1-(2,3-DIDEOXY-BETA-D-GLYCERO-PENT-2-ENOFURANOSYL)THYMINE - A HIGHLY POTENT AND SELECTIVE ANTI-HIV AGENT
1-(2,3-DIDEOXY-BETA-D-GLYCERO-PENT-2-ENOFURANOSYL)THYMINE - A HIGHLY POTENT AND SELECTIVE ANTI-HIV AGENT
复制标题
DOI：
10.1021/jm00122a029
复制
发表时间：
1989-02-01
影响因子：
7.3
通讯作者：
MARTIN, JC
中科院分区：
文献类型：
--
作者：
MANSURI, MM;STARRETT, JE;MARTIN, JC
核苷类似物1-（2，3-二脱氧-β- D-甘油-β-2-烯呋喃糖基）胸腺嘧啶（d4 T，1）通过3 ″，5 ″-脱水化合物5的开环制备。该方法已被改进，使得其可用于大规模制备d4 T（1）。还从1合成了d4 T（8）的三磷酸，以检查作用模式。发现d4 T的体外抑制活性与AZT在HIV感染的CEM细胞中的抑制活性相当。d4 T（8）的三磷酸和AZT的三磷酸抑制以poly（rA）：oligo（dT）作为模板：引物的HIV逆转录酶，Ki值分别为0.032和0.007 μ M。与AZT相比，测定了d4 T对正常人造血祖细胞（CFU-GM）的体外毒性。虽然d4 T在100 μ M的浓度下使集落形成单位减少50%，但仅需要1 μ MAZT就具有类似的毒性作用。对于红细胞爆发形成单位（BFU-E），d4 T和AZT的体外毒性具有相当的ID 50值，分别为10和6.7 μ M。
The nucleoside analogue 1-(2,3-dideoxy-.beta.-D-glycero-pent-2-enofuranosyl)thymine (d4T, 1) was prepared by ring opening of the 3'',5''-anhydro compound 5. This method has been refined such that it can be used to prepare d4T (1) on a large scale. The triphosphate of d4T (8) was also synthesized from 1 in order to examine the mode of action. The in vitro inhibitory activity of d4T was found to be comparable to that of AZT in HIV-infected CEM cells. The triphosphate of d4T (8) and that of AZT inhibited the HIV reverse transcriptase with poly(rA):oligo(dT) as the template:primer with Ki values of 0.032 and 0.007 .mu.M, respectively. The in vitro toxicity of d4T against normal human hematopoietic progenitor cells (CFU-GM) was measured in comparison to AZT. While d4T reduces colony-forming units by 50% at a concentration of 100 .mu.M, it takes only 1 .mu.M AZT to have a similar toxic effect. With erythrocyte burst forming units (BFU-E) the in vitro toxicities for d4T and AZT have comparable ID50 values values of 10 and 6.7 .mu.M, respectively.