METHYLENECYCLOPROPANE ANALOGS AND PRODRUGS FOR HCMV

选择6-氨基嘌呤和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）作为抗人巨细胞病毒（HCMV）的潜在药物进行生物学评价。本文将合成新的2,6-二取代嘌呤亚甲基环丙烷，用于研究其构效关系。还将制备几种对映体Z-亚甲基环丙烷类似物的前药，进行详细的体外和体内评价。该项目的主要目的是提供多图数量的对异构形式的类似物（亲脂磷酸盐前药各为两种非对异构体），以便(i)在体外对野生型和突变型巨细胞病毒（CMV）进行评估，（ii）在感染巨细胞病毒的动物体内进行研究，（iii）调查与现有药物的交叉耐药性，（iv）研究这些类似物的作用机制。这些研究与核苷类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.