Im C, Knaus E E, Thuynsma R P, Allen T M
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Drug Des Deliv. 1990 Mar;5(3):239-48.
1-(2-Nitrovinyl) derivatives of nuclear substituted 1,4-dihydropyridines (7a-c), and 1-(N-tert-butyl-formiminyl) derivatives of 1,4-dihydropyridines (9a-c) or 2-pyridones (11a-c) were synthesized for evaluation as cytotoxic agents (see Table I for structures). The in vitro cytotoxic activities, determined in the L1210 assay, indicated that the 4-substituent on a 1,4-dihydropyridine ring system was a determinant of activity in both the 1-(2-nitrovinyl) (7) and 1-(N-tert-butylformiminyl) (9) series, the relative activity order being n-Bu > Ph > Me. In the 1-(N-tert-butylformiminyl) series, the 1,4-dihydropyridine derivatives (9) were generally more cytotoxic than the 2-pyridone derivatives (11). The most active compound was 1-(N-tert-butylformiminyl)-3-(4,4-dimethyloxazolin-2-yl)-4-n -butyl-1,4- dihydropyridine (9b), but it was 2-3 log units less active than the reference standard melphalan.
合成了核取代的1,4 - 二氢吡啶的1-(2 - 硝基乙烯基)衍生物(7a - c)以及1,4 - 二氢吡啶(9a - c)或2 - 吡啶酮(11a - c)的1-(N - 叔丁基 - 甲亚胺基)衍生物，以评估其作为细胞毒性剂的活性(结构见表I)。在L1210试验中测定的体外细胞毒性活性表明，1,4 - 二氢吡啶环系统上的4 - 取代基是1-(2 - 硝基乙烯基)(7)和1-(N - 叔丁基甲亚胺基)(9)系列活性的决定因素，相对活性顺序为正丁基>苯基>甲基。在1-(N - 叔丁基甲亚胺基)系列中，1,4 - 二氢吡啶衍生物(9)通常比2 - 吡啶酮衍生物(11)具有更强的细胞毒性。活性最高的化合物是1-(N - 叔丁基甲亚胺基)-3-(4,4 - 二甲基恶唑啉 - 2 - 基)-4 - 正丁基 - 1,4 - 二氢吡啶(9b)，但其活性比参考标准美法仑低2 - 3个对数单位。
