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

A series of novel pyrrolo[2,3-d]pyrimidine derivatives was designed and syn thesized as thymidylate synthase (TS) inhibitors. Molecular design was perf ormed on the human TS complex model built on the basis of the reported stru cture 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 b ridge carbon could be replaced with an alkyl group to fill out the unoccupi ed space. Based on this design, we synthesized five pyrrolo[2,3-d]pyrimidin e derivatives with one-carbon bridge and evaluated their TS inhibitory acti vities. 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).