BIOLOGICALLY ACTIVE FLUOROPHOSPHONATE DERIVATIVES

生物活性氟代磷酸盐衍生物

• 批准号: 3132316
• 负责人: CHARLES E MCKENNA
• 金额: $ 9.3万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-01-01 至 1987-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3132316
• 关键词: Betaherpesvirinae; DNA directed DNA polymerase; Epstein Barr virus; acyclovir; antiviral agents; calcium; chemical structure function; deoxyribonucleoside triphosphate; diphosphonate; drug design /synthesis /production; fluorine; guanosine; herpes simplex virus 1; herpes simplex virus 2; manganese; methane; nucleoside analog; phosphonate; pyrophosphates; thymidine; varicella zoster virus; virus diseases; zinc

The five major herpes viruses (Herpes simplex-1 (HSV-1), Herpes simplex-2 (HSV-2), Varicella-Zoster virus (VZV), Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are responsible for a variety of serious human diseases. Several of these viruses have also been linked to human maligancies. Anti-viral agents can be based on selective inhibition of virus-induced enzymes in infected or transformed cells. Two potent anti-viral agents, phosphonoacetate (PAA) and phosphonoformate (PFA), strongly inhibit virus-specific DNA polymerase. The inhibitory mechanism is not clear, but is related to their structural similarity to pyrophosphoric acid. It is proposed to develop new fluorinated and other phosphonate derivatives that may be useful to study and treat viral infections. Three new classes of fluorinecontaining pyrophosphate analog will be synthesized: a) fluoromethanediphosphonates (F-MDP); b) fluorophosphonoacetates (F-PAA); c) fluoromethanephosphonophosphinates (F-MPP). Desoxyribonucleoside triphosphate (dNTP) analogs of these compounds will also be synthesized, as probes of DNA polymerase inhibition. Novel hybrid nucleotides that combine in one molecule known anti-viral nucleosides (e.g. DHPG, BVdU, and acyclovir) with potent pyrophosphate analogs (e.g. monofluoro-PAA) will be prepared to determine whether enhanced inhibition occurs. The results will be compared with inhibition effects obtained with both independent drugs used in combination. In addition, PAA, MDP, and MPP derivatives containing a diazo group on the bridging methylene carbon will be investigated as possible photoaffinity inactivators of HSV-specific DNA polymerase. The new analogs will be tested for a) inhibition of HSV, CMV, and EBV replication in cell culture; b) inhibition of PFA-and acyclovir-resistant variants of HSV-1; c) in vivo activity against HSV-1 and HSV-2 in mice. Acid-base parameters and divalent cation (Zn, Mn, Ca) complexation constants will be determined for the analogs. The results, together with data obtained on structure-activity relationships, will be used to elucidate the mechanism of DNA polymerase inhibition by PAA-like substances with reference to their selectivity against the virus-induced enzyme. The research should materially aid the continuing search for compounds that have clinical value in the treatment of herpes virus infections and related diseases.

五种主要的疱疹病毒（单纯疱疹-1（HSV-1）、单纯疱疹-2（HSV-2） （HSV-2）、水痘-带状疱疹病毒（VZV）、巨细胞病毒（CMV）和 EB病毒（EBV）是导致多种严重人类 疾病 其中一些病毒也与人类有关。 恶意中伤 抗病毒剂可以基于选择性抑制 在感染或转化的细胞中病毒诱导的酶。 两种有效 抗病毒剂，膦酰基乙酸酯（PAA）和膦酰基甲酸酯（PFA）， 强烈抑制病毒特异性DNA聚合酶。 抑制机制 不清楚，但与它们的结构相似性有关。 焦磷酸 建议开发新的氟化和其他 可用于研究和治疗病毒的膦酸酯衍生物 感染. 三类新的含氟焦磷酸盐类似物 将合成：a）氟代甲烷二膦酸酯（F-MDP）; B） 氟膦乙酸酯（F-PAA）; c）氟甲烷膦膦酸酯 （F-MPP）。 这些的脱氧核糖核苷三磷酸（dNTP）类似物 还将合成化合物，作为DNA聚合酶的探针 抑制作用 在一个已知分子中联合收割机的新的杂合核苷酸 抗病毒核苷（如DHPG、BVdU和阿昔洛韦）， 将制备焦磷酸盐类似物（例如，单氟-PAA）以确定 是否发生了增强的抑制。 结果将与 使用两种独立药物获得的抑制作用， 组合. 此外，含有重氮基的PAA、MDP和MPP衍生物也可用于制备含重氮基的PAA、MDP和MPP。 将尽可能研究桥连亚甲基碳上的基团 HSV特异性DNA聚合酶的光亲和灭活剂。 新的类似物 a）抑制细胞中HSV、CMV和EBV复制 培养; B）抑制HSV-1的PFA-和阿昔洛韦-抗性变体; c） 小鼠体内抗HSV-1和HSV-2活性。 酸碱参数和 二价阳离子（Zn，Mn，Ca）络合常数将被确定为 类似物。 结果，以及获得的数据， 构效关系，将被用来阐明机制 PAA样物质对DNA聚合酶的抑制作用， 对病毒诱导的酶的选择性。 这一研究应 为继续寻找具有临床价值的化合物提供了实质性帮助 治疗疱疹病毒感染和相关疾病。