Pyrrolo[2,3-d]pyrimidine thymidylate synthase inhibitors:: Design and synthesis of one-carbon bridge derivatives

被引:13
作者
Aso, K
Imai, Y
Yukishige, K
Ootsu, K
Akimoto, H
机构
[1] Takeda Chem Ind Ltd, Med Chem Res Labs, Yodogawa Ku, Osaka 5328686, Japan
[2] Takeda Chem Ind Ltd, Takeda RABICS, Yodogawa Ku, Osaka 5328686, Japan
[3] Takeda Chem Ind Ltd, Intellectual Property Dept, Yodogawa Ku, Osaka 5328686, Japan
[4] Takeda Chem Ind Ltd, Pharmaceut Business Dev Dept, Chuo Ku, Osaka 5408645, Japan
关键词
pyrrolo[2,3-d]pyrimidine; thymidylate synthase (TS); molecular design; ternary complex;
D O I
10.1248/cpb.49.1280
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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).
引用
收藏
页码:1280 / 1287
页数:8
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