新型拟天然芪类拓扑异构酶I抑制剂的设计与合成

doi:10.6023/cjoc202102031

摘要/Abstract

为了寻找新型抗肿瘤药物先导, 设计合成了23个含噻唑环的天然芪类似物, 其结构均经NMR和ESI-HRMS表征确证. 通过Top1-介导的松散实验筛选了目标化合物的拓扑异构酶I (Top1)抑制活性, 其中(E)-5-溴-2-(2-氯苯乙烯基)-4-对氟苯基噻唑(6k)显示出了良好的Top1抑制活性. 同时通过分子对接研究其构效关系, 结果表明化合物的Top1抑制活性与分子对接研究之间具有良好的相关性. 此外, 采用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐(MTT)法测定了化合物对人乳腺癌细胞(MCF-7)和人结肠癌细胞(HCT116)的体外抗肿瘤活性, 结果表明(E)-5-溴-4-对氟苯基- 2-(4-三氟甲基苯乙烯基)噻唑(6e)、(E)-5-溴-2-(2-氯苯乙烯基)-4-对氟苯基噻唑(6k)和(E)-5-溴-2-(4-氯苯乙烯基)-4-对氟苯基噻唑(6l)在低摩尔浓度下表现出较高的细胞毒活性.

关键词: 天然芪, 噻唑, 拓扑异构酶I抑制剂, 合成, 细胞毒性

In order to find novel antitumor drug leads, twenty-three nature-inspired stilbene analogues containing thiazole moiety were designed and synthesized, and their structures were confirmed by NMR and ESI-HRMS. These compounds were screened for their topoisomerase I (Top1) inhibitory activity using Top1-mediated relaxation assay, and (E)-5-bromo-2- (2-chlorostyryl)-4-(4-fluorophenyl)thiazole (6k) possessed promising Top1 inhibitory activity. Molecular docking was also established to study the structure-activity relationship and a good correlation was observed between Top1 inhibitory activity and molecular docking study. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against human breast cancer (MCF-7) and human colon cancer (HCT116) cell lines indicated that (E)-5-bromo-4-(4-fluorophenyl)- 2-(4-(trifluoromethyl)styryl)thiazole (6e), (E)-5-bromo-2-(2-chlorostyryl)-4-(4-fluorophenyl)thiazole (6k), and (E)-5-bromo- 2-(4-chlorostyryl)-4-(4-fluorophenyl)thiazole (6l) showed high cytotoxicity at low micromolar concentrations.

Key words: natural stilbene, thiazole, topoisomerase 1 inhibitor, synthesis, cytotoxicity

引用此文

陆棋, 叶飞霞, 孙晓彤, 翁建全, 余茜, 胡德玄. 新型拟天然芪类拓扑异构酶I抑制剂的设计与合成[J]. 有机化学, 2021, 41(8): 3321-3329.

Qi Lu, Feixia Ye, Xiaotong Sun, Jianquan Weng, Qian Yu, Dexuan Hu. Design and Synthesis of Novel Nature-Inspired Stilbene Analogues as Potential Topoisomerase 1 Inhibitors[J]. Chinese Journal of Organic Chemistry, 2021, 41(8): 3321-3329.

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Compd.	X	R	Relaxation assay^a	Compd.	X	R	Relaxation assay^a
6a	F	H	+	6m	F	2,4-Cl₂	++
6b	F	2-Me	+	6n	F	2-Br	++
6c	F	3-Me	+	6o	F	3-Br	+
6d	F	4-Me	+	6p	Cl	4-CF₃	++
6e	F	4-CF₃	++	6q	Cl	4-tert-Bu	+
6f	F	4-tert-Bu	+	6r	Cl	3-OMe	+
6g	F	2-OMe	+	6s	Cl	3,4,5-(OMe)₃	+
6h	F	3-OMe	+	6t	Cl	2-F	+
6i	F	4-OMe	+	6u	Cl	3-Br	+
6j	F	4-F	++	6v	Br	2-F	++
6k	F	2-Cl	+++	6w	Br	4-F	++
6l	F	4-Cl	++

Compd.	X	R	Relaxation assay^a	Compd.	X	R	Relaxation assay^a
6a	F	H	+	6m	F	2,4-Cl₂	++
6b	F	2-Me	+	6n	F	2-Br	++
6c	F	3-Me	+	6o	F	3-Br	+
6d	F	4-Me	+	6p	Cl	4-CF₃	++
6e	F	4-CF₃	++	6q	Cl	4-tert-Bu	+
6f	F	4-tert-Bu	+	6r	Cl	3-OMe	+
6g	F	2-OMe	+	6s	Cl	3,4,5-(OMe)₃	+
6h	F	3-OMe	+	6t	Cl	2-F	+
6i	F	4-OMe	+	6u	Cl	3-Br	+
6j	F	4-F	++	6v	Br	2-F	++
6k	F	2-Cl	+++	6w	Br	4-F	++
6l	F	4-Cl	++

Compd.	IC₅₀/(µmol•L^–1)		Compd.	IC₅₀/(µmol•L^–1)
Compd.	MCF-7	HCT116	Compd.	MCF-7	HCT116
6a	22.16±5.01	15.78±1.89	6n	20.95±1.41	58.38±3.49
6b	>100	>100	6o	>100	>100
6c	>100	>100	6p	>100	>100
6d	95.52±3.11	31.87±4.29	6q	>100	>100
6e	6.31±0.51	0.72±0.09	6r	61.92±8.05	5.26±0.35
6f	59.42±4.21	6.47±0.62	6s	>100	>100
6g	49.53±9.08	17.8±1.16	6t	>100	>100
6h	29.85±5.47	4.99±0.80	6u	>100	62.91±2.34
6i	57.20±1.79	17.32±1.05	6v	64.57±1.45	37.18±6.65
6j	49.64±3.58	8.06±0.92	6w	>100	63.25±6.17
6k	2.29±1.08	7.37±1.15	vp-16^a	24.68±3.12	18.95±1.35
6l	13.45±2.46	3.07±0.53	CPT^a	0.34	0.012
6m	72.43±2.15	4.79±0.73

Compd.	IC₅₀/(µmol•L^–1)		Compd.	IC₅₀/(µmol•L^–1)
Compd.	MCF-7	HCT116	Compd.	MCF-7	HCT116
6a	22.16±5.01	15.78±1.89	6n	20.95±1.41	58.38±3.49
6b	>100	>100	6o	>100	>100
6c	>100	>100	6p	>100	>100
6d	95.52±3.11	31.87±4.29	6q	>100	>100
6e	6.31±0.51	0.72±0.09	6r	61.92±8.05	5.26±0.35
6f	59.42±4.21	6.47±0.62	6s	>100	>100
6g	49.53±9.08	17.8±1.16	6t	>100	>100
6h	29.85±5.47	4.99±0.80	6u	>100	62.91±2.34
6i	57.20±1.79	17.32±1.05	6v	64.57±1.45	37.18±6.65
6j	49.64±3.58	8.06±0.92	6w	>100	63.25±6.17
6k	2.29±1.08	7.37±1.15	vp-16^a	24.68±3.12	18.95±1.35
6l	13.45±2.46	3.07±0.53	CPT^a	0.34	0.012
6m	72.43±2.15	4.79±0.73