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

• Published in: Chemical & pharmaceutical bulletin Vol. 49; no. 10; pp. 1280 - 1287
• Main Authors: ASO, Kazuyoshi, IMAI, Yumi, YUKISHIGE, Koichi, OOTSU, Koichiro, AKIMOTO, Hiroshi
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 2001; Pharmaceutical Soc Japan; Maruzen
• Subjects: Amino Acid Sequence; Animals; Antineoplastic agents; Biological and medical sciences; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; General aspects; Humans; Hydrogen Bonding; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Mass Spectrometry; Medical sciences; Mice; Models, Molecular; molecular design; Molecular Sequence Data; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Pyrroles - chemical synthesis; Pyrroles - pharmacology; pyrrolo[2,3-d]pyrimidine; Science & Technology; Spectrophotometry, Infrared; ternary complex; thymidylate synthase (TS); Thymidylate Synthase - antagonists & inhibitors; pyrrolo[2,3-d]pyrimidine; molecular design; NON-GLUTAMATE TYPE; ternary complex; ALPHA; ANTITUMOR-ACTIVITY; thymidylate synthase (TS); Antineoplastic agent; Human; Enzyme; Nitrogen heterocycle; Transferases; Lactam; Enzyme inhibitor; Inhibitor enzyme complex; Thymidylate synthase; In vitro; Modeling; α-Aminoacid; Methyltransferases; Structure activity relation; Molecular model; Bicyclic compound; Binding mode; Chemical synthesis
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.49.1280

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).