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

doi:10.6023/cjoc202312015

有机化学 ›› 2024, Vol. 44 ›› Issue (6): 1967-1977.DOI: 10.6023/cjoc202312015 上一篇下一篇

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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

秦丽清^a^,^b, 林桂汕^a^,^b^,^*(), 段文贵^a^,^b^,^*(), 崔玉成^a^,^b, 杨卯芳^a^,^b, 李芳耀^c, 李典鹏^d

a 广西大学化学化工学院南宁 530004
b 广西高校应用化学技术与资源开发重点实验室南宁 530004
c 桂林医学院药学院广西桂林 541100
d 广西植物功能物质与资源持续利用重点实验室广西桂林 541006

收稿日期:2023-12-16 修回日期:2024-01-23 发布日期:2024-02-27
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

Liqing Qin^a^,^b, Guishan Lin^a^,^b,*(), Wengui Duan^a^,^b,*(), Yucheng Cui^a^,^b, Maofang Yang^a^,^b, Fangyao Li^c, Dianpeng Li^d

a School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004
b Guangxi Colleges and Universities Key Laboratory of Applied Chemistry Technology and Resource Development, Nanning 530004
c College of Pharmacy, Guilin Medical University, Guilin, Guangxi 541100
d Guangxi Key Laboratory of Functional Phytochemicals Research and Utilization, Guilin, Guangxi 541006

Received:2023-12-16 Revised:2024-01-23 Published:2024-02-27
Contact: * E-mail: gslin@gxu.edu.cn; wgduan@gxu.edu.cn
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)

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摘要/Abstract

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.

关键词: 长叶烯基萘满, N-酰基吡唑, 合成, 抗增殖活性, 三维定量构效关系(3D-QSAR), 分子对接

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.

Key words: longifolene-derived tetraline, N-acyl-pyrazole, synthesis, antiproliferative activity, 3D-quantitative structure- activity relationship (3D-QSAR), molecular docking

引用此文

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.

Liqing Qin, Guishan Lin, Wengui Duan, Yucheng Cui, Maofang Yang, Fangyao Li, Dianpeng Li. Synthesis, Antiproliferative Activity, 3D-QSAR and Molecular Docking Study of Novel Longifolene-Derived Tetraline Fused N-Acyl-pyrazole Compounds[J]. Chinese Journal of Organic Chemistry, 2024, 44(6): 1967-1977.

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Compd.	IC₅₀^a/(μmol•L^–1)
Compd.	MCF-7	SW480	Hela
6a	>100	78.62±0.23	>100
6b	58.64±0.22	>100	>100
6c	25.60±1.09	>100	>100
6d	57.43±0.14	>100	68.95±0.15
6e	23.47±0.24	49.93±0.20	>100
6f	32.02±0.16	26.10±0.45	>100
6g	44.40±0.58	>100	>100
6h	31.63±2.05	41.32±0.23	>100
6i	27.19±0.24	69.78±0.08	25.43±4.03
6j	37.37±0.88	>100	>100
6k	22.62±0.19	29.28±0.98	>100
6l	22.72±0.23	28.06±0.64	33.86±0.32
6m	20.40±0.21	19.84±0.69	36.46±0.32
6n	13.38±0.35	23.69±1.16	14.68±0.28
6o	32.01±1.43	25.73±1.14	>100
6p	14.45±0.36	24.35±1.56	32.20±0.33
6q	10.92±0.49	8.02±0.39	20.15±1.47
6r	4.97±0.21	18.77±0.09	>100
6s	>100	49.75±0.11	>100
6t	>100	>100	>100
6u	47.55±3.64	61.67±0.09	>100
5-FU^b	27.05±1.85	13.72±0.21	23.07±0.99

Compd.	IC₅₀^a/(μmol•L^–1)
Compd.	MCF-7	SW480	Hela
6a	>100	78.62±0.23	>100
6b	58.64±0.22	>100	>100
6c	25.60±1.09	>100	>100
6d	57.43±0.14	>100	68.95±0.15
6e	23.47±0.24	49.93±0.20	>100
6f	32.02±0.16	26.10±0.45	>100
6g	44.40±0.58	>100	>100
6h	31.63±2.05	41.32±0.23	>100
6i	27.19±0.24	69.78±0.08	25.43±4.03
6j	37.37±0.88	>100	>100
6k	22.62±0.19	29.28±0.98	>100
6l	22.72±0.23	28.06±0.64	33.86±0.32
6m	20.40±0.21	19.84±0.69	36.46±0.32
6n	13.38±0.35	23.69±1.16	14.68±0.28
6o	32.01±1.43	25.73±1.14	>100
6p	14.45±0.36	24.35±1.56	32.20±0.33
6q	10.92±0.49	8.02±0.39	20.15±1.47
6r	4.97±0.21	18.77±0.09	>100
6s	>100	49.75±0.11	>100
6t	>100	>100	>100
6u	47.55±3.64	61.67±0.09	>100
5-FU^b	27.05±1.85	13.72±0.21	23.07±0.99

Compd.	Dipole moment^a/D	The electrostatic potential of benzene ring center^a/(kJ•mol^–1)
6h	5.06	–38.01
6r	5.17	17.79
6q	5.37	26.45

Compd.	Dipole moment^a/D	The electrostatic potential of benzene ring center^a/(kJ•mol^–1)
6h	5.06	–38.01
6r	5.17	17.79
6q	5.37	26.45

Compd.	IC₅₀^a/(μmol•L^–1)
Compd.	A549	HepG2	MGC-803
6m	13.70±0.61	37.98±3.41	18.98±2.06
6n	41.05±2.31	12.02±1.08	15.14±0.67
6p	30.91±2.90	27.78±4.21	25.90±3.37
6q	23.45±0.99	19.78±0.79	11.95±0.71
6r	28.98±0.72	22.89±1.22	9.83±0.19
5-FU^b	31.41±0.41	26.56±1.25	14.55±1.24

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

Synthesis, Antiproliferative Activity, 3D-QSAR and Molecular Docking Study of Novel Longifolene-Derived Tetraline Fused N-Acyl-pyrazole Compounds

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Compd.	pIC₅₀	CoMFA	pIC₅₀"	Residue
6a	3.996	166	3.982	0.014
6b	4.232	162	4.238	0.006
6c*	4.592	156	4.601	0.009
6d*	4.241	158	4.299	–0.058
6e	4.629	160	4.634	–0.005
6f	4.495	160	4.479	0.016
6g	4.353	156	4.347	0.006
6h	4.500	162	4.469	0.031
6i	4.566	152	4.598	–0.032
6j	4.427	158	4.529	–0.102
6k	4.646	158	4.667	–0.021
6l	4.644	154	4.640	0.004
6m	4.690	158	4.630	0.06
6n	4.874	156	4.864	0.01
6o	4.495	154	4.478	0.017
6p	4.840	156	4.821	0.019
6q	4.961	166	4.996	–0.035
6r	5.304	158	5.282	0.022

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q²	r²	S	F	Contribution/%
q²	r²	S	F	Steric	Electrostatic
0.631	0.986	0.046	107.042	42.7	57.3

q²	r²	S	F	Contribution/%
q²	r²	S	F	Steric	Electrostatic
0.631	0.986	0.046	107.042	42.7	57.3