D'yakonov Vladimir A, Tuktarova Regina A, Dzhemileva Lilya U, Ishmukhametova Svetlana R, Dzhemilev Usein M
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, pr. Oktyabrya 141, 450075 Ufa, Russia.
Pharmaceuticals (Basel). 2021 Jan 23;14(2):84. doi: 10.3390/ph14020084.
For the first time, hybrid molecules were synthesized on the basis of lithocholic and (5,9)-1,14-tetradeca-5,9-dienedicarboxylic acids, obtained in two stages using the homo-cyclomagnesiation reaction of 2-(hepta-5,6-diene-1-yloxy)tetrahydro-2H-pyran at the key stage. The resulting hybrid molecules containing 5,9-dienoic acids are of interest as novel synthetic biologically active precursors to create modern drugs for the treatment of human oncological diseases. The synthesized hybrid molecules were found to exhibit extremely high in vitro inhibitory activity against human topoisomerase I, which is 2-4 times higher than that of camptothecin, a known topoisomerase I inhibitor. Using flow cytometry and fluorescence microscopy, it was first shown that these new molecules are efficient apoptosis inducers in HeLa, U937, Jurkat, K562, and Hek293 cell cultures. In addition, the results of investigations into the effect of the synthesized acids on mitochondria and studies of possible DNA damage in Jurkat tumor cells are also presented.
首次以石胆酸和(5,9)-1,14-十四碳-5,9-二烯二羧酸为基础合成了杂化分子，在关键步骤通过2-(庚-5,6-二烯-1-基氧基)四氢-2H-吡喃的同环镁化反应分两步得到。所得含5,9-二烯酸的杂化分子作为新型合成生物活性前体具有重要意义，可用于开发治疗人类肿瘤疾病的现代药物。研究发现，合成的杂化分子对人拓扑异构酶I具有极高的体外抑制活性，比已知的拓扑异构酶I抑制剂喜树碱高2至4倍。利用流式细胞术和荧光显微镜，首次表明这些新分子是HeLa、U937、Jurkat、K562和Hek293细胞培养物中的有效凋亡诱导剂。此外，还展示了合成酸对线粒体影响的研究结果以及对Jurkat肿瘤细胞中可能的DNA损伤的研究。
