新型长叶烯基萘满并N-酰基吡唑化合物的合成、抗增殖活性、三维定量构效关系及分子对接研究
收稿日期: 2023-12-16
修回日期: 2024-01-23
网络出版日期: 2024-02-28
基金资助
国家自然科学基金(32260366); 国家自然科学基金(32360360); 广西植物功能物质研究与利用重点实验室基金(FPRU2020-3)
Synthesis, Antiproliferative Activity, 3D-QSAR and Molecular Docking Study of Novel Longifolene-Derived Tetraline Fused N-Acyl-pyrazole Compounds
Received date: 2023-12-16
Revised date: 2024-01-23
Online published: 2024-02-28
Supported by
National Natural Science Foundation of China(32260366); National Natural Science Foundation of China(32360360); Fund of Guangxi Key Laboratory of Functional Phytochemicals Research and Utilization(FPRU2020-3)
为了探寻新型的抗癌药, 以可再生的天然产物长叶烯为原料, 设计并合成了21个新型长叶烯基萘满并N-酰基吡唑化合物, 利用FT-IR, 1H NMR, 13C NMR, HRMS和X射线单晶衍射等方法对目标化合物的结构作了表征. 采用噻唑蓝(MTT)法测定目标化合物的体外抗增殖活性. 结果表明, 部分化合物的抗增殖活性优于阳性对照5-氟尿嘧啶(5-FU). 其中, 长叶烯基萘满并N-对氰基苯甲酰基吡唑(6r) (R=p-CNC6H4)对人乳腺癌(MCF-7)细胞株的IC50为4.97 μmol/L, 长叶烯基萘满并N-对硝基苯甲酰基吡唑(6q) (R=p-NO2C6H4)对人结肠癌(SW480)细胞株的IC50为8.02 μmol/L, 均表现出显著的抗增殖活性. 化合物6q (R=p-NO2C6H4)对MCF-7细胞株、人胃癌(MGC-803)细胞株、人肝癌(HePG2)细胞株、人宫颈癌(Hela)细胞株和人肺癌(A549)细胞株的IC50值分别为10.97, 11.95, 19.78, 20.15和23.45 μmol/L, 表现出良好的广谱抗增殖活性. 此外, 利用构建的三维定量构效关系(3D-QSAR)模型(r2=0.986, q2=0.631)研究目标化合物分子结构与抗增殖活性之间的关系, 并通过分子对接模拟目标化合物与Survivin蛋白的相互作用模式.
秦丽清 , 林桂汕 , 段文贵 , 崔玉成 , 杨卯芳 , 李芳耀 , 李典鹏 . 新型长叶烯基萘满并N-酰基吡唑化合物的合成、抗增殖活性、三维定量构效关系及分子对接研究[J]. 有机化学, 2024 , 44(6) : 1967 -1977 . DOI: 10.6023/cjoc202312015
In search of novel anticancer drugs, twenty-one novel longifolene-derived tetraline fused N-acylpyrazole compounds 6a~6u were designed and synthesized from renewable natural product longifolene. Their structures were characterized by FT-IR, NMR, HRMS, and X-ray single-crystal diffraction. The in vitro antiproliferative activity of the target compounds was evaluated by the methylthiazolyldiphenyl-tetrazolium bromide (MTT) method. As a result, some of the target compounds showed better antiproliferative activity than that of the positive control fluorouracil (5-FU). Among these, 4-(7-isopropyl-5,5-dimethyl-4,5-dihydro-2H-benzo[g]indazole-2-carbonyl)benzonitrile (6r) (R=p-CNC6H4) had IC50 of 4.97 μmol/L against SW480 cell (human colon cancer cell), and (7-isopropyl-5,5-dimethyl-4,5-dihydro-2H-benzo[g]indazol-2-yl)-(4-nitrophenyl) methanone (6q) (R=p-NO2C6H4) had IC50 of 8.02 μmol/L against MCF-7 cell (human breast cancer cell), exhibiting significant antiproliferative activity. Compound 6q (R=p-NO2C6H4) displayed good and broad-spectrum antiproliferative activity, with IC50 of 10.97, 11.95, 19.78, 20.15 and 23.45 μmol/L against MCF-7 cell, MGC-803 cell (human gastric cancer cell line), HepG2 cell (human hepatocellular carcinoma cell), Hela cell (human cervical cancer cell), and A549 cell (human lung adenocarcinoma cell), respectively. Furthermore, the relationship between structures and their antiproliferative activity was investigated by the established 3D-quantitative structure-activity relationship (3D-QSAR) model (r2=0.986 and q2=0.631), and the interaction mode between the target compounds and Survivin was also simulated by molecular docking.
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