Peterson M L, Vince R
Department of Medicinal Chemistry, University of Minnesota, College of Pharmacy, Minneapolis 55455.
J Med Chem. 1991 Sep;34(9):2787-97. doi: 10.1021/jm00113a017.
The synthesis of several novel carbocyclic purine nucleosides that incorporate a nitrogen in place of carbon 3 of the cyclopentyl moiety are described. These analogues are all derived from the key stereochemically defined intermediate N-(tert-butoxycarbonyl)-O-[(4-methoxyphenyl)diphenylmethyl]-trans- 4- hydroxy-D-prolinol (19), which was accessible in 61.1% overall yield for a five-step sequence starting from cis-4-hydroxy-D-proline. The heterocyclic bases, 6-chloropurine and 2-amino-6-chloropurine, are efficiently introduced onto the pyrrolidine ring via a Mitsunobu-type coupling procedure with triphenylphosphine and diethyl azodicarboxylate. Standard transformations and removal of protecting groups gave the cis-adenine (26), hypoxanthine (27), 2,6-diaminopurine (28), and guanine (29) D-prolinol derivatives. In addition, a related sequence from trans-4-hydroxy-L-proline provided the enantiomeric L-prolinol guanine derivative (36). Lastly, the 6-(dimethylamino)purine analogue, 37, was coupled to N-(benzyl-oxycarbonyl)-p-methoxy-L-phenylalanine to provide, after deprotection, the novel puromycin-like analogue 39. The analogues 26-29, 36, and 39 were all evaluated for antitumor and, except for 39, for antiviral activity. These compounds failed to appreciably inhibit the growth of P388 mouse leukemia cells in vitro at concentrations up to 100 micrograms/mL. In addition, they did not exhibit noticeable activity against the human immunodeficiency virus or herpes simplex virus type 1 at concentrations as high as 100 microM. The adenine analogue, 26, did, however, prove to be a substrate for adenosine deaminase. It possessed an affinity for the enzyme only 50% less than that of adenosine with a Ki = 85 microM.
本文描述了几种新型碳环嘌呤核苷的合成方法，这些核苷在环戊基部分的3位碳原子处引入了氮原子。这些类似物均由关键的立体化学定义中间体N-（叔丁氧羰基）-O-[(4-甲氧基苯基)二苯基甲基]-反式-4-羟基-D-脯氨醇（19）衍生而来，从顺式-4-羟基-D-脯氨酸开始，经过五步反应，该中间体的总产率可达61.1%。通过与三苯基膦和偶氮二羧酸二乙酯的Mitsunobu型偶联反应，可将杂环碱6-氯嘌呤和2-氨基-6-氯嘌呤有效地引入到吡咯烷环上。经过标准转化和保护基去除反应，得到了顺式腺嘌呤（26）、次黄嘌呤（27）、2,6-二氨基嘌呤（28）和鸟嘌呤（29）的D-脯氨醇衍生物。此外，从反式-4-羟基-L-脯氨酸出发的相关反应序列得到了对映体L-脯氨醇鸟嘌呤衍生物（36）。最后，将6-（二甲氨基）嘌呤类似物37与N-（苄氧羰基）-对甲氧基-L-苯丙氨酸偶联，脱保护后得到新型嘌呤霉素样类似物39。对类似物26-29、36和39进行了抗肿瘤活性评估，除39外，还评估了其抗病毒活性。在浓度高达100微克/毫升时，这些化合物在体外未能明显抑制P388小鼠白血病细胞的生长。此外，在浓度高达100微摩尔时，它们对人类免疫缺陷病毒或1型单纯疱疹病毒均未表现出明显活性。然而，腺嘌呤类似物26被证明是腺苷脱氨酶的底物。它对该酶的亲和力仅比对腺苷低50%，其Ki = 85微摩尔。
