METHYLENECYCLOPROPANE ANALOGS AND PRODRUGS FOR HCMV

精选的6-氨基和2-氨基-6-取代嘌呤-Z-亚甲基环丙烷核苷类似物(主要是S对映体)将作为潜在的抗人巨细胞病毒药物进行生物学评价。为了研究构效关系，将合成新的2，6-二取代嘌呤亚甲基环丙烷。还将制备几种类型的Z-亚甲基环丙烷对映体类似物前药，以进行详细的体外和体内评价。该项目的主要目的是提供多克数量的对映体形式的类似物(亲脂性磷酸前药作为两种非对映异构体)，以便(I)在体外评价它们对巨细胞病毒(CMV)野生型和变异体的作用，(Ii)在感染CMV的动物身上进行体内研究，(Iii)研究与现有药物的交叉耐药性，以及(Iv)研究这些类似物的作用机制。这些研究对于亚甲基环丙烷核苷类似物作为抗巨细胞病毒药物的临床前开发具有重要意义。

Selected 6-amino- and 2-amino-6-substituted purine Z- methylenecyclopropane nucleoside analogues (mostly S-enantiomers) will be prepared for biological evaluation as potential drugs against human cytomegalovirus (HCMV). New 2,6-disubstituted purine methylenecyclopropanes will be synthesized for studies of structure- activity relationships. Several types of prodrugs of enantiomeric Z- methylenecyclopropane analogues will also be prepared for a detailed in vitro and in vivo evaluation. The major aim of the project is to provide multigram quantities of analogues in enantiopure form (lipophilic phosphate prodrugs as two diastereoisomers each) to permit (i) their evaluation in vitro against wild type and mutated forms of cytomegalovirus (CMV), (ii) in vivo studies in animals infected with CMV, (iii) investigation of cross-resistance with current drugs and (iv) studies of mechanism of action of these analogues. These studies are relevant for preclinical development of methylenecyclopropane analogues of nucleosides as anti-HCMV drugs.