Synthesis and Antiproliferative Activity Evaluation of Novel Glaucocalyxin A-1,2,3-Triazole Derivatives

doi:10.6023/cjoc202205049

Abstract

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

Cite this article

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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Fig. & Tab. 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

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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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