PHOSPHONATE NUCLEOTIDE ANALOGS FOR AIDS THERAPY

申请人摘要： 在这里提出的研究集中在设计，合成和 新型非环磷酸盐核苷酸类似物AS的评价 治疗艾滋病和吸毒者的抗病毒/抗HIV药物 艾滋病患者。具体地说，调查试图利用最近的 观察到一组无环的磷酸盐核苷酸显示 体外抗HIV/抗病毒活性显著(IC50为0.13微米)。 几个设计注意事项表明，也许有可能 进化出新的、人工容易获得的非环核苷酸 类似物作为潜在的抗病毒药物治疗艾滋病通过(A) 修饰磷酸盐胸腺嘧啶和尿嘧啶核苷酸的杂环尾巴， (B)在C-6处取代苯硫基或苯基亚硒基 尿嘧啶核的位置，以及(C)代以选择性晕， 尿嘧啶核C-5位的烷基和芳基取代基。 将合成足够数量的这些化合物来制造它们 可用于抗艾滋病病毒检测。 这项建议将采用的方法包括，发展 合成方法学，它们的核磁共振表征，质谱学， 紫外光和其他光谱技术。建议的化合物将是 根据(1)抑制复制的能力进行评估 HIV-1病毒，(2)毒性，以及(3)对AZT的交叉敏感模式- 细胞培养中的抗性菌株通过与 新奥尔良杜兰大学医学中心的克里希纳·C·阿格拉瓦尔博士， 路易斯安那州70112。这一生物检测的当地安排将 允许最大效率地实现最有效 非环不饱和核苷酸类似物的化学修饰 快速将生物观察转化为设计 改进的抗艾滋病毒化合物。

APPLICANT'S ABSTRACT: The investigation proposed herein focuses on the design, synthesis, and evaluation of novel acyclic phosphonate nucleotide analogs as antiviral/anti- HIV agents for treatment of the AIDS and drug addicted AIDS patients. Specifically, the investigation seeks to exploit recent observation that a group of acyclic phosphonate nucleotides exhibited remarkable anti-HIV/antiviral activity in vitro (IC50 0.13 microM). Several design considerations indicate that it might be possible to evolve new and synthetically readily accessible acyclic nucleotide analogs as potential antiviral agents for the treatment of AIDS by (a) modifying the acyclo tail of phosphonate thymine and uracil nucleotides, (b) substituting the phenylthio or phenylselenenyl group at the C-6 position of the uracil nucleus, and (c) substituting selective halo, alkyl and aryl substituents at the C-5 position of the uracil nucleus. Adequate quantities of these compounds will be synthesized to make them available for testing against AIDS virus. The approaches to be employed in this proposal include, the development of synthetic methologies, their characterization by NMR, mass spectrum, UV, and other spectroscopic techniques. Proposed compounds will be evaluated with respect to (1) ability to inhibit the replication of HIV-1 virus, (2) toxicity, and (3) cross-sensitivity patterns to AZT- resistant strain in cell culture through collaborative arrangements with Dr. Krishna C. Agrawal at Tulane University Medical Center, New Orleans, Louisiana 70112. This local arrangement of biological testing will allow maximum efficiency in the attainment of the most effective chemical modification of acyclic unsaturated nucleotide analogs by rapidly translating the biological observations into the design of improved anti-HIV compounds.