新型噻唑取代双吡唑啉肟衍生物的设计、合成及通过选择性诱导癌细胞凋亡和 ROS 产生的抗肿瘤活性的生物评价。
Design, Synthesis, and Biological Evaluation of Novel Thiazolyl Substituted Bis-pyrazole Oxime Derivatives with Potent Antitumor Activities by Selectively Inducing Apoptosis and ROS in Cancer Cells.
机构信息
School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, China.
College of Chemistry and Chemical Engineering, Nantong University, Nantong 226001, China.
出版信息
Med Chem. 2019;15(7):743-754. doi: 10.2174/1573406414666180827112724.
BACKGROUND
A large number of pyrazole derivatives have different biological activities such as anticancer, antimicrobial, anti-inflammatory, analgesic and antiepileptic activity. Among them, pyrazole oximes have attracted much attention due to their potential pharmacological activities, particularly anticancer activities.
OBJECTIVE
Our goal is to synthesize novel thiazolyl substituted bis-pyrazole oxime derivatives with potent antitumor activities by selectively inducing apoptosis and Reactive Oxygen Species (ROS) accumulation in cancer cells.
METHODS
Eighteen bis-pyrazole oximes were synthesized by conjugating thiazolyl substituted pyrazoles with pyrazoxime. The target compounds were characterized by 1HNMR, 13C NMR, and HRMS, and screened for their antiproliferative activity against four cancer cells in MTT assay. The most potent compound was examined for its inhibitory effect and ROS accumulation in both cancer cells HCT116 and normal intestinal epithelial cells CCD841. Finally, the most potent compound was further evaluated for its apoptotic induction by flow cytometry analysis and immunoblot analysis of apoptosis-related proteins and DNA damage proteins.
RESULTS
Most compounds displayed potent antiproliferative activity against four cancer cell lines in vitro, displaying potencies superior to 5-FU. In particular, the most potent compound 13l selectively inhibited proliferation of colorectal cancer HCT116 cells but not normal colon CCD841 cells. Furthermore, compound 13l also selectively promoted intracellular ROS accumulation in HCT116 which was involved in 13l inhibition of cancer cell proliferation and induction of cell apoptosis. Finally, compound 13l also dose-dependently induced cancer cell apoptosis by regulating apoptotic and DNA damage related proteins expressions.
CONCLUSION
Our synthetic bis-pyrazole oxime derivatives possess potent antitumor activities by selectively inducing apoptosis and ROS accumulation in cancer cells, which may hold great promise as therapeutic agents for the treatment of human cancers.
背景
大量的吡唑衍生物具有不同的生物活性，如抗癌、抗菌、抗炎、镇痛和抗癫痫活性。其中，吡唑肟因其潜在的药理活性，特别是抗癌活性，引起了广泛关注。
目的
我们的目标是通过选择性地诱导癌细胞凋亡和活性氧（ROS）积累，合成具有潜在抗肿瘤活性的新型噻唑取代双吡唑肟衍生物。
方法
通过将噻唑取代的吡唑与吡唑肟偶联，合成了 18 个双吡唑肟。目标化合物通过 1HNMR、13C NMR 和 HRMS 进行表征，并通过 MTT 法测定其对四种癌细胞的增殖抑制活性。对最有效的化合物进行了在癌细胞 HCT116 和正常肠上皮细胞 CCD841 中的抑制作用和 ROS 积累的检测。最后，通过流式细胞术分析和凋亡相关蛋白和 DNA 损伤蛋白的免疫印迹分析进一步评价最有效的化合物对凋亡的诱导作用。
结果
大多数化合物在体外对四种癌细胞系均表现出较强的增殖抑制活性，其活性优于 5-FU。特别是最有效的化合物 13l 选择性地抑制结直肠癌细胞 HCT116 的增殖，而对正常结肠 CCD841 细胞没有影响。此外，化合物 13l 还选择性地促进了 HCT116 细胞内 ROS 的积累，这涉及到 13l 抑制癌细胞增殖和诱导细胞凋亡。最后，化合物 13l 还通过调节凋亡和 DNA 损伤相关蛋白的表达，剂量依赖性地诱导癌细胞凋亡。
结论
我们合成的双吡唑肟衍生物通过选择性地诱导癌细胞凋亡和 ROS 积累，具有较强的抗肿瘤活性，有望成为治疗人类癌症的治疗剂。
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