Kimura Hiroyuki, Katoh Takahiro, Kajimoto Tetsuya, Node Manabu, Hisaki Masakatsu, Sugimoto Yoshikazu, Majima Tetsuo, Uehara Yoshimasa, Yamori Takao
Department of Pharmaceutical Manufacturing Chemistry 21st Century COE program, Kyoto Pharmaceutical University, 1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
Anticancer Res. 2006 Jan-Feb;26(1A):91-7.
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.
最初作为抗病毒剂开发的2,4-二氨基嘧啶衍生物通过以下方式被修饰为抗肿瘤剂：(i) 在嘧啶环的C-5位引入一个氨基；(ii) 改变ω-羟烷基氨基β位上的烷基和环烷基的环大小；(iii) 用3,4,5-三甲氧基苯基烷基取代环烷基上的苯基烷基；(iv) 用磷酸二乙酯将伯醇酯化；以及(v) 在嘧啶环的C-2位引入硫甲基。在所制备的21种化合物中，6在β位具有环丁基，对P-388白血病表现出强效活性。此外，14在苯环上有甲氧基，17在嘧啶环上有硫甲基，对表皮生长因子受体（EGFR）蛋白激酶表现出特异性抑制作用。而且，15和16在伯醇上带有二乙基磷酰基，对P-糖蛋白表现出抑制活性。
