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Design, Synthesis, and Molecular Docking of Paracyclophanyl-Thiazole Hybrids as Novel CDK1 Inhibitors and Apoptosis Inducing Anti-Melanoma Agents
Molecules ( IF 4.6 ) Pub Date : 2020-11-27 , DOI: 10.3390/molecules25235569
Ashraf A. Aly , Stefan Bräse , Alaa A. Hassan , Nasr K. Mohamed , Lamiaa E. Abd El-Haleem , Martin Nieger , Nesrin M. Morsy , Mohammed B. Alshammari , Mahmoud A. A. Ibrahim , Elshimaa M. N. Abdelhafez

Three new series of paracyclophanyl-dihydronaphtho[2,3-d]thiazoles and paracyclophanyl-thiazolium bromides were designed, synthesized, and characterized by their spectroscopic data, along with X-ray analysis. One-dose assay results of anticancer activity indicated that 3a–e had the highest ability to inhibit the proliferation of different cancer cell lines. Moreover, the hybrids 3c–e were selected for five-dose analyses to demonstrate a broad spectrum of antitumor activity without apparent selectivity. Interestingly, series I compounds (Z)-N-substituted-4,9-dihydronaphtho[2,3-d]thiazol-3(2H)-yl)-4′-[2.2]paracyclophanylamide) that are carrying 1,4-dihydronaphthoquinone were more active as antiproliferative agents than their naphthalene-containing congeners (series II: substituted 2-(4′-[2.2]paracyclophanyl)hydrazinyl)-4-(naphth-2-yl)-thiazol-3-ium bromide hybrids) and (series III: 3-(4′-[2.2]paracyclophanyl)amido-2-(cyclopropylamino)-4-(naphth-2-yl)thiazol-3-ium bromide) toward the SK-MEL-5 melanoma cell line. Further antiproliferation investigations of 3c and 3e on the healthy, normal unaffected SK-MEL-5 cell line indicated their relative safety. Compound 3c showed an inhibition of eight isoforms of cyclin-dependent kinases (CDK); however, it exhibited the lowest IC50 of 54.8 nM on CDK1 in comparison to Dinaciclib as a reference. Additionally, compound 3c revealed a remarkable downregulation of phospho-Tyr15 with a level (7.45 pg/mL) close to the reference. 3c mainly showed cell cycle arrest in the pre-G1 and G2/M phases upon analysis of the SK-MEL-5 cell line. The sequential caspase-3 assay for 3c indicated a remarkable overexpression level. Finally, a molecular docking study was adopted to elucidate the binding mode and interactions of the target compounds with CDK1.

中文翻译:

作为新型 CDK1 抑制剂和细胞凋亡诱导抗黑色素瘤药物的对环芳基-噻唑杂化物的设计、合成和分子对接

设计、合成了三个新系列的对环芳基-二氢萘并 [2,3-d] 噻唑和对环芳基-噻唑鎓溴化物,并通过它们的光谱数据和 X 射线分析进行了表征。抗癌活性的单剂量测定结果表明,3a-e 具有最高的抑制不同癌细胞系增殖的能力。此外,杂交体 3c-e 被选择用于五剂量分析,以证明广谱的抗肿瘤活性而没有明显的选择性。有趣的是,I系列化合物 (Z)-N-取代的-4,9-二氢萘并[2,3-d]噻唑-3(2H)-基)-4'-[2.2]对环芳基酰胺)携带1,4-二氢萘醌作为抗增殖剂的活性高于其含萘的同类物(系列 II:取代的 2-(4'-[2. 2]paracyclophanyl)hydrazinyl)-4-(naphth-2-yl)-thiazol-3-ium bromide 杂化物)和(系列 III:3-(4'-[2.2]paracyclophanyl)amido-2-(cyclopropylamino)-4 -(naphth-2-yl)thiazol-3-ium bromide) 对 SK-MEL-5 黑色素瘤细胞系。3c 和 3e 对健康、正常未受影响的 SK-MEL-5 细胞系的进一步抗增殖研究表明它们相对安全。化合物 3c 对细胞周期蛋白依赖性激酶 (CDK) 的八种亚型有抑制作用;然而,与作为参考的 Dinaciclib 相比,它对 CDK1 的 IC50 最低,为 54.8 nM。此外,化合物 3c 显示磷酸化 Tyr15 显着下调,其水平 (7.45 pg/mL) 接近参考值。图3c主要显示在分析SK-MEL-5细胞系时细胞周期停滞在前G1和G2/M期。3c 的连续 caspase-3 测定表明显着的过表达水平。最后,通过分子对接研究来阐明目标化合物与 CDK1 的结合模式和相互作用。
更新日期:2020-11-27
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