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Synthesis, antitumor activity, 3D-QSAR and molecular docking studies of new iodinated 4-(3H)-quinazolinones 3N-substituted
RSC Advances ( IF 3.9 ) Pub Date : 2022-08-02 , DOI: 10.1039/d2ra03684c
Marcia Pérez-Fehrmann 1 , Víctor Kesternich 1 , Arturo Puelles 1 , Víctor Quezada 1 , Fernanda Salazar 1 , Philippe Christen 2, 3 , Jonathan Castillo 4 , Juan Guillermo Cárcamo 4, 5 , Alejandro Castro-Alvarez 6, 7 , Ronald Nelson 1
Affiliation  

A novel series of 6-iodo-2-methylquinazolin-4-(3H)-one derivatives, 3a–n, were synthesized and evaluated for their in vitro cytotoxic activity. Compounds 3a, 3b, 3d, 3e, and 3h showed remarkable cytotoxic activity on specific human cancer cell lines when compared to the anti-cancer drug, paclitaxel. Compound 3a was found to be particularly effective on promyelocytic leukaemia HL60 and non-Hodgkin lymphoma U937, with IC50 values of 21 and 30 μM, respectively. Compound 3d showed significant activity against cervical cancer HeLa (IC50 = 10 μM). The compounds 3e and 3h were strongly active against glioblastoma multiform tumour T98G, with IC50 values of 12 and 22 μM, respectively. These five compounds showed an interesting cytotoxic activity on four human cancer cell types of high incidence. The molecular docking results reveal a good correlation between experimental activity and calculated binding affinity on dihydrofolate reductase (DHFR). Docking studies proved 3d as the most potent compound. In addition, the three-dimensional quantitative structure–activity relationship (3D-QSAR) analysis exhibited activities that may indicate the existence of electron-withdrawing and lipophilic groups at the para-position of the phenyl ring and hydrophobic interactions of the quinazolinic ring in the DHFR active site.

中文翻译:

新型碘化 4-(3H)-喹唑啉酮 3N-取代的合成、抗肿瘤活性、3D-QSAR 和分子对接研究

合成了一系列新的 6-iodo-2-methylquinazolin-4-(3 H )-one 衍生物3a-n,并评估了它们的体外细胞毒活性。与抗癌药物紫杉醇相比,化合物3a3b3d3e3h对特定人类癌细胞系显示出显着的细胞毒活性。发现化合物3a对早幼粒细胞白血病 HL60 和非霍奇金淋巴瘤 U937 特别有效,IC 50值分别为 21 和 30 μM。化合物3d对宫颈癌 HeLa 显示出显着的活性(IC 50= 10微米)。化合物3e3h对多形性胶质母细胞瘤 T98G 具有很强的活性,IC 50值分别为 12 和 22 μM。这五种化合物对四种高发病率的人类癌细胞类型显示出有趣的细胞毒活性。分子对接结果揭示了实验活性和计算的二氢叶酸还原酶 (DHFR) 结合亲和力之间的良好相关性。对接研究证明3d是最有效的化合物。此外,三维定量构效关系(3D-QSAR)分析显示的活性可能表明在对位存在吸电子和亲油基团。DHFR活性位点中苯环的位置和喹唑啉环的疏水相互作用。
更新日期:2022-08-02
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