Pyrrolo[2,3-d]pyrimidine thymidylate synthase inhibitors:: Design and synthesis of one-carbon bridge derivatives
Pyrrolo[2,3-d]pyrimidine thymidylate synthase inhibitors:: Design and synthesis of one-carbon bridge derivatives
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DOI：
10.1248/cpb.49.1280
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发表时间：
2001-10-01
影响因子：
1.7
通讯作者：
Akimoto, H
中科院分区：
文献类型：
--
作者：
Aso, K;Imai, Y;Akimoto, H
设计并合成了一系列新型吡咯并[2,3-d]嘧啶衍生物作为胸苷酸合酶（TS）抑制剂。根据已报道的 TS-脱氧尿苷单磷酸 (dUMP)-CB3717 三元复合物的结构，对人 TS 复合物模型进行了分子设计。通过对接研究，我们预计吡咯并[2,3-d]嘧啶和芳香环之间的单碳桥是合适的。此外，我们发现桥碳可以被烷基取代以填充未占据的空间。基于该设计，我们合成了五种具有一碳桥的吡咯并[2,3-d]嘧啶衍生物，并评估了它们的TS抑制活性。所有合成的化合物对 TS 的抑制作用均强于化合物 2 (LY231514)，并且 C8-乙基类似物 (7) 对 TS 显示出显着的抑制活性 (IC50=0.017 mum)。
A series of novel pyrrolo[2,3-d]pyrimidine derivatives was designed and synthesized as thymidylate synthase (TS) inhibitors. Molecular design was performed on the human TS complex model built on the basis of the reported structure of TS-deoxyuridinemonophosphate (dUMP)-CB3717 ternary complex. From a docking study, we expected that a one-carbon bridge between pyrrolo[2,3-d]pyrimidine and an aromatic ring was suitable. Moreover, we found that the bridge carbon could be replaced with an alkyl group to fill out the unoccupied space. Based on this design, we synthesized five pyrrolo[2,3-d]pyrimidine derivatives with one-carbon bridge and evaluated their TS inhibitory activities. All synthesized compounds inhibited TS more potently than compound 2 (LY231514), and the C8-ethyl analogue (7) showed a remarkable inhibitory activity against TS (IC50=0.017 mum).