Gul Halise Inci, Gul Mustafa, Vepsälainen Jouko, Erciyas Ercin, Hänninen Osmo
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ataturk University, Erzurum, Turkey.
Biol Pharm Bull. 2003 May;26(5):631-7. doi: 10.1248/bpb.26.631.
Acetophenone derived mono-Mannich bases (Ig1-Ig4), 1-aryl-3-amino-1-propanone hydrochlorides, which are known to have cytotoxicity in Jurkat cells, were synthesized. Then, they were converted to corresponding azine derivatives (D1-D4), N, N'-bis(3-amino-1-aryl-propylidene)hydrazine dihydrochlorides, which are bifunctional agents. The aryl part was replaced by phenyl in Ig1, Ig2, Ig3, D1, D2, and D3, and by p-hydroxyphenyl in Ig4 and D4. The amine part was replaced by dimethylamine in Ig1, D1, Ig4 and D4, by piperidine in Ig2 and D2, and by morpholine in Ig3 and D3. The aim of this study was to investigate whether the modification in chemical structure, converting the mono-Mannich base to a corresponding azine derivative, improves the cytotoxicity. In addition, the effect of the representative compound, D3, N, N'-bis(3-morpholine-4-yl-1-phenylpropylidene)hydrazine dihydrochloride, on cellular glutathione level after 1 h exposure in phosphate buffer at 37 degrees C was also determined to provide information on a possible mechanism of cytotoxic action. Compounds D2-D4 are reported for the first time in this study. Except for Ig2 and D2, the cytotoxicity of mono-Mannich bases, Ig1, Ig3 and Ig4 and corresponding azine derivatives, D1, D3 and D4 were higher than the reference compound 5-FU. Azine derivatives D1 and D4 had almost equal cytotoxic potency with corresponding mono-Mannich bases Ig1 and Ig4, respectively. On the other hand, azine derivatives D2 and D3, had 1.28 and 1.90-times less cytotoxicity in Jurkat cells compared with the mono-Mannich bases, Ig2 and Ig3, respectively, from which they are derived. Azine derivative D3 dose-dependently decreased the total cellular glutathione level, suggesting that azine derivatives may exert cytotoxicity by thiol alkylation. Azine derivatives with equal or less cytotoxic potency compared to the mono-Mannich bases they are derived from seemed to be less suitable derivatives for the development of new cytotoxic compounds.
合成了已知在Jurkat细胞中具有细胞毒性的苯乙酮衍生的单曼尼希碱（Ig1 - Ig4），即1 - 芳基 - 3 - 氨基 - 1 - 丙酮盐酸盐。然后，将它们转化为相应的嗪衍生物（D1 - D4），即N，N'-双（3 - 氨基 - 1 - 芳基 - 亚丙基）肼二盐酸盐，它们是双功能试剂。在Ig1、Ig2、Ig3、D1、D2和D3中，芳基部分被苯基取代，在Ig4和D4中被对羟基苯基取代。胺部分在Ig1、D1、Ig4和D4中被二甲胺取代，在Ig2和D2中被哌啶取代，在Ig3和D3中被吗啉取代。本研究的目的是研究将单曼尼希碱转化为相应的嗪衍生物的化学结构修饰是否能提高细胞毒性。此外，还测定了代表性化合物D3，即N，N'-双（3 - 吗啉 - 4 - 基 - 1 - 苯基亚丙基）肼二盐酸盐在37℃的磷酸盐缓冲液中暴露1小时后对细胞内谷胱甘肽水平的影响，以提供细胞毒性作用可能机制的信息。化合物D2 - D4在本研究中首次报道。除了Ig2和D2外，单曼尼希碱Ig1、Ig3和Ig4以及相应的嗪衍生物D1、D3和D4的细胞毒性均高于参考化合物5 - FU。嗪衍生物D1和D4分别与相应的单曼尼希碱Ig1和Ig4具有几乎相同的细胞毒性效力。另一方面，嗪衍生物D2和D3在Jurkat细胞中的细胞毒性分别比其来源的单曼尼希碱Ig2和Ig3低1.28倍和1.90倍。嗪衍生物D3剂量依赖性地降低细胞内总谷胱甘肽水平，表明嗪衍生物可能通过硫醇烷基化发挥细胞毒性。与它们所衍生的单曼尼希碱相比，细胞毒性效力相同或更低的嗪衍生物似乎不太适合作为开发新的细胞毒性化合物的衍生物。
