新型苯氧苯基嘧啶-5-甲腈衍生物作为潜在的凋亡性抗增殖剂。
Novel Benzyloxyphenyl Pyrimidine-5-Carbonitrile Derivatives as Potential Apoptotic Antiproliferative Agents.
机构信息
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, 21589, Saudi Arabia.
出版信息
Anticancer Agents Med Chem. 2022;22(5):978-990. doi: 10.2174/1871520621666210612043812.
BACKGROUND
Pyrimidine-5-carbonitrile has a broad spectrum of biological activities such as antiviral, antioxidant, and anticancer activities. Among similar compounds, monastrol is the most prominent cell-permeant inhibitor of mitosis; therefore, we investigated the new Pyrimidine-5-carbonitrile as a cytotoxic agent for the p53 pathway.
OBJECTIVE
Several new benzyloxyphenyl pyrimidine-5-carbonitrile derivatives were designed, synthesized, and characterized, and their cytotoxicity was evaluated. The most active compounds were tested for their activity against p53 as a mechanistic target for antiproliferative action.
METHODS
The key intermediate tetrahydropyrimidine-5-carbonitrile derivative 4 was prepared by a multicomponent reaction (MCR) of the Biginelli type. S-alkylation of the key intermediate with the required alkyl or aralkyl halides or refluxing 4 with POCl3 followed by an amino acid yielded the target compounds. The cytotoxicity of 5c-e, 7a-c, 9, 10a, b, and 11 was evaluated using the A549 cell line of human lung adenocarcinoma, HepG2 liver cell line, and MDAMB- 231 cell line of breast cancer using the MTT assay. The transcription effects of 7a, 7c, and 11 on the p53 were assessed and compared with the reference doxorubicin.
RESULTS
Compounds 7a, 7c, and 11 have the highest cytotoxic effect when applied to most cancer cells. The tested compounds with 5-FU showed a significant increase in the anticancer activity more than 5-FU alone. Compounds 7a, 7c, and 11 increased the level of active caspase 3 by 4-6-fold compared to untreated control cells in the human liver cancer cell line (HepG2). Compounds 7a, 7c, and 11 increased the levels of caspase 8 and 9, indicating activation of both intrinsic and extrinsic pathways and showing potent induction of Bax, down-regulation of Bcl-2 protein levels, and over-expression of Cytochrome C levels in HepG2 cell lines. Compound 11 exhibited cell cycle arrest at the Pre- G1 and G2/M phases in the cell cycle analysis of the HepG2 cell line. The results revealed an increase of 12.40-19.10 in p53 level compared to the test cells and that p53 protein level of 7a, 7c, and 11 was significantly inductive (636, 861, and 987 pg/mL, respectively) in relation to doxorubicin (1263 pg/mL).
CONCLUSION
Pyrimidine-5-carbonitrile derivatives have potent apoptotic and antiproliferative properties.
背景
嘧啶-5-甲腈具有广泛的生物活性，如抗病毒、抗氧化和抗癌活性。在类似的化合物中，单体酶是最突出的细胞穿透性有丝分裂抑制剂；因此，我们研究了新的嘧啶-5-甲腈作为 p53 途径的细胞毒性剂。
目的
设计、合成并表征了几种新的苄氧基苯基嘧啶-5-甲腈衍生物，并评估了它们的细胞毒性。对最活跃的化合物进行了测试，以评估它们作为增殖作用的机制靶点对 p53 的活性。
方法
通过 Biginelli 型的多组分反应（MCR）制备关键中间体四氢嘧啶-5-甲腈衍生物 4。用所需的烷基或芳基卤化物对关键中间体进行 S-烷基化，或回流 4 与 POCl3 反应，然后与氨基酸反应，得到目标化合物。使用 MTT 法，用人肺腺癌 A549 细胞系、肝癌 HepG2 细胞系和乳腺癌 MDAMB-231 细胞系评估 5c-e、7a-c、9、10a、b 和 11 的细胞毒性。评估了 7a、7c 和 11 对 p53 的转录作用，并与参比药物阿霉素进行了比较。
结果
当应用于大多数癌细胞时，化合物 7a、7c 和 11 具有最高的细胞毒性作用。与单独使用 5-FU 相比，用测试化合物处理显示出对癌症活性的显著增加。与未处理的对照细胞相比，化合物 7a、7c 和 11 在人肝癌细胞系（HepG2）中使活性 caspase 3 的水平增加了 4-6 倍。化合物 7a、7c 和 11 增加了 caspase 8 和 9 的水平，表明同时激活了内在和外在途径，并显示出在 HepG2 细胞系中强烈诱导 Bax、下调 Bcl-2 蛋白水平和过表达细胞色素 C 水平。化合物 11 在 HepG2 细胞周期分析中使细胞周期在 Pre-G1 和 G2/M 期停滞。结果显示与测试细胞相比，p53 水平增加了 12.40-19.10，并且 7a、7c 和 11 的 p53 蛋白水平明显诱导（分别为 636、861 和 987 pg/mL）与阿霉素（1263 pg/mL）相比。
结论
嘧啶-5-甲腈衍生物具有很强的凋亡和抗增殖特性。
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