Discovery of 5-substituted pyrrolo[2,3-d]pyrimidine antifolates as dual-acting inhibitors of glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase in de novo purine nucleotide biosynthesis: implications of inhibiting 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase to ampk activation and antitumor activity.
Discovery of 5-substituted pyrrolo[2,3-d]pyrimidine antifolates as dual-acting inhibitors of glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase in de novo purine nucleotide biosynthesis: implications of inhibiting 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase to ampk activation and antitumor activity.
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DOI：
10.1021/jm401328u
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发表时间：
2013-12-27
影响因子：
7.3
通讯作者：
Gangjee A
中科院分区：
文献类型：
--
作者：
Mitchell-Ryan S;Wang Y;Raghavan S;Ravindra MP;Hales E;Orr S;Cherian C;Hou Z;Matherly LH;Gangjee A
我们合成了5-取代吡咯并[2，3-d]嘧啶类抗叶酸剂（化合物5-10），它们具有1 - 6个桥碳和侧链上的苯甲酰环，作为抗肿瘤剂。具有4-碳桥的化合物8是最具活性的类似物，并且有效地抑制表达叶酸受体（FR）α的中国仓鼠卵巢和KB人肿瘤细胞的增殖。过量叶酸可完全或部分逆转细胞生长抑制，表明FRα参与细胞摄取，并导致S期积累和细胞凋亡。化合物8对KB细胞的抗增殖作用受到过量腺苷而不是胸苷的保护，从而建立了嘌呤核苷酸从头生物合成作为靶向途径。然而，5-氨基咪唑-4-甲酰胺（AICA）的保护是不完全的，这表明AICA核糖核苷酸甲酰转移酶（AICARFTase）和甘氨酰胺核糖核苷酸甲酰转移酶（GARFTase）的抑制。通过细胞代谢测定证实化合物8对GARFT酶和AICARFT酶的抑制，并导致ATP库耗尽。据我们所知，这是抗叶酸剂作为GARFT酶和AICARFT酶的双重抑制剂作为其主要作用机制的第一个例子。
We synthesized 5-substituted pyrrolo[2,3-d]pyrimidine antifolates (compounds 5–10) with 1 to 6 bridge carbons and a benozyl ring in the side chain as antitumor agents. Compound 8 with a 4-carbon bridge was the most active analog and potently inhibited proliferation of folate receptor (FR) α-expressing Chinese hamster ovary and KB human tumor cells. Growth inhibition was reversed completely or in part by excess folic acid, indicating that FRα is involved in cellular uptake, and resulted in S-phase accumulation and apoptosis. Anti-proliferative effects of compound 8 toward KB cells were protected by excess adenosine but not thymidine, establishing de novo purine nucleotide biosynthesis as the targeted pathway. However, 5-aminoimidazole-4-carboxamide (AICA) protection was incomplete, suggesting inhibition of both AICA ribonucleotide formyltransferase (AICARFTase) and glycinamide ribonucleotide formyltransferase (GARFTase). Inhibition of GARFTase and AICARFTase by compound 8 was confirmed by cellular metabolic assays and resulted in ATP pool depletion. To our knowledge, this is the first example of an antifolate that acts as a dual inhibitor of GARFTase and AICARFTase as its principal mechanism of action.
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影响因子：
1.7
作者：
Aso, K;Imai, Y;Akimoto, H
通讯作者：
Akimoto, H
影响因子：
3.4
作者：
Barnett, CJ;Wilson, TM;Kobierski, ME
通讯作者：
Kobierski, ME
高效液相色谱法分析正常细胞系和肿瘤细胞系的细胞内三磷酸核苷水平
DOI：
10.1016/s1570-0232(02)00780-8
发表时间：
2003-01-25
影响因子：
3
作者：
Huang, D;Zhang, YH;Chen, XG
通讯作者：
Chen, XG
影响因子：
78.5
作者：
Brown, JM;Attardi, LD
通讯作者：
Attardi, LD
影响因子：
3
作者：
Budman, DR;Johnson, R;Walling, J
通讯作者：
Walling, J