Synthesis and biological properties of C-2, C-8, N-9 substituted 6-(3-chloroanilino)-purine derivatives as cyclin-dependent kinase inhibitors. Part II

• Published in: Archiv der Pharmazie (Weinheim) Vol. 334; no. 11; pp. 345 - 350
• Main Authors: Oh, Chang-Hyun, Kim, Hee-Kwon, Lee, Su-Chul, Oh, Changsok, Yang, Boem-Seok, Rhee, Hak June, Cho, Jung-Hyuck
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag GmbH 01.12.2001; WILEY‐VCH Verlag GmbH; Wiley; Wiley-VCH
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antiproliferative effect; Biological and medical sciences; CDK2 inhibitor; Cell cycle regulation; Cell Division - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Cyclin-Dependent Kinases - antagonists & inhibitors; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; General aspects; Humans; Inhibitory Concentration 50; Life Sciences & Biomedicine; m-Chloroanilinopurine; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Purines - chemical synthesis; Purines - pharmacology; Science & Technology; Structure-Activity Relationship; Tumor Cells, Cultured; SELECTIVE INHIBITOR; CDK INHIBITORS; POTENT; ROSCOVITINE; antiproliferative effect; m-chloroanilinopurine; PURINE ANALOGS; cell cycle regulation; CANCER; CDK2 inhibitor; CDC2 KINASE; Antineoplastic agent; Cell proliferation; Five membered ring; Purine derivatives; Enzyme; Nitrogen heterocycle; Transferases; Enzyme inhibitor; In vitro; Pyrrolidine derivatives; Cell line; Structure activity relation; Protein kinase; Chlorine Organic compounds; Cell cycle; Bicyclic compound; Inhibition; Chemical synthesis; Tumor cell
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/1521-4184(200112)334:11<345::AID-ARDP345>3.0.CO;2-1

In this study, C‐2, C‐8, N‐9 substituted 6‐(3‐chloroanilino)purine derivatives were synthesized and their inhibitory effects on cyclin‐dependent kinases (CDK2, 4) as well as their cytotoxicities were evaluated. The effects of substituents at the C‐2, C‐8, and N‐9 positions of the substituted purine were investigated. Among the compounds tested, [6‐(3‐chloroanilino)‐2‐(2‐hydroxymethyl‐4‐hydroxypyrrolidyl)‐9‐isopropylpurine] (4h) was the most active inhibitor of CDK2 with IC50 of 0.3μM, i.e. a two‐fold increased inhibitory activity as compared to roscovitine. Results from structure‐activity relationship studies should allow the design of more potent and selective CDK2 inhibitors, which may provide an effective therapy for cancer or other CDK‐dependent diseases.