Besada Pedro, Mamedova Liaman K, Palaniappan Krishnan K, Gao Zhan-Guo, Joshi Bhalchandra V, Jeong Lak Shin, Civan Mortimer M, Jacobson Kenneth A
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, U.S.A.
Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.
Collect Czechoslov Chem Commun. 2006;71(6):912-928. doi: 10.1135/cccc20060912.
9-(β-D-Ribosfuranosyluronamide)adenine derivatives that are selective agonists and antagonists of the A adenosine receptor (AR) have been derivatized as prodrugs for delivery. The free hydroxy groups at the 2' and 3' positions of the agonists 2-chloro- -(3-iodobenzyl)-9-(-methyl-(β-D-ribosfuranosyluronamide)adenine , the corresponding 4'-thio nucleoside , and antagonists and (5'-,-dimethylamides related to and , respectively) were derivatized through simple acylation reactions. The prodrug derivatives were tested in radioligand binding assays at ARs and in a functional assay of adenylate cyclase at the AAR and found to be considerably less active than the parent drugs. The hydrolysis of nucleoside 2',3'-diesters to regenerate the parent compound in the presence of human blood was demonstrated. 2',3'-Dipropionate esters of and were readily cleaved in a two-step reaction to regenerate the parent drug, on a time scale of two hours. The cleavage of a 2',3'-dihexanoate ester occurred at a slower rate. This indicates that the prodrugs are suitable as masked forms of the biologically active AAR agonists and antagonists for future evaluation .
作为A1腺苷受体（AR）选择性激动剂和拮抗剂的9-(β-D-呋喃核糖基脲酰胺)腺嘌呤衍生物已被衍生化为用于递送的前药。激动剂2-氯- -(3-碘苄基)-9-(-甲基-(β-D-呋喃核糖基脲酰胺)腺嘌呤、相应的4'-硫代核苷以及拮抗剂和（分别与和相关的5'-,-二甲基酰胺）在2'和3'位的游离羟基通过简单的酰化反应进行衍生化。在前药衍生物在ARs的放射性配体结合试验以及A1AR的腺苷酸环化酶功能试验中进行了测试，发现其活性比母体药物低得多。已证明在人血液存在下核苷2',3'-二酯水解以再生母体化合物。和的2',3'-二丙酸酯在两步反应中易于裂解以再生母体药物，时间尺度为两小时。2',3'-二己酸酯的裂解速率较慢。这表明前药适合作为生物活性A1AR激动剂和拮抗剂的掩蔽形式以供未来评估。
