SYNTHESIS OF QUINOLONE ANTIHIV-1/HIV-2 AGENTS

3，5，8-三羟基-4-喹啉(THQ)，从海绵中分离得到， 和半合成的衍生物5，8-二甲氧基-e-羟基-4-喹诺酮 (6)抑制HIV-1和HIV-2的逆转录酶，与 IC50值在2.4到43微米之间。THQ与RT-1相互作用 DNA复合体与其他已知的RT抑制剂不同，提示 该分子通过一种新的机制抑制RT。THQ和6因此 代表了寻找非核苷类逆转录酶抑制剂的重要线索 用于治疗艾滋病。这个第一阶段项目的目标是 开发一种高效的合成6，它具有改进的化学成分 相对于THQ的稳定性。我们还将合成一系列类似物 代表区域异构体、异构体和同系物，目的是 还确定了生物活性所必需的结构特征 因为可能识别具有更高活性的同系物。这个 将评估化合物抑制HIV-1和-1的能力 HIV-2介导的体外细胞病变。先导化合物6和 在初始检测中具有显著活性的同系物也将是 评估对一组病毒耐药突变株的细胞保护作用 核苷和非核苷逆转录酶抑制剂，以及 抑制HIV-1和HIV-2逆转录酶以及DNA聚合酶α和 贝塔。未来的第二阶段项目将涉及合成更多 广泛的类似物系列和体内测定 动物的药代动力学、毒理学和抗病毒参数 模特们。

3,5,8-Trihydroxy-4-quinoline (THQ), isolated from a marine sponge, and a semi-synthetic derivative, 5,8-dimethoxy-e-hydroxy-4-quinolone (6), inhibited reverse transcriptase (RT) from HIV-1 and HIV-2, with IC50 values ranging from 2.4 to 43 muM. THQ interacted with a RT- DNA complex differently that other known RT inhibitors, suggesting this molecule inhibits RT via a novel mechanism. THQ and 6 thus represent important leads in the quest for non-nucleoside RT inhibitors for the treatment of AIDS. The goal of this Phase I project is to develop an efficient synthesis of 6, which possessed improved chemical stability relative to THQ. We will also synthesize a series of analogues representing regioisomers, isosteres and homologues with the intent of determining structural feature necessary for biological activity, as well as possibly identifying congeners having increased activity. The compounds will be evaluated for their ability to inhibit HIV-1- and HIV-2-mediated cytopathicity in vitro. The lead compound 6 and congeners possessing significant activity in the initial assay will also be evaluated for cytoprotection against a panel of viral mutants resistant to both nucleoside and non-nucleoside RT inhibitors, as well as for inhibition of HIV-1 and HIV-2 RT, and DNA polymerases alpha and beta. A future Phase II project will involve synthesis of a more extensive series of analogues, and determination of in vivo pharmacokinetic, toxicological and antiviral parameters using animal models.