METHYLENECYCLOPROPANE ANALOGS AND PRODRUGS FOR HCMV

将制备选定的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），用于作为抗人巨细胞病毒（HCMV）的潜在药物进行生物学评价。 本论文将合成新的2，6-二取代嘌呤亚甲基环丙烷类化合物，用于构效关系的研究.还将制备几种类型的对映体Z-亚甲基环丙烷类似物的前药，用于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纯形式的类似物（亲脂性磷酸盐前药，各为两种非对映异构体），以允许（i）对野生型和突变型巨细胞病毒（CMV）进行体外评价，（ii）在感染CMV的动物中进行体内研究，（iii）调查与当前药物的交叉耐药性，以及（iv）研究这些类似物的作用机制。 这些研究与核苷的亚甲基环丙烷类似物作为抗HCMV药物的临床前开发相关。

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.