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.

五种主要疱疹病毒（单纯疱疹-1 (HSV-1)、单纯疱疹-2 (HSV-2)、水痘带状疱疹病毒 (VZV)、巨细胞病毒 (CMV) 和 EB 病毒 (EBV) 导致多种严重的人类疾病 疾病。 其中一些病毒也与人类有关 恶性肿瘤。 抗病毒剂可以基于选择性抑制 感染或转化细胞中病毒诱导的酶。 两强 抗病毒剂，膦酰乙酸酯（PAA）和膦酰甲酸酯（PFA）， 强烈抑制病毒特异性DNA聚合酶。 抑制机制 尚不清楚，但与它们的结构相似性有关 焦磷酸。 建议开发新型含氟及其他 可能有助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类似物 将合成：a)氟代甲烷二膦酸盐(F-MDP)； b) 氟膦酰乙酸酯（F-PAA）； c) 氟代甲烷膦酰基次膦酸盐 （F-MPP）。 这些的脱氧核糖核苷三磷酸 (dNTP) 类似物 化合物也将被合成，作为DNA聚合酶的探针 抑制。 结合在一个已知分子中的新型杂交核苷酸 具有强效抗病毒核苷（例如 DHPG、BVdU 和阿昔洛韦） 将制备焦磷酸类似物（例如单氟-PAA）以确定 是否发生增强抑制。 结果将与 使用两种独立药物获得的抑制效果 组合。 此外，含有重氮基的PAA、MDP和MPP衍生物 将尽可能研究桥接亚甲基碳上的基团 HSV 特异性 DNA 聚合酶的光亲和灭活剂。 新的类似物 将测试 a) 对细胞中 HSV、CMV 和 EBV 复制的抑制 文化; b) 抑制 HSV-1 的 PFA 和阿昔洛韦耐药变体； c) 小鼠体内针对 HSV-1 和 HSV-2 的活性。 酸碱参数和 二价阳离子（Zn、Mn、Ca）络合常数将确定为 类似物。 结果以及获得的数据 结构-活性关系，将用于阐明机制 PAA 类物质对 DNA 聚合酶的抑制作用 对病毒诱导的酶的选择性。 研究应该 实质上有助于继续寻找具有临床价值的化合物 用于治疗疱疹病毒感染及相关疾病。