Synthesis and Antitumor Activity of Hederagenin Derivatives

doi:10.6023/cjoc202204021

Chinese Journal of Organic Chemistry ›› 2022, Vol. 42 ›› Issue (9): 2877-2887.DOI: 10.6023/cjoc202204021 Previous Articles Next Articles

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常春藤皂苷元衍生物的合成和抗肿瘤活性

黄兴, 张昌浩, 邓浩, 沈庆坤, 郭红艳, 全哲山, 李志勇^*(), 金莉莉^*()

延边大学药学院长白山天然药物教育部重点实验室吉林延吉 133000

收稿日期:2022-04-07 修回日期:2022-05-25 发布日期:2022-06-08
通讯作者: 李志勇, 金莉莉
作者简介:
^† 共同第一作者
基金资助:
国家自然科学基金(81960626); 国家自然科学基金(82160666); 国家自然科学基金(82160628); 中国吉林省教育厅(JJKH 20191156KJ)

Synthesis and Antitumor Activity of Hederagenin Derivatives

Xing Huang, Changhao Zhang, Hao Deng, Qingkun Shen, Hongyan Guo, Zheshan Quan, Zhiyong Li(), Lili Jin()

Key Laboratory of Natural Medicines of the Changbai Mountain (Ministry of Education), College of Pharmacy, Yanbian University, Yanji, Jilin 133000

Received:2022-04-07 Revised:2022-05-25 Published:2022-06-08
Contact: Zhiyong Li, Lili Jin
About author:
^† These authors contributed equally to this work
Supported by:
National Natural Science Foundation of China(81960626); National Natural Science Foundation of China(82160666); National Natural Science Foundation of China(82160628); Jilin Provincial Education Department of China(JJKH 20191156KJ)

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Abstract

Using hederagenin as lead compound, three series of novel hederagenin derivatives containing various heterocycles were designed and synthesized. Their structures were characterized by ¹H NMR, ¹³C NMR and HRMS. The in vitro antitumor activities of these compounds on human non-small cell lung cancer cells (A549), human breast cancer cells (MCF-7), human colon cancer cells (HCT116), human colon cancer cells (SW620), human hepatoma cells (HepG-2) and human hepatoma cells (BEL7402) were evaluated by thiazolyl blue (MTT) method. The experimental results showed that (3β,4α)-3,23-dihydroxy- olean-12-ene-28-acid-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl) methyl ester (A5) had the strongest anti-proliferative activity (IC₅₀=2.05 μmol/L) on HCT116 cells. Western blotting experiments showed that compound A5 may exert its antitumor activity through NF-κB signaling pathway.

Key words: hederagenin, anticancer, thiazolyl blue (MTT) assay, Western blotting

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Xing Huang, Changhao Zhang, Hao Deng, Qingkun Shen, Hongyan Guo, Zheshan Quan, Zhiyong Li, Lili Jin. Synthesis and Antitumor Activity of Hederagenin Derivatives[J]. Chinese Journal of Organic Chemistry, 2022, 42(9): 2877-2887.

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Fig. & Tab. 12

Figure 1. Chemical structure of hederagenin and the serial number of its carbon atom

Figure 2. Structures of natural-product derivatives containing phenyl-1,2,3-triazole and 3H-1,2,4-triazol-3-one

Scheme 1. Design of hederagenin derivatives containing phenyl-1,2,3-triazole and 3H-1,2,4-triazol-3-one or coumarin

Scheme 2. Synthesis of intermediates Reagents and conditions: (a) (i) HCl (ω=10%), NaNO2, H2O, 0~5 ℃, 30 min; (ii) NaN3, H2O, 0~5 ℃, 2~4 h. (b) propynol, Na ascorbate, CuSO4•5H2O, H2O, t-BuOH/H2O, 25 ℃, overnight. (c) thionyl chloride, CH2Cl2, r.t., overnight. (d) (i) methyl hydrazinocarboxylate, triethyl orthoformate, EtOH, reflux, 48 h; (ii) CH3ONa, EtOH, reflux, 48 h. (e) 1,2-dibromoethane, DMF, K2CO3, 60 ℃, 4~6 h.

Scheme 3. Synthesis of hederagenin derivatives

Compd.	R	Growth inhibition/%
Compd.	R	HCT116	SW620	BEL7402	HepG2	MCF-7	A549
He	—	26.21	24.22	31.19	19.69	32.43	NA
A1	4-H	46.13	24.42	34.24	39.81	NA	NA
A2	4-Cl	NA	28.11	30.67	NA	17.38	NA
A3	3,4-Cl₂	31.23	20.86	NA	56.07	NA	32.54
A4	4-OCH₃	NA	NA	NA	NA	36.86	NA
A5	4-NO₂	90.48	27.22	39.52	53.79	11.00	44.60
B1	4-H	29.55	NA	17.24	32.26	37.48	25.71
B2	4-F	28.77	NA	53.10	34.31	34.81	NA
B3	4-Cl	NA	12.81	27.10	31.26	44.29	23.73
B4	3,4-Cl₂	NA	17.94	NA	NA	45.76	55.56
B5	4-OCH₃	NA	44.08	NA	46.43	48.24	41.75
B6	3,4-(OCH₃)₂	24.19	13.03	10.29	NA	NA	5.08
B7	3,4,5-(OCH₃)₂	24.77	34.97	23.38	36.36	21.00	54.60
B8	4-CH₃	11.39	NA	26.14	43.21	32.95	NA
C1	—	88.91	30.16	14.11	74.53	49.59	NA
C2	—	79.49	26.57	NA	10.38	78.31	NA

Table 1. Antiproliferative activity of compounds A1~A5, B1~B8, C1 and C2 (30 μmol/L)

Compd.	R	IC₅₀ value^b/(μmol•L^–1)
Compd.	R	HCT116	HepG2	MCF-7
A5	4-NO₂	2.05	27.89	>30
C1	—	16.02	16.31	>30
C2	—	18.12	>30	19.12
5-FU	—	24.80	10.93	28.11

Table 2. IC50 of compounds A5, C1 and C2 against three human cancer cell lines

Compd.	R	IC₅₀^a/(μmol•L^–1)	SI^b
Compd.	R	IC₅₀^a/(μmol•L^–1)	HCT116	HepG2	MCF-7
A5	4-NO₂	>30	14.63	1.07	NT
C1	—	>30	1.87	1.84	NT
C2	—	>30	1.65	NT	1.57
5-FU		19.12	0.77	1.75	0.68

Table 3. In vitro cytotoxicity of compounds A5, C1 and C2 against normal cell line (L02)

Figure 3. Colony formation of HCT116 cells inhibited by compound A5 (A) HCT116 cells were incubated with varying concentrations of A5 (0, 7.5, 15, 30 μmol/L) and stained with crystal violet. (B) micrographic differences between the colonies. Images were taken of stained single colonies observed under a microscope.

Figure 4. HCT116 cell morphology stained by H&E

Figure 5. Effect of compound A5 on the levels of Bax, Bcl-2 and NF-κB signaling pathway in HCT116 cells Cells were pretreated with the various concentrations of compound A5 (7.5, 15 and 30 μmol/L) for 24 h. The expression of Bax, Bcl-2, p-NF-κB p65, NF-κB p65, p-IκB-α, IκB-α were analyzed by Western blot. ***p<0.001, **p<0.01, *p<0.05 vs control group.

Figure 6. Effect of compound A5 on MAPK signaling pathway in HCT116 cells Cells were pretreated with the various concentrations of compound A5 (7.5, 15 and 30 μmol/L) for 24 h. The expression of p-ERK, ERK, p-JNK, JNK, p-p38, p38 were analyzed by Western blot. ***p<0.001, **p<0.01, *p<0.05 vs control group.

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常春藤皂苷元衍生物的合成和抗肿瘤活性

Synthesis and Antitumor Activity of Hederagenin Derivatives

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