Gul Halise Inci, Gul Mustafa, Hänninen Osmo
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ataturk University, Erzurum, Turkey.
Arzneimittelforschung. 2002;52(11):840-3. doi: 10.1055/s-0031-1299977.
Some mono Mannich bases (1-phenyl-3-amino-1-propanone salts) and bis Mannich bases (1-phenyl-3-amino-2-amino-methyl-1-propanone salts) derived from acetophenone and a few representative quaternary derivatives were synthesised and their cytotoxicity was tested using the brine shrimp bioassay. This assay may serve as an intermediate test before further in vivo animal experiments in large scale, since brine shrimp nauplii as whole organisms were used in this test. Mono Mannich bases were generally more cytotoxic than their corresponding bis Mannich bases. Mannich bases synthesised were cytotoxic in both brine shrimp bioassay in this study and cell culture tests using Jurkat and Renca cells in a previous study. However, the order of the cytotoxic potency of the compounds were reverse, which may result from faster deamination of bis derivatives than optimal level, and different species and test media used in the two test systems. Faster deamination of bis derivatives might have led to elimination of active metabolites before reaching its target. The cytotoxicity of the compounds might have been altered by amino acids and proteins present in cell culture medium but not in sea water used in brine shrimp bioassay affecting their transport through the cell membrane and metabolism in the cell by binding with the compounds. With higher cytotoxic activity compared with 5-fluorouracil (CAS 51-21-8) in brine shrimp bioassay, mono Mannich base 1 and its quaternary derivative 4 and quaternary bis derivative 8 seem to be candidate compounds for further drug design.
合成了一些由苯乙酮衍生的单曼尼希碱（1-苯基-3-氨基-1-丙酮盐）和双曼尼希碱（1-苯基-3-氨基-2-氨甲基-1-丙酮盐）以及一些代表性的季铵衍生物，并使用卤虫生物测定法测试了它们的细胞毒性。由于该测试使用卤虫无节幼体作为完整生物体，此测定可作为大规模进一步体内动物实验之前的中间测试。单曼尼希碱通常比其相应的双曼尼希碱具有更高的细胞毒性。本研究中合成的曼尼希碱在卤虫生物测定中以及先前研究中使用Jurkat和Renca细胞的细胞培养测试中均具有细胞毒性。然而，这些化合物的细胞毒性效力顺序相反，这可能是由于双衍生物的脱氨速度比最佳水平快，以及两个测试系统中使用的物种和测试介质不同所致。双衍生物更快的脱氨可能导致活性代谢物在到达其靶点之前就被消除。细胞培养基中存在的氨基酸和蛋白质可能改变了这些化合物的细胞毒性，但卤虫生物测定中使用的海水中不存在这些物质，这会影响它们通过细胞膜的转运以及在细胞内与化合物结合的代谢过程。在卤虫生物测定中，单曼尼希碱1及其季铵衍生物4和季铵双衍生物8与5-氟尿嘧啶（CAS 51-21-8）相比具有更高的细胞毒性活性，似乎是进一步药物设计的候选化合物。
