Modification of pyrimidine derivatives from antiviral agents to antitumor agents.
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 beta-position of the omega-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 beta-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.
Department of Pharmaceutical Manufacturing Chemistry 21st Century COE program, Kyoto Pharmaceutical University, 1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
Hiroyuki
H
Kimura
Takahiro
T
Katoh
Tetsuya
T
Kajimoto
Manabu
M
Node
Masakatsu
M
Hisaki
Yoshikazu
Y
Sugimoto
Tetsuo
T
Majima
Yoshimasa
Y
Uehara
Takao
T
Yamori
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C017205:2,4-diaminopyrimidine