Sinniah Saravana Kumar, Tan Kong Wai, Ng Seik Weng, Sim Kae Shin
Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
Anticancer Agents Med Chem. 2017;17(5):741-753. doi: 10.2174/1871520616666160926110929.
Thiosemicarbazone (TSC) is a Schiff base that has been receiving considerable attention owing to its promising biological implication and remarkable pharmacological properties. The most promising drug candidate of this class would be Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) which has entered phase II clinical trials as a potent anti-cancer chemotherapeutic agent.
The current research aimed to synthesize several Schiff base ligands from (3-formyl-4-hydroxyphenyl) methyltriphenylphosphonium (T). Additionally, the current research aimed to study the growth inhibitory effect of triphenylphosphonium containing thiosemicarbazone derivatives on PC-3 cells by deciphering the mechanisms involved in cell death.
The compounds were characterized by various spectroscopic methods (infrared spectra, 1H NMR, 13C NMR, HRESIMS and X-ray crystallography) and the results were in conformity with the structure of the targeted compounds. Growth inhibitory effect of the compounds were performed against six human cell lines.
DM(tsc)T displayed most potent activity against PC-3 cells with IC50 value of 2.64 ± 0.33 μM, surpassing that of the positive control cisplatin (5.47 ± 0.06 μM). There were marked morphological changes observed in DM(tsc)T treated cells stained with acridine orange and ethidium bromide which were indicative of cell apoptosis. Treatment with DM(tsc)T showed that the cell cycle is arrested in the G0/G1 phase after 72 hours. Mitochondrial membrane potential loss was observed in cells treated with DM(tsc)T, indicating the apoptosis could be due to mitochondria mediated pathway.
This study indicates that DM(tsc)T would serve as a lead scaffold for rational anticancer agent development.
硫代氨基脲（TSC）是一种席夫碱，因其具有良好的生物学意义和显著的药理特性而备受关注。该类最具潜力的候选药物是曲拉滨（3-氨基吡啶-2-甲醛硫代氨基脲），它已作为一种有效的抗癌化疗药物进入二期临床试验。
当前研究旨在从（3-甲酰基-4-羟基苯基）甲基三苯基鏻（T）合成几种席夫碱配体。此外，当前研究旨在通过解读细胞死亡相关机制，研究含三苯基鏻硫代氨基脲衍生物对PC-3细胞的生长抑制作用。
通过各种光谱方法（红外光谱、1H NMR、13C NMR、高分辨电喷雾电离质谱和X射线晶体学）对化合物进行表征，结果与目标化合物的结构相符。对化合物针对六种人类细胞系进行生长抑制作用研究。
DM(tsc)T对PC-3细胞显示出最强活性，IC50值为2.64±0.33μM，超过阳性对照顺铂（5.47±0.06μM）。用吖啶橙和溴化乙锭染色观察到，经DM(tsc)T处理的细胞有明显的形态变化，这表明细胞发生了凋亡。用DM(tsc)T处理表明，72小时后细胞周期停滞在G0/G1期。在用DM(tsc)T处理的细胞中观察到线粒体膜电位丧失，表明凋亡可能是由线粒体介导的途径引起的。
本研究表明，DM(tsc)T可作为合理开发抗癌药物的先导支架。
