has recently reported the use of 3H-1,2-benzodithiole-3- one 1,1-dioxide as a sulfur-transfer reagent in the synthesis of oligodeoxyribonucleoside phosphorothioates. To promote the accessibility of the sulfur-transfer reagent, Judith B. regan and the P.I. have scaled up and improved the preparation of the reagent. This procedure has been published in Organic Preparations and Procedures International. Oligonucleoside phosphorothioates are inherently resistant to nucleases and are therefore difficult to characterize. One approach to the facile characterization of oligonucleoside phosphorothioates would be to convert them to natural oligonucleotides via oxidative desulfurization. Our laboratory has invested considerable efforts in screening various oxidants for the solid-phase conversion of oligonucleoside phosphorothioate triesters to the corresponding phosphotriesters. It has been found that a 0.05 M solution of monoperoxyphthalic acid in glacial acetic acid was ideal for the desulfurization of phosphorothioate oligomers. However, this reagent caused the modification of the cytosine ring. The search for new oxidants for the desulfurization of phosphorothioate oligomer was abandoned. In addition, the conversion of phosphorothioate oligomers to phosphoramidate oligonucleotides, another class of nuclease-resistant oligonucleotides, has been investigated but has not led to a reagent capable of performing a clean and rapid conversion.