Molecular design and synthesis of anti-cancer compounds that cause apoptosis

细胞凋亡是由肿瘤坏死因子或Fas配体与细胞表面受体结合，通过细胞内信号转导途径诱导的细胞程序性死亡。在导致细胞凋亡的信号转导通路中，活性氧物种的参与已被推迟。本研究的目的是合成能够为肿瘤细胞信号转导途径提供活性氧的人工分子，通过在二甲氨基吡啶中引入咪唑等官能团，成功地合成了高效的氧活化分子。该合成分子对小鼠白血病L1210细胞、人白血病K562/ADM细胞、人癌细胞KB-C4、人胰腺癌ASPC-1细胞均有诱导凋亡作用，且呈时间和浓度依赖性。根据细胞的形态变化和DNA在核小体内的降解，发现细胞死亡是一种凋亡。细胞凋亡被抗氧化剂抗坏血酸抑制，这表明活性氧参与了这一过程。结果发现，caspase-1、caspase-3、bc l-2、Bax、p53和p21不参与由合成的分子诱导的细胞凋亡，从而成功地设计和合成了一种能产生活性氧物种以诱导癌细胞凋亡的人工分子。

Apoptosis is a programmed cell death induced through the intracellular signalling pathway caused by the binding of TNF or Fas ligand with receptors of cell surface. Involvement of active oxygen species has been postdated in the signal transduction pathway leading to apoptosis. The objective of the present research is to synthesize man-made molecules that supply active oxygen into the signalling pathway to induce apoptosis in the tumor cells.The head investigators are successful in the synthesis of highly efficient oxygen activating molecules by introducing various functional groups such as imidazole into dimethylaminopyridine. The synthesitic molecule induced apoptosis in mouse leukaemia L1210 cells, human leukaemia K562/ADM cells, human carcinoma KB-C4 cells, and human pancreatic carcinoma AsPC-1 cells depending on time and concentration. The cell death was found to be apoptosisbased on the morphological change of the cells and intranucleosomal degradation of DNA.The apoptosis was inhibited by an antioxidant ascorbic acid suggesting the involvement of active oxygen species. It was found that caspase-1, caspase-3, Bcl-2, Bax, p53, and p21 do not participate in the apoptosis caused by the synthetic molecule.Thus the head investigators are successful in the molecular design and synthesis of an artificial molecule that generates active oxygen species to induce apoptosis in carcinoma cells.