Rakesh Kumar, E. Knaus, L. Wiebe
Jul 1, 1991
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Influential Citations
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Quality indicators
Journal
European Journal of Medicinal Chemistry
Abstract
Abstract A series of 5-(1-hydroxy-2-haloethyl) 6, 7, 13, 14a , 5-oxiranyl 8, 9 and ( E )-5-(2-iodovinyl)-2,4-dichloro(or dimethoxy)pyrimidines 11, 12 were synthesized for evaluation as cytotoxic agents. The nuclear C-2 and C-4 substituents were determinants of activity since the 2,4-dichloro compounds 6, 8 and 11 were more potent (ED 50 = 0.2–0.3 μg/ml) than the corresponding 2,4-dimethoxypyrimidine analogues 7, 9 and 12 (ED 50 = 4–28 μg/ml), relative to melphalan (ED 50 = 0.15 μg/ml), in the in vitro L1210 screen. Within the 2,4-dichloro series of compounds 6, 8 and 11 , the C-5 substituent was not a determinant of activity. In contrast, in the 2,4-dimethoxypyrimidine series, the C-5 substituents influenced activity significantly where the relative potency order was oxiranyl 9 > -CH(OH)CH 2 I 7 > (E)-CH = CHI 12 > CH(OH)CHI 2 13 , CH(OH)CHBr(I) 14a and CH(Br)CHOH(I) 14b . The most active compound ( E )-5-(2-iodovinyl)-2,4-dichloropyrimidine 11 exhibited weak activity in the in vivo P388 screen (% T C = 116 for a 10 mg/kg ip dose) relative to the reference drug 5-fluorouracil (% T C = 135 for a 20 mg/kg dose).