Vince R, Lee H, Narang A S, Shirota F N
J Med Chem. 1981 Dec;24(12):1511-4. doi: 10.1021/jm00144a027.
A facile, two-step conversion of puromycin aminonucleoside (PAN) into 5'-deoxy-PAN (5) via 5'-chloro-5'-deoxy-PAN (1) was accomplished. Replacement of the 5'-OH group of PAN with H or Cl resulted in the elimination of kidney toxicity associated with the administration of PAN. The corresponding puromycin derivatives, 5'-chloro-5'-deoxypuromycin (4) and 5'-deoxypuromycin (6), derived from 1 and 5, respectively, were compared in a ribosomal peptidyltransferase assay. Both compounds were excellent substrates for the transpeptidation reaction, confirming our previous observations with 6 that the 5'-OH of puromycin is not essential for activity at the ribosomal level. Thus, 4 represents a new puromycin derivative that retains puromycin-like activity at the ribosomal site but is capable of releasing only a nonnephrotoxic aminonucleoside upon enzymatic release of the p-methoxyphenylalanyl side chain. The chloro derivative 4 exhibited significant antitrypanosomal activity in mice infected with Trypanosoma rhodesiense. The 5'-deoxy derivative 6 was inactive against trypanosomes.
通过5'-氯-5'-脱氧嘌呤霉素核苷（1）实现了嘌呤霉素氨基核苷（PAN）向5'-脱氧-PAN（5）的简便两步转化。用H或Cl取代PAN的5'-OH基团可消除与PAN给药相关的肾脏毒性。分别从1和5衍生的相应嘌呤霉素衍生物5'-氯-5'-脱氧嘌呤霉素（4）和5'-脱氧嘌呤霉素（6）在核糖体肽基转移酶测定中进行了比较。两种化合物都是转肽反应的优良底物，证实了我们之前对6的观察结果，即嘌呤霉素的5'-OH对于核糖体水平的活性不是必需的。因此，4代表一种新的嘌呤霉素衍生物，它在核糖体部位保留嘌呤霉素样活性，但在酶促释放对甲氧基苯丙氨酰侧链后仅能释放非肾毒性的氨基核苷。氯衍生物4在感染罗得西亚锥虫的小鼠中表现出显著的抗锥虫活性。5'-脱氧衍生物6对锥虫无活性。
