Govindaraj Senthilnathan, Ganesan Kilivelu, Dharmasivam Mahendiran, Raman Lakshmisundaram, Kuppusamy Kalaivani M, Pandiappan Viswanathan, Alam Mohammed Mujahid, Mohammed Amanullah
PG and Research Department of Chemistry, Presidency College, Chennai 600005, India.
Centre for Cancer Cell Biology and Drug Discovery, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland 4111, Australia.
ACS Omega. 2023 Mar 27;8(14):13243-13251. doi: 10.1021/acsomega.3c00526. eCollection 2023 Apr 11.
Flexible dimeric substituted pyridinium bromides with primary and tertiary amines are prepared by conventional and solvent-free methods. The formation of compounds and is much easier than that of compounds and because of the benzyl carbon which is more electropositive than the primary alkyl carbon. The newly synthesized dimeric pyridinium compounds are optimized using DFT and B3LYP 6-31 g(d,p). The antiproliferative activity is studied in lung (A549) and breast cancer cell lines (MDA-MB 231). Among the four compounds, 1,1'-(1,3-phenylene bis(methylene)bis 2-aminopyridinium bromide showed potent anticancer activity when compared to the standard drug 5-fluorouracil. 1,1'-(1,3-Phenylene bis(methylene)bis 2-aminopyridinium bromide is not toxic to normal cell lines 3T3-L1 and MRC-5 cell lines. Also, 1,1'-(1,3-phenylene bis(methylene)bis 2-aminopyridinium bromide induced apoptosis in cancer cell lines is examined using AO/EB and Hoechst staining, which is further supported by cell cycle analysis. Western blot analysis showed that 1,1'-(1,3-phenylene bis(methylene)bis 2-aminopyridinium bromide induces apoptosis through the extrinsic apoptotic pathway by upregulating caspase 3 and caspase 9. This compound also downregulates intrinsic apoptotic proteins, including Bcl-2, Bcl-x, and Bad. From the present study results, it is confirmed that 1,1'-(1,3-phenylene bis(methylene)bis 2-aminopyridinium bromide has potent anticancer activity when compared to other compounds.
含有伯胺和叔胺的柔性二聚体取代溴化吡啶鎓通过常规方法和无溶剂方法制备。由于苄基碳比伯烷基碳的电正性更强，化合物 和 的形成比化合物 和 容易得多。新合成的二聚吡啶鎓化合物使用DFT和B3LYP 6-31 g(d,p)进行优化。在肺癌（A549）和乳腺癌细胞系（MDA-MB 231）中研究了其抗增殖活性。在这四种化合物中，与标准药物5-氟尿嘧啶相比，1,1'-(1,3-亚苯基双(亚甲基)双2-氨基吡啶鎓溴化物显示出强大的抗癌活性。1,1'-(1,3-亚苯基双(亚甲基)双2-氨基吡啶鎓溴化物对正常细胞系3T3-L1和MRC-5细胞系无毒。此外，使用AO/EB和Hoechst染色检测了1,1'-(1,3-亚苯基双(亚甲基)双2-氨基吡啶鎓溴化物在癌细胞系中诱导的凋亡，细胞周期分析进一步支持了这一结果。蛋白质免疫印迹分析表明，1,1'-(1,3-亚苯基双(亚甲基)双2-氨基吡啶鎓溴化物通过上调半胱天冬酶3和半胱天冬酶9，通过外源性凋亡途径诱导凋亡。该化合物还下调包括Bcl-2、Bcl-x和Bad在内的内源性凋亡蛋白。从本研究结果可以证实，与其他化合物相比，1,1'-(1,3-亚苯基双(亚甲基)双2-氨基吡啶鎓溴化物具有强大的抗癌活性。
