Novel 5-substituted pyrrolo[2,3-d]pyrimidines as dual inhibitors of glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase and as potential antitumor agents.
Novel 5-substituted pyrrolo[2,3-d]pyrimidines as dual inhibitors of glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase and as potential antitumor agents.
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新型 5-取代吡咯并[2,3-d]嘧啶作为甘氨酰胺核糖核苷酸甲酰基转移酶和 5-氨基咪唑-4-甲酰胺核糖核苷酸甲酰基转移酶的双重抑制剂，并作为潜在的抗肿瘤剂。
DOI：
10.1021/jm501787c
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发表时间：
2015
影响因子：
7.3
通讯作者：
Gangjee,Aleem
中科院分区：
文献类型：
--
作者：
Wang,Yiqiang;Mitchell-Ryan,Shermaine;Raghavan,Sudhir;George,Christina;Orr,Steven;Hou,Zhanjun;Matherly,LarryH;Gangjee,Aleem
设计并合成了一系列不同链长(n=1-6)的5-取代噻吩基并[2，3-d]吡咯并[2，3-d]嘧啶类化合物6-11，它们是由临床常用抗癌药物培美曲塞与我们的6-取代噻吩基并[2，3-d]嘧啶与叶酸受体(FR)α和质子偶联叶酸转运体(PCFT)杂交而成。化合物6-11抑制KB人肿瘤细胞的顺序为9=10>；8>；7>；6=11。化合物8-10由FRα、PCFT和RFC不同地转运，并且与PMX不同，它抑制从头合成的嘌呤核苷酸，而不是胸腺苷的生物合成。8和9的抗增殖作用可能是由于其对GARFTase和5-氨基咪唑-4-甲酰转移酶的双重抑制作用。我们的研究确定了转运和双靶抑制的独特结构-活性关系。
A new series of 5-substituted thiopheneyl pyrrolo[2,3-d]pyrimidines6–11with varying chain lengths (n= 1–6) were designed and synthesized as hybrids of the clinically used anticancer drug pemetrexed (PMX) and our 6-substituted thiopheneyl pyrrolo[2,3-d]pyrimidines2cand2dwith folate receptor (FR) α and proton-coupled folate transporter (PCFT) uptake specificity over the reduced folate carrier (RFC) and inhibition of de novo purine nucleotide biosynthesis at glycinamide ribonucleotide formyltransferase (GARFTase). Compounds6–11inhibited KB human tumor cells in the order9=10>8>7>6=11. Compounds8–10were variously transported by FRα, PCFT, and RFC and, unlike PMX, inhibited de novo purine nucleotide rather than thymidylate biosynthesis. The antiproliferative effects of8and9appeared to be due to their dual inhibitions of both GARFTase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase. Our studies identify a unique structure–activity relationship for transport and dual target inhibition.