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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >6-Methylpurine derived sugar modified nucleosides: Synthesis and in vivo antitumor activity in D54 tumor expressing M64V-Escherichia coli purine nucleoside phosphorylase
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6-Methylpurine derived sugar modified nucleosides: Synthesis and in vivo antitumor activity in D54 tumor expressing M64V-Escherichia coli purine nucleoside phosphorylase

机译：6-甲基嘌呤衍生的糖修饰的核苷：表达M64V-大肠杆菌嘌呤核苷磷酸化酶的D54肿瘤的合成和体内抗肿瘤活性

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摘要

Impressive antitumor activity has been observed with fiudarabine phosphate against tumors that express Escherichia coli purine nucleoside phosphorylase (PNP) due to the liberation of 2-fluoroadenine in, the tumor tissue. 6-Methylpurine (MeP) is another cytotoxic adenine analog that does not exhibit selectivity when administered systemically, and could be very useful in a gene therapy approach to cancer treatment involving E. coli PNP. The prototype MeP releasing prodrug 9-(2-deoxy-beta-D-ribofuranosyl)-6-methylpurine (1) [MeP-dR] has demonstrated good activity against tumors expressing E. coli PNP, but its antitumor activity is limited due to toxicity resulting from the generation of MeP from gut bacteria. Therefore, we have embarked on a medicinal chemistry program to identify a combination of non-toxic MeP prodrugs and non-human adenosine glycosidic bond cleaving enzymes. The two best MeP-based substrates with M64V-E coli PNP, a mutant which was engineered to tolerate modification at the 5'-position of adenosine and its analogs, were 9-(6-deoxy-alpha-L-talofuranosyl)-6-methylpurine (3) [methyl(talo)-MeP-R] and 9-(alpha-L-lyxofuranosyl)6-methylpurine (4) [lyxo-MeP-R]. The detailed synthesis methyl(talo)-MeP-R and lyxo-MeP-R, and the evaluation of their substrate activity with 4 enzymes not normally associated with cancer patients is described. In addition, we have determined the intraperitoneal pharmacokinetic (ip-PK) properties of methyl(talo)-MeP-R and have determined its in vivo bystander activity in mice bearing D54 tumors that express M64V PNP. The observed good in vivo bystander activity of [methyl(talo)-MeP-R/M64V-E coli PNP combination suggests that these agents could be useful for the treatment of cancer. (C) 2015 Elsevier Masson SAS. All rights reserved.
机译：由于2-氟腺嘌呤在肿瘤组织中的释放，已经用磷酸氟达拉滨对表达大肠杆菌嘌呤核苷磷酸化酶（PNP）的肿瘤具有令人印象深刻的抗肿瘤活性。 6-甲基嘌呤（MeP）是另一种细胞毒性腺嘌呤类似物，当全身给药时不显示选择性，在涉及大肠杆菌PNP的癌症治疗的基因治疗方法中可能非常有用。 MeP原型释放前药9-（2-脱氧-β-D-核呋喃糖基）-6-甲基嘌呤（1）[MeP-dR]对表达大肠杆菌PNP的肿瘤表现出良好的活性，但其抗肿瘤活性受到限制肠道细菌产生MeP会产生毒性。因此，我们已着手进行一项药物化学计划，以鉴定无毒的MeP前药和非人腺苷糖苷键裂解酶的组合。具有M64V-E.coli PNP的两个最好的基于MeP的底物是9-（6-deoxy-alpha-L-talofuranosyl）-6-，该突变体经工程改造可以耐受腺苷及其类似物在5'-位的修饰。 -甲基嘌呤（3）[甲基（talo）-MeP-R]和9-（α-L-lyxofura呋喃糖基）6-甲基嘌呤（4）[lyxo-MeP-R]。描述了详细的合成甲基（talo）-MeP-R和lyxo-MeP-R，以及使用通常与癌症患者无关的4种酶评估其底物活性的方法。此外，我们已经确定了甲基（talo）-MeP-R的腹膜内药代动力学（ip-PK）特性，并确定了其在表达M64V PNP的D54肿瘤小鼠体内的体内旁观者活性。观察到的[甲基（talo）-MeP-R / M64V-大肠杆菌PNP组合物]的体内良好旁观者活性表明，这些药物可用于治疗癌症。 （C）2015 Elsevier Masson SAS。版权所有。

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