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

细胞凋亡是通过TNF或Fas配体与细胞表面受体结合而引起的细胞内信号转导途径诱导的程序性细胞死亡。活性氧参与细胞凋亡的信号转导通路已被推迟。本研究的目的是合成人工合成的分子，为信号通路提供活性氧，诱导肿瘤细胞凋亡，主要研究人员通过在二甲基氨基吡啶中引入咪唑等多种功能基团，成功合成了高效的氧活化分子。该合成分子可诱导小鼠白血病L1210细胞、人白血病K562/ADM细胞、人癌KB-C4细胞和人胰腺癌AsPC-1细胞凋亡，其诱导作用与时间和浓度有关。细胞形态学改变和核内DNA降解表明细胞凋亡是一种抑制性过程，抗氧化剂抗坏血酸可抑制细胞凋亡，表明活性氧参与了细胞凋亡过程。发现caspase-1、caspase-3、Bcl-2、Bax、p53和p21不参与该合成分子诱导的细胞凋亡，从而成功地进行了产生活性氧的人工分子的分子设计和合成。

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.