Modification of Pyrimidine Derivatives from Antiviral Agents to Antitumor Agents

• Published in: Anticancer research 2006-01, Vol.26 (1A), p.91-97
• Main Authors: KIMURA, Hiroyuki, KATOH, Takahiro, KAJIMOTO, Tetsuya, NODE, Manabu, HISAKI, Masakatsu, SUGIMOTO, Yoshikazu, MAJIMA, Tetsuo, UEHARA, Yoshimasa, YAMORI, Takao
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; Biological and medical sciences; Cell Line; Cell Line, Tumor; Dogs; Drug Screening Assays, Antitumor; Humans; Leukemia P388 - drug therapy; Medical sciences; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship; Tumors
• ISSN: 0250-7005; 1791-7530

2,4-Diaminopyrimidine derivatives, that were originally developed as antiviral agents, were modified to antitumor agents by: i) introducing an amino group at C-5 on the pyrimidine ring, ii) changing the alkyl group and the ring size of the cycloalkyl group on the β-position of the ω-hydroxyalkylamino group, iii) replacing the phenylalkyl group on the cycloalkyl group with the 3,4,5-trimethoxyphenylalkyl group, iv) the esterification of the primary alcohol with diethyl phosphate and v) introducing the thiomethyl group at C-2 on the pyrimidine ring. Among the 21 compounds prepared, 6 , which has cyclobutyl at the β-position, exhibited potent activity towards P-388 leukemia. In addition, 14 , with methoxyl groups on the phenyl ring and 17 , with the thiomethyl group on the pyrimidine ring, showed specific inhibition for the EGFR protein kinase. Moreover, 15 and 16 , which carry the diethyl phosphoryl group on the primary alcohol, exhibited inhibitory activity towards P-glycoprotein.