Dideoxynucleosides as Potential Anti-AIDS Drugs

具有常规2-脱氧核糖骨架的抗HIV核苷的研究 继续，保持而不是消除3-OH基团，但添加4-烷基 （甲基和乙基）以干扰链延长步骤。最近合成的 相应的4-甲基-2-脱氧腺苷系列提供了既成功地 被细胞激酶磷酸化，在感染细胞中对HIV非常有效。这 代表了该类化合物的首次成功设计， 通过细胞激酶和能够作为一个有效的延迟（动力学延迟）链 病毒DNA合成终止子。申请了美国专利。对另一种化合物的研究， D-卡巴胸苷，也可被细胞酶磷酸化，对所有 艾滋病毒耐药菌株，代表了我们在药物设计方面的重要一步， 克服艾滋病毒的抗药性。对该化合物作用机理的研究也即将展开 (J.出版中）。构象锁定和平面构型的合成 二环[3.1.0]己-3-烯核苷在伪旋转的南北半球 含有胸腺嘧啶、胞嘧啶、鸟嘌呤和腺嘌呤作为核碱基的循环完成。的 大多数带有腺嘌呤和胸腺嘧啶环的活性化合物存在于北半球。这些 结果最近发表在ChemMedChem上，该工作的图形摘要 被选为该杂志的封面（ChemMedChem 2009，出版中）。这个目标 该项目是使用基本的药物设计原则，从我们的知识， HIV逆转录合成新分子的机制， 延迟链终止子，并作为激活细胞的有效底物 激酶。

The study of anti-HIV nucleosides bearing a conventional 2-deoxyribose backbone continued, maintaining rather than eliminating the 3-OH group, but adding a 4-alkyl group (methyl and ethyl) to interfere with the chain elongation step. The recent synthesis of the corresponding 4-methyl-2-deoxyadenosine series provided a compound that is both successfully phosphorylated by cellular kinases and extremely potent against HIV in infected cells. This represents the first successful design of a compound in this class capable of being activated by cellular kinases and able to function as an effective delay (kinetic delay) chain terminator of viral DNA synthesis. A US patent was filed. Studies on another compound, D-carbathymidine, which is also phosphorylated by cellular enzymes and active against all HIV-resistant strains, represents an important step forward in our drug design efforts to overcome HIV resistance. The investigations on the mechanism of this compound will appear soon (J. Med. Chem. in press). The syntheses of conformationally locked and flat bicyclo[3.1.0]hex-3-ene nucleosides in both north and south hemisphere of the pseudorotational cycle containing thymine, cytosine, guanine, and adenine as nucleobases were completed. The most active compounds bearing adenine and thymine rings reside in the North hemisphere. These results were published recently in ChemMedChem and the graphical abstract of the work was selected for the cover page of the journal (ChemMedChem 2009, in press). The goal of this project is to use fundamental drug design principles derived from our knowledge about the mechanism of HIV reverse transcription to synthesize new molecules that might function as delayed chain terminators, and work as efficient substrates for the activating cellular kinases.