新型蓝萼甲素-1,2,3-三氮唑类衍生物的合成与抗增殖活性研究

doi:10.6023/cjoc202205049

摘要/Abstract

设计并合成了一系列新型的天然产物蓝萼甲素(Glaucocalyxin A, GLA)-1,2,3-三氮唑类衍生物, 并评估该系列衍生物对HepG2、NCI-H460、JEG-3、K562、HL-60和Hela等六种人肿瘤细胞株的抗增殖活性. 结果表明大多数化合物具有很强的抗增殖作用, 其中一些化合物的活性明显优于GLA. 其中(3S,3aR,3a1R,6aR,11aR)-5-(1-(4-羟基苯基)-1H-1,2,3-三唑-4-基)-8,8,11a-三甲基-13-亚甲基十氢-1H-3,3a1-乙吩并[1,10-de][1,3]二噁-9,12(2H)-二酮(16)对HL-60细胞株表现出最强的抑制作用(IC₅₀=0.25 μmol•L^－1), 其活性比阳性药阿霉素强6.9倍, 比蓝萼甲素强25.8倍. 这些结果表明在保留D环上α,β-不饱和酮药效基团的前提下, 间羟基或对羟基苯基取代的1,2,3-三氮唑缩醛结构片段的引入是提高蓝萼甲素抗肿瘤活性的有效途径. 细胞凋亡形态学和流式细胞仪测定表明蓝萼甲素-1,2,3-三氮唑类衍生物具有诱导肿瘤细胞凋亡的作用.

关键词: 蓝萼甲素, 三氮唑, 缩醛衍生物, 抗增殖活性

A series of novel 1,2,3-triazole derivatives based on natural product glaucocalyxin A (GLA) were designed and prepared. Their antiproliferative activity was evaluated against six human tumor cell lines (HepG2, NCI-H460, JEG-3, K562, HL-60, Hela). Most compounds exhibited potent antiproliferative effects with low micromolar IC₅₀ values. The activity of some of the compounds is significantly superior to GLA. In particular, (3S,3aR,3a1R,6aR,11aR)-5-(1-(4-hydroxyphenyl)-1H- 1,2,3-triazol-4-yl)-8,8,11a-trimethyl-13-methylenedecahy-dro-1H-3,3a1-ethanophenanthro[1,10-de][1,3]dioxine-9,12(2H)-dione (16) displayed the highest inhibition efficacy (IC₅₀=0.25 μmol•L^－1), which was 6.9 times higher than that of the positive control adriamycin and 25.8 times higher than that of GLA against HL-60 cells. The results also demonstrated that the introduction of triazole acetal with meta- and para-hydroxyl substitution on phenyl without change of methylene cyclopentanone on the D-ring could improve the antitumor activity of GLA significantly. The apoptosis morphology and flow cytometry studies indicated that the triazole-fused GLA derivatives could induce apoptosis of tumor cells.

Key words: glaucocalyxin A, triazole, acetal derivative, antiproliferative activity

引用此文

张涛, 卫海沅, 马雯, 李张媛, 胡盼盼, 周楠茜, 贺建超, 李婷, 苏明明, 白素平. 新型蓝萼甲素-1,2,3-三氮唑类衍生物的合成与抗增殖活性研究[J]. 有机化学, 2022, 42(11): 3668-3683.

Tao Zhang, Haiyuan Wei, Wen Ma, Zhangyuan Li, Panpan Hu, Nanqian Zhou, Jianchao He, Ting Li, Mingming Su, Suping Bai. Synthesis and Antiproliferative Activity Evaluation of Novel Glaucocalyxin A-1,2,3-Triazole Derivatives[J]. Chinese Journal of Organic Chemistry, 2022, 42(11): 3668-3683.

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图/表 10

Figure 1. Structures of representative natural products with exo- methylene cyclopentanone on the D-ring

Scheme 1. Synthesis of compounds 1~6 Reaction and Condition: (a) NaNO2, HCl, Na2CO3, NaN3, 0 oC, 4 h; (b) propargyl alcohol, CuSO4, sodium ascobate, BPDS, DMF, r.t., 5 h, nitrogen; (c) SIBX, DMSO, r.t., 5 h; (d) Glaucocalyxin A, H2SO4, CH2Cl2, r.t., 1 h

Scheme 2. Synthesis of compounds 7~13 Reaction and condition: (a) NaN3, r.t., 24 h; (b) propargyl alcohol, CuSO4, sodium ascobate, BPDS, DMF, r.t., 5 h, nitrogen; (c) SIBX, DMSO, r.t., 5 h; (d) Glaucocalyxin A, H2SO4, CH2Cl2, r.t., 1 h.

Scheme 3. Synthesis of compounds 14~16 Reaction and condition: (a) NaNO2, HCl, Na2CO3, NaN3, 0 oC, 4 h; (b) 3,3-diethoxy-1-propyne, CuSO4, sodium ascobate, BPDS, DMF, r.t., 5 h, nitrogen; (c) TFA, H2O, DCM, r.t., 5 h; (d) Glaucocalyxin A, H2SO4, CH2Cl2, r.t., 1 h.

Scheme 4. Synthesis of compounds 17~19 Reaction and condition: (a) NaN3, PhP3, DMF, CCl4, 90 oC, 24 h; (b) 3,3-diethoxy-1-propyne, CuSO4, sodium ascobate, t-BuOH, H2O, r.t., 5 h, nitrogen; (c) TFA, H2O, DCM, r.t., 5 h; (d) Glaucocalyxin A, H2SO4, CH2Cl2, r.t., 1 h.

Scheme 5. Synthesis of compounds 20~21 Reaction and condition: (a) NaN3, DMF, 90 oC, 24 h; (b) 3,3-diethoxy- 1-propyne, CuSO4, sodium ascobate, t-BuOH, H2O, r.t., 5 h, Nitrogen; (c) TFA, H2O, DCM, r.t., 5 h; (d) acetic anhydride, pyridine, DCM, 0 oC, 0.5 h; (e) Glaucocalyxin A, H2SO4, CH2Cl2, r.t., 1 h.

Scheme 6. Synthetic routes of compounds 21 and 22 Reaction and condition: (a) Glaucocalyxin A, H2SO4, CH2Cl2, r.t., 1 h.

Compd.	HepG2	NCI-H460	JEG-3	K562	HL-60	Hela
1	5.78±0.10	8.30±0.38	5.15±0.26	8.28±0.15	4.52±0.17	5.85±0.61
2	21.57±0.39	13.46±0.61	3.22±0.25	14.52±0.19	2.29±0.10	15.12±0.59
3	30.38±0.18	80.34±2.96	5.32±0.30	60.62±0.62	24.05±2.46	16.39±0.23
4	2.89±0.01	21.71±0.17	4.15±0.04	9.03±0.06	1.98±0.13	2.77±0.06
5	25.27±2.06	31.87±0.16	14.94±1.90	28.71±2.16	14.75±0.35	14.19±0.97
6	>100	>100	>100	>100	29.23±0.29	72.13±2.40
7	13.69±0.13	21.34±1.03	9.51±0.15	32.00±0.38	14.28±1.51	12.32±0.21
8	1.85±0.28	4.66±0.09	2.53±0.02	5.04±0.26	1.97±0.06	1.59±0.09
9	12.23±1.06	29.33±0.59	5.50±0.04	19.69±0.24	11.55±1.32	7.88±0.13
10	3.03±0.14	4.70±0.05	2.86±0.07	5.40±0.40	2.40±0.11	3.28±0.06
11	5.83±0.14	9.68±0.19	2.93±0.17	13.77±0.27	3.22±0.19	5.56±0.57
12	8.05±0.31	18.44±0.55	1.66±0.03	18.29±0.94	12.37±0.50	16.27±0.61
13	5.45±0.24	13.09±1.02	12.49±0.23	18.30±0.55	5.96±0.42	7.45±0.12
14	16.42±0.45	13.27±0.28	5.07±0.05	67.11±0.91	1.18±0.02	2.15±0.18
15	2.53±0.14	24.52±0.26	6.21±0.10	17.05±0.76	0.36±0.02	6.78±0.10
16	1.43±0.04	5.56±0.06	1.18±0.05	5.08±0.22	0.25±0.01	2.85±0.03
17	18.19±1.11	16.61±1.00	18.39±0.53	>100	4.73±0.36	10.60±0.45
18	4.49±0.08	2.85±0.07	1.47±0.25	3.77±0.10	1.16±0.12	3.00±0.14
19	12.16±0.64	7.56±0.11	20.18±0.32	14.14±0.88	2.53±0.12	5.06±0.22
20	11.98±0.14	10.87±0.84	9.92±0.82	16.35±0.54	4.75±0.03	4.64±0.10
21	21.88±1.01	51.64±0.37	19.59±0.38	81.4±4.61	>100	29.61±0.84
22	6.81±0.53	4.92±0.17	6.40±0.18	16.03±0.45	3.47±0.05	4.27±0.11
GLA	3.94±0.07	8.99±0.18	4.25±0.08	7.20±0.17	6.46±0.05	8.19±1.96
Adriamycin	0.50±0.01	0.29±0.02	0.52±0.02	5.15±0.11	1.73±0.02	0.69±0.01

Compd.	HepG2	NCI-H460	JEG-3	K562	HL-60	Hela
1	5.78±0.10	8.30±0.38	5.15±0.26	8.28±0.15	4.52±0.17	5.85±0.61
2	21.57±0.39	13.46±0.61	3.22±0.25	14.52±0.19	2.29±0.10	15.12±0.59
3	30.38±0.18	80.34±2.96	5.32±0.30	60.62±0.62	24.05±2.46	16.39±0.23
4	2.89±0.01	21.71±0.17	4.15±0.04	9.03±0.06	1.98±0.13	2.77±0.06
5	25.27±2.06	31.87±0.16	14.94±1.90	28.71±2.16	14.75±0.35	14.19±0.97
6	>100	>100	>100	>100	29.23±0.29	72.13±2.40
7	13.69±0.13	21.34±1.03	9.51±0.15	32.00±0.38	14.28±1.51	12.32±0.21
8	1.85±0.28	4.66±0.09	2.53±0.02	5.04±0.26	1.97±0.06	1.59±0.09
9	12.23±1.06	29.33±0.59	5.50±0.04	19.69±0.24	11.55±1.32	7.88±0.13
10	3.03±0.14	4.70±0.05	2.86±0.07	5.40±0.40	2.40±0.11	3.28±0.06
11	5.83±0.14	9.68±0.19	2.93±0.17	13.77±0.27	3.22±0.19	5.56±0.57
12	8.05±0.31	18.44±0.55	1.66±0.03	18.29±0.94	12.37±0.50	16.27±0.61
13	5.45±0.24	13.09±1.02	12.49±0.23	18.30±0.55	5.96±0.42	7.45±0.12
14	16.42±0.45	13.27±0.28	5.07±0.05	67.11±0.91	1.18±0.02	2.15±0.18
15	2.53±0.14	24.52±0.26	6.21±0.10	17.05±0.76	0.36±0.02	6.78±0.10
16	1.43±0.04	5.56±0.06	1.18±0.05	5.08±0.22	0.25±0.01	2.85±0.03
17	18.19±1.11	16.61±1.00	18.39±0.53	>100	4.73±0.36	10.60±0.45
18	4.49±0.08	2.85±0.07	1.47±0.25	3.77±0.10	1.16±0.12	3.00±0.14
19	12.16±0.64	7.56±0.11	20.18±0.32	14.14±0.88	2.53±0.12	5.06±0.22
20	11.98±0.14	10.87±0.84	9.92±0.82	16.35±0.54	4.75±0.03	4.64±0.10
21	21.88±1.01	51.64±0.37	19.59±0.38	81.4±4.61	>100	29.61±0.84
22	6.81±0.53	4.92±0.17	6.40±0.18	16.03±0.45	3.47±0.05	4.27±0.11
GLA	3.94±0.07	8.99±0.18	4.25±0.08	7.20±0.17	6.46±0.05	8.19±1.96
Adriamycin	0.50±0.01	0.29±0.02	0.52±0.02	5.15±0.11	1.73±0.02	0.69±0.01

Table 1. IC50 values (μmol?L－1) of triazole-GLA derivativesa

Figure 2. Effects of compound 8 on nuclear morphological of (A) HepG2 and (B) Hela, and effects of compound 16 on nuclear morphological of (C) HepG2 and (D) Hela

Figure 3. Effects of compounds 8 and 16 on apoptosis of HepG2 cells detected by flow cytometry After HepG2 cells were treated with compound 8 (A) or compound 16 (B) at the indicated concentrations for 48 h, the cells were stained with Annexin V-FITC/PI and then analyzed by flow cytometry.

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