9-( 2-phosphonylmethoxyethyl)-N6-cyclopropyl-2,6-diaminopurine (cpr-PMEDAP) as a prodrug of 9-(2-phosphonylmethoxyethyl)guanine (PMEG)
9-( 2-phosphonylmethoxyethyl)-N6-cyclopropyl-2,6-diaminopurine (cpr-PMEDAP) as a prodrug of 9-(2-phosphonylmethoxyethyl)guanine (PMEG)
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DOI：
10.1016/s0006-2952(99)00138-0
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发表时间：
1999-08-15
影响因子：
5.8
通讯作者：
Paborsky, LR
中科院分区：
文献类型：
--
作者：
Compton, ML;Toole, JJ;Paborsky, LR
9-（2-膦酰基甲氧基乙基）-N-6 -环丙基-2，6-二氨基嘌呤（cpr-PMEDAP）是[9-（2-膦酰基甲氧基乙基）-]（PME）系列的无环核苷酸类似物，在2，6-二氨基嘌呤（DAP）碱基的N-6位上含有环丙基取代基。在广泛范围的肿瘤细胞系中的生长抑制试验证明，该类似物具有有效的抗增殖活性，其IC 1值与结构相关的鸟嘌呤类似物9-（2-膦酰基甲氧基乙基）鸟嘌呤（PMEG）的IC 1值相似。观察到2，6-二氨基嘌呤类似物PMEDAP的生长抑制作用显著降低。为了剖析这些不同效力的基础，在人胰腺癌细胞系BxPC-3中检查了三种类似物的代谢。细胞内代谢物的HPLC分析表明，cpr-PMEDAP脱氨基为PMEG，随后磷酸化为PMEG单磷酸和二磷酸（PMEGp和PMEGpp）。由cpr-PMEDAP处理的细胞产生的PMEC;pp的水平比由与PMEG孵育的细胞产生的水平高50%。与cpr-PMEDAP孵育的细胞的DNA中PMEG的存在证实了cpr-PMEDAP转化为PMEG。相反，PMEDAP不脱氨基为PMEG，而是直接磷酸化为PMEDAPp和PMEDAPpp。腺苷酸脱氨酶抑制剂2 '-脱氧coformycin（dCF）抑制大鼠肝胞质提取物中cpr-PMEDAP的转化，并使生长抑制的IC 50值增加40倍。PMEG和PMEDAP的抗增殖活性不受dCF的影响。因此，似乎cpr-PMEDAP而不是PMEDAP被腺苷酸脱氨酶样酶转化，并作为PMEG的前药发挥作用。(C)1999 Elsevier Science Inc.
9-(2-Phosphonylmethoxyethyl) -N-6 -cyclopropyl-2,6-diaminopurine (cpr-PMEDAP) is an acyclic nucleotide analog of the [9-(2-phosphonylmethoxyethyl)-] (PME) series containing a cyclopropyl substituent on the N-6 position of the 2,6-diaminopurine (DAP) base. Growth inhibition assays in a broad range of tumor cell lines demonstrated that this analog had potent antiproliferative activity with Ic,, values similar to those of the structurally related guanine analog 9-(2-phosphonylmethoxyethyl)guanine (PMEG). A substantially lower growth inhibitory effect was observed for the 2,6-diaminopurine analog, PMEDAP. To dissect the basis for these varying potencies, the metabolism of the three analogs was examined in a human pancreatic carcinoma cell line, BxPC-3. HPLC analysis of the intracellular metabolites demonstrated that the cpr-PMEDAP was deaminated to PMEG and subsequently phosphorylated to PMEG mono- and diphosphates (PMEGp and PMEGpp). The lever of PMEC;pp generated from cpr-PMEDAP treated cells was 50% greater than the level generated from cells incubated with PMEG. The presence of PMEG in the DNA of cells incubated with cpr-PMEDAP confirmed that the cpr-PMEDAP was converted to PMEG. In contrast, PMEDAP was not deaminated to PMEG, but directly phosphorylated to PMEDAPp and PMEDAPpp. The adenylate deaminase inhibitor 2'-deoxycoformycin (dCF) inhibited the conversion of cpr-PMEDAP in a rat liver cytosolic extract and increased the IC50 value for growth inhibition by 40-fold. The antiproliferative activities of PMEG and PMEDAP were unaffected by dCF. Thus, it appears that cpr-PMEDAP, but not PMEDAP, is converted by an adenylate deaminase-like enzyme and functions as a prodrug of PMEG. (C) 1999 Elsevier Science Inc.