Prodrug forms of N-[(4-deoxy-4-amino-10-methyl)pteroyl]glutamate-γ-[ψP(O)(OH)-glutarate, a potent inhibitor of folylpoly-γ-glutamate synthetase:: Synthesis and hydrolytic stability
Prodrug forms of N-[(4-deoxy-4-amino-10-methyl)pteroyl]glutamate-γ-[ψP(O)(OH)-glutarate, a potent inhibitor of folylpoly-γ-glutamate synthetase:: Synthesis and hydrolytic stability
复制标题
DOI：
10.1021/jm050871p
复制
发表时间：
2006-01-26
影响因子：
7.3
通讯作者：
Coward, JK
中科院分区：
文献类型：
--
作者：
Feng, Y;Coward, JK
合成了次膦酸酯假肽N-[（4-脱氧-4-氨基-10-甲基）蝶酰基]谷氨酸-γ-[psi P（0）（OH）]-戊二酸酯（1a）的酯前药。衍生自N-Cbz乙烯基甘氨酸酯的H-次膦酸通过与α-亚甲基戊二酸酯的Michael加成转化为所需的假肽。新戊酰氧基甲基（POM）酯部分在形成任一C-P键之前并入N-末端和C-末端片段中。对（N-甲基）氨基苯甲酸衍生的酰胺与2，4-二氨基-6-溴甲基蝶啶进行N-烷基化反应，得到目标化合物。甲氨蝶呤的POM酯和相应的γ-谷氨酰缀合物也使用相同的策略合成。在中国仓鼠卵巢细胞中评价所有前药。尽管假肽前药无效，但甲氨蝶呤前药和相应的γ-谷氨酰缀合物与母体化合物等效。在磷酸盐缓冲液和细胞系培养基中研究了前药的稳定性，为观察到的生物学数据提供依据。
Ester prodrugs of the phosphinate pseudopeptide N-[(4-deoxy-4-amino-10-methyl)pteroyl]glutamate-gamma-[psi P(0)(OH)]-glutarate (1a) were synthesized. H-phosphinic acids derived from N-Cbz vinyl glycine esters were converted to the desired pseudopeptides by Michael addition to alpha-methyleneglutarate esters. Pivaloyloxymethyl (POM) ester moieties were incorporated in both the N-terminal and C-terminal fragments prior to formation of either C-P bond. N-Alkylation of the corresponding amides derived from p-(N-methyl)aminobenzoic acid with 2,4-diamino-6-(bromomethyl)pteridine gave the target compounds. POM esters of methotrexate and the corresponding gamma-glutamyl conjugate were also synthesized using the same strategy. All prodrugs were evaluated in Chinese hamster ovary cells. Although the pseudopeptide prodrugs were ineffective, prodrugs of methotrexate and the corresponding gamma-glutamyl conjugate were equipotent with the parent compounds. Stability of the prodrugs was investigated in both phosphate buffer and cell line medium to provide a rationale for the observed biological data.