ChemInform Abstract: Pyrrolo[2,3-d]pyrimidine Thymidylate Synthase Inhibitors: Design and Synthesis of One-Carbon Bridge Derivatives

Autor:	Koichiro Ootsu, Hiroshi Akimoto, Kazuyoshi Aso, Yumi Imai, Koichi Yukishige
Rok vydání:	2010
Předmět:	chemistry.chemical_classification Pyrimidine biology Stereochemistry chemistry.chemical_element General Medicine Ring (chemistry) Thymidylate synthase chemistry.chemical_compound chemistry Docking (molecular) biology.protein IC50 Carbon Ternary complex Alkyl
Zdroj:	ChemInform. 33
ISSN:	1522-2667 0931-7597
Popis:	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 μM).
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::065575641438207957e7bfa843079384 https://doi.org/10.1002/chin.200212270 Zobrazit plný text záznamu Plný text