BIOLOGICALLY ACTIVE FLUOROPHOSPHONATE DERIVATIVES

五大疱疹病毒(单纯疱疹病毒1型、单纯疱疹2型 水痘-带状疱疹病毒(VZV)、巨细胞病毒(CMV)和 爱泼斯坦-巴尔病毒(EBV)是导致多种严重人类 疾病。其中几种病毒也被认为与人类 恶性疾病。抗病毒药物可以基于选择性抑制 病毒在感染或转化的细胞中诱导的酶。两个强有力的 抗病毒药物，磷酸乙酸酯(PAA)和磷酸甲酸盐(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有关 焦磷酸。建议开发新的氟化和其他 可能用于研究和治疗病毒的膦酸衍生物 感染。三类新的含氟焦磷类似物 将合成：a)氟甲基二膦酸盐(F-MDP)；b) 氟代膦(F-PAA)；c)氟甲基膦 (F-MPP)。它们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。 抑制力。结合在一个已知分子中的新型杂交核苷酸 有效的抗病毒核苷(如DHPG、BVdU和阿昔洛韦) 将制备焦磷酸盐类似物(如一氟-PAA)以确定 是否发生了增强的抑制。结果将与 两种独立用药对人体的抑制作用 组合。此外，含有重氮基的PAA、MDP和MPP衍生物 将尽可能研究桥联亚甲基碳的基团 单纯疱疹病毒特异性DNA聚合酶的光亲和失活剂。新的类比 将测试a)抑制HSV、CMV和EBV在细胞中的复制 培养；b)抑制对PFA和阿昔洛韦耐药的HSV-1变异；c) 小鼠体内抗单纯疱疹病毒1型和2型的活性。酸碱参数和 将测定二价阳离子(锌、锰、钙)的络合常数 类比。结果，连同在 结构-活性关系，将用来阐明其作用机制 类PAA物质对DNA聚合酶抑制作用的研究 对病毒诱导的酶的选择性。这项研究应该 为继续寻找具有临床价值的化合物提供了实质性的帮助 用于治疗疱疹病毒感染和相关疾病。

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.