Dideoxynucleosides as Potential Anti-AIDS Drugs

携带传统2-脱氧核糖骨架的抗hiv核苷的研究继续进行，保留而不是消除3-OH基团，但加入一个4-烷基（甲基和乙基）来干扰链延伸步骤。最近相应的4-甲基-2-脱氧腺苷系列的合成提供了一种化合物，它既能被细胞激酶成功磷酸化，又能在感染细胞中对HIV病毒极有效。这代表了这类化合物的第一个成功设计，能够被细胞激酶激活，并能够作为病毒DNA合成的有效延迟（动力学延迟）链终止器。申请了美国专利。另一种化合物d -氨基乙胺的研究也被细胞酶磷酸化，对所有HIV耐药菌株都有活性，这是我们在克服HIV耐药的药物设计工作中迈出的重要一步。对该化合物作用机理的研究将很快出现（J. Med. Chem.）。在出版社)。在以胸腺嘧啶、胞嘧啶、鸟嘌呤和腺嘌呤为核碱基的假旋回循环中，完成了构象锁定和平面双环[3.1.0]己-3-烯核苷的合成。最活跃的含有腺嘌呤和胸腺嘧啶环的化合物存在于北半球。这些结果最近发表在ChemMedChem杂志上，该工作的图形摘要被选为该杂志的封面（ChemMedChem 2009，出版中）。这个项目的目标是利用我们对HIV逆转录机制的了解得出的基本药物设计原则来合成可能作为延迟链终止子的新分子，并作为激活细胞激酶的有效底物。

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.