哌嗪是许多临床批准药物的重要功能单位,包括化疗药物。在目前的研究中,掺入甲基哌嗪,并制备了八个水杨醛衍生的哌嗪官能化的腙ONN供体配体(L)及其Pt(II)配合物(L-PtCl)。使用1H和13CNMR确定所有这些配体(L1-L8)和Pt(II)配合物(C1-C8)的结构,UV-vis,FT-IR和HR-ESIMS分析,而C1,C5,C6,C7和C8的结构是使用单晶X射线衍射分析在固态下确定的。C3、C4、C5和C6的溶液状态稳定性通过时间依赖性UV-vis光谱法测定。研究了所有这些复合物(C1-C8)在胰腺导管腺癌细胞中的抗癌作用,包括BxPC3、MIAPaCa-2和PANC1细胞。C1-C8在所有这些癌细胞中显示出潜在的细胞毒性作用,其中C5,C6和C8与标准化疗药物相比表现出最强的抑制作用,包括5-氟尿嘧啶(5-FU),顺铂(CP),奥沙利铂和阿霉素(DOX)。C5、C6和C8以剂量依赖性方式抑制胰腺癌细胞的生长。此外,C5,C6和C8抑制PANC1细胞的克隆形成潜能和侵袭能力,并诱导细胞凋亡。重要的是,C5,C6和C8与PARP抑制剂协同抗癌作用,包括奥拉帕利,veliparib和niraparib,在胰腺癌细胞中,因此表明C5,C6和C8与PARP抑制剂联合在诱导细胞凋亡中的重要作用。C5与PARP抑制剂联合诱导caspase3/7活性并抑制ATP产生。机械上,C5、C6和C8抑制EZH2蛋白表达以抑制EZH2依赖性肿瘤发生。总的来说,这些结果强调了这些哌嗪官能化的Pt(II)配合物作为潜在的抗癌剂通过靶向EZH2依赖性途径抑制胰腺导管腺癌肿瘤发生的重要性.
Piperazine is an important functional unit of many clinically approved drugs, including chemotherapeutic agents. In the current study, methyl
piperazine was incorporated and eight salicylaldehyde-derived
piperazine-functionalized hydrazone ONN-donor ligands (L) and their Pt(II) complexes (L-PtCl) were prepared. The structures of all these ligands (L1-L8) and Pt(II) complexes (C1-C8) were determined using 1H and 13C NMR, UV-vis, FT-IR and HR-ESI MS analyses, whereas the structures of C1, C5, C6, C7 and C8 were determined in the solid state using single crystal X-ray diffraction analysis. Solution state stabilities of C3, C4, C5 and C6 were determined via time-dependent UV-vis spectroscopy. All these complexes (C1-C8) were studied for their anticancer effect in pancreatic ductal adenocarcinoma cells, including BxPC3, MIAPaCa-2 and PANC1 cells. C1-C8 displayed a potential cytotoxic effect in all these cancer cells, among which C5, C6 and C8 showed the strongest inhibitory effect in comparison with standard chemotherapeutic agents, including 5-fluorouracil (5-FU), cisplatin (CP), oxaliplatin and doxorubicin (DOX). C5, C6 and C8 suppressed the growth of pancreatic cancer cells in a dose-dependent manner. Moreover, C5, C6 and C8 inhibited clonogenic potential and invasion ability and induced apoptosis in PANC1 cells. Importantly, C5, C6 and C8 synergized the anticancer effect with PARP inhibitors, including olaparib, veliparib and niraparib, in pancreatic cancer cells, thus suggesting an important role of C5, C6 and C8 in induction of apoptosis in combination with PARP inhibitors. C5 combined with PARP inhibitors induced caspase3/7 activity and suppressed ATP production. Mechanistically, C5, C6 and C8 inhibited EZH2 protein expression to suppress EZH2-dependent tumorigenesis. Overall, these results highlighted the importance of these
piperazine-functionalized Pt(II) complexes as potential anticancer agents to suppress pancreatic ductal adenocarcinoma tumorigenesis by targeting the EZH2-dependent pathway.