Zemlicka Jiri
Department of Chemistry, Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, 110 E. Warren Ave., Detroit, MI 48201-1379, USA.
Biochim Biophys Acta. 2002 Jul 18;1587(2-3):276-86. doi: 10.1016/s0925-4439(02)00090-x.
In order to overcome restrictions imposed by activation (phosphorylation) mechanism of antiviral and antitumor nucleoside analogues several prodrug approaches have been designed. Lipophilic pronucleotides are capable of intracellular delivery of monophosphates of nucleoside analogues, thus circumventing the limitations of enzymic phosphorylation. One of the successful approaches employs lipophilic amino acid ester (alanine) phenyl phosphoramidates as pronucleotides. This approach was applied to AIDS drugs such as AZT, d4T and related analogues but also to nonclassical nucleoside analogues based on allenic and methylenecyclopropane structure. Antiviral effects of the parent analogues were in many cases increased by conversion to phenyl phosphoralaninate (PPA) pronucleotides. Although cytotoxicity increase frequently accompanies antiviral effects of these pronucleotides, a favorable selectivity index can be obtained by manipulation of the parent structure as shown, e.g., for 2,6-diaminopurine methylenecyclopropane pronucleotide 15c. A lack of in vivo toxicity was demonstrated for 2-amino-6-methoxypurine methylenecyclopropane pronucleotide 15e in mice. The PPA pronucleotides can overcome deficiency of phosphorylating enzymes and offer favorable cross-resistance patterns when compared with other antiviral drugs.
为了克服抗病毒和抗肿瘤核苷类似物激活（磷酸化）机制所带来的限制，人们设计了几种前药方法。亲脂性前核苷酸能够将核苷类似物的单磷酸盐递送至细胞内，从而规避酶促磷酸化的局限性。一种成功的方法是使用亲脂性氨基酸酯（丙氨酸）苯基磷酰胺作为前核苷酸。这种方法不仅应用于艾滋病药物如齐多夫定（AZT）、司他夫定（d4T）及相关类似物，还应用于基于丙二烯和亚甲基环丙烷结构的非经典核苷类似物。在许多情况下，母体类似物转化为苯基磷酰胺酯（PPA）前核苷酸后，其抗病毒效果会增强。尽管这些前核苷酸的细胞毒性增加常常伴随着抗病毒作用，但通过对母体结构进行操作，例如对于2,6 - 二氨基嘌呤亚甲基环丙烷前核苷酸15c，可以获得良好的选择性指数。在小鼠中，2 - 氨基 - 6 - 甲氧基嘌呤亚甲基环丙烷前核苷酸15e显示出缺乏体内毒性。与其他抗病毒药物相比，PPA前核苷酸可以克服磷酸化酶的缺陷，并呈现出良好的交叉耐药模式。
