(5R)-5-羟基雷公藤硫氰酸基内酯醇的半合成及其体外生物活性研究

doi:10.3969/j.issn.0253-2417.2020.06.011

Abstract

Abstract:

(5R)-5-hydroxyltripthiocyanatolide(compound 5) was synthesized with triptonide as starting material through hydroxylation, reduction and nucleophilic substitution. On the basis of NMR and HRMS analysis, the structures were characterized and the results showed that compound 5 was successfully synthesized. The biological activities of compound 5 were tested and the results showed that compound 5 had inhibition rate of 69.95% against human lung cancer cell(A549 cells) at the concentration of 10 mg/L, which was equivalent to the level of the positive control (5R)-5-hydroxyltriptolide(LLDT-8), indicating that compound 5 had a certain antitumor activity; compound 5 was found to exhibit less inhibitory effect on leukomonocyte activation than the parent compound; more safety than LLDT-8 was observed on cytotoxicity assay on 293T cells. Target compound might mean an antitumor molecule for further development.

Key words: triptolide, (5R)-5-hydroxyltriptolide, semi-synthesis

CLC Number:

TQ35

Wei LI, Shunmin GUO, Huiqing QUE, Ahong CHEN, Sui LIN. Semi-synthesis of (5R)-5-Hydroxyltripthiocyanatolide and Their Biological Activities in vitro[J]. Chemistry and Industry of Forest Products, 2020, 40(6): 85-92.

Figures/Tables 4

Fig.1

Table 1

Table 2

Table 3

References 16

1	徐晓昱, 郑伟娟, 华子春. 雷公藤内酯醇抗肿瘤作用机理研究进展[J]. 中国医药生物技术, 2009, 4 (5): 367- 369.
	XU X Y , ZHENG W J , HUA Z C . Research progress on antitumor mechanism of triptolide[J]. Chinese Medicinal Biotechnology, 2009, 4 (5): 367- 369.
2	梅之南, 杨祥良, 徐辉碧. 雷公藤内酯醇的药理研究[J]. 中国医院药学杂志, 2003, 23 (9): 557- 558.
	MEI Z N , YANG X L , XU H B . Research progress on pharmacological effects of triptolide[J]. Chinese Journal of Hospital Pharmacy, 2003, 23 (9): 557- 558.
3	LU L , KANWAR J , SCHMITT S , et al. Inhibition of tumor cellular proteasome activity by triptolide extracted from the Chinese medicinal plant 'thunder god vine'[J]. Anticancer Research, 2011, 31 (1): 1- 10.
4	HE M F , LIU L , GE W , et al. Antiangiogenic activity of Tripterygium wilfordii and its terpenoids[J]. Journal of Ethnopharmacology, 2009, 121 (1): 61- 68.
5	HE Q L , TITOV D V , LI J , et al. Covalent modification of a cysteine residue in the XPB subunit of the general transcription factor TFⅡH through single epoxide cleavage of the transcription inhibitor triptolide[J]. Angewandte Chemie International Edition, 2015, 54 (6): 1859- 1863.
6	FU J , ZANG Y , ZHOU Y , et al. A novel triptolide derivative ZT01 exerts anti-inflammatory effects by targeting TAK1 to prevent macrophage polarization into pro-inflammatory phenotype[J]. Biomedicine & Pharmacotherapy, 2020, 126, 110084.
7	中华本草编委会. 中华本草[M]. 上海: 上海科技出版社, 1999: 4134
	Zhonghua Bencao Commission . Chinese Materia Medica(Zhonghua Bencao)[M]. Shanghai: Scientific & Technical Publishers, 1999: 4134
8	HOU W , LIU B , XU H . Triptolide:Medicinal chemistry, chemical biology and clinical progress[J]. European Journal of Medicinal Chemistry, 2019, 176, 378- 392.
9	李援朝. 雷腾舒的研究及展望[J]. 中国中西医结合杂志, 2018, 38 (3): 269- 271.
	LI Y C . Perspective of "Leitengshu"[J]. Chinese Journal of Integrated Traditional and Western Medicine, 2018, 38 (3): 269- 271.
10	NOEL P , VON HOFF D D , SALUJA A K , et al. Triptolide and its derivatives as cancer therapies[J]. Trends in Pharmacological Sciences, 2019, 40 (5): 327- 341.
11	郭舜民, 林绥, 林文津, 等. 雷公藤硫氰酸基内酯醇的半合成研究[J]. 中国现代应用药学, 2009, 26 (11): 919- 920.
	GUO S M , LIN S , LIN W J , et al. Study on the semi-synthesis of tripthiocyanatolide[J]. Chinese Journal of Modern Applied Pharmacy, 2009, 26 (11): 919- 920.
12	WANG D, GAO X, LI W, et al.Derivatives of triptolideand preparation and uses thereof: WO00/63212[P]. 2000-10-26.
13	LIU M , SONG W , DU X , et al. NQO1-selective activated prodrug of triptolide:Synthesis and antihepatocellular carcinoma activity evaluation[J]. ACS Medicinal Chemistry Letters, 2018, 9 (12): 1253- 1257.
14	QING L H , MINN I , WANG Q , et al. Targeted delivery and sustained antitumor activity of triptolide through glucose conjugation[J]. Angewandte Chemie International Edition, 2016, 128 (39): 12214- 12218.
15	LI Y C, ZUO J P, ZHANG F, et al.Triptolide derivatives and their uses: US2007/0197476[P]. 2007-01-29.
16	NING L , ZHAN J , QU G , et al. Biotransformation of triptolide by Cunninghamella blakesleana[J]. Tetrahedron, 2003, 59 (23): 4209- 4213.

化合物 compounds	不同质量浓度化合物的细胞抑制率inhibition rate of cell at difference mass concentration/%						IC₅₀¹⁾/ (mg·L^-1)
化合物 compounds	0.001 mg/L	0.01 mg/L	0.1 mg/L	1 mg/L	10 mg/L	100 mg/L	IC₅₀¹⁾/ (mg·L^-1)
4	-0.57	0.13	16.30	17.50	35.44	71.63	20.36
5	-0.51	-0.19	9.80	17.41	69.95	74.44	6.78
6	0.10	-0.76	-0.06	9.44	16.60	74.96	35.54
3	12.10	21.06	31.13	72.09	73.78	74.84	0.49

化合物 compounds	不同质量浓度化合物的细胞抑制率inhibition rate of cell at difference mass concentration/%						IC₅₀/ (mg·L^-1)
化合物 compounds	0.001 mg/L	0.01 mg/L	0.1 mg/L	1 mg/L	10 mg/L	100 mg/L	IC₅₀/ (mg·L^-1)
4	2.58	2.34	12.14	29.96	52.31	62.80	13.78
5	1.04	-0.27	11.90	16.34	53.37	63.56	17.36
6	1.70	1.85	5.56	29.17	48.32	54.32	26.33
3	3.52	12.39	31.06	53.38	71.23	70.71	1.58

化合物 compounds	不同质量浓度化合物的细胞抑制率inhibition rate of cell at difference mass concentration/%						IC₅₀/ (mg·L^-1)
化合物 compounds	0.001 mg/L	0.01 mg/L	0.1 mg/L	1 mg/L	10 mg/L	100 mg/L	IC₅₀/ (mg·L^-1)
4	1.88	12.20	25.94	42.47	47.96	59.67	10.65
5	1.94	11.81	32.29	44.58	54.41	60.04	9.38
6	3.01	12.57	22.79	34.34	43.69	59.90	18.12
3	5.42	17.82	37.98	51.13	58.84	70.63	1.93

[1]	Xuezhen FENG, Zhuanquan XIAO, Guorong FAN, Jinmeng QIN, Zongde WANG. Synthesis and Antifungal Activity of Rigid Hydronopyl Gemini Quaternary Ammonium Salts [J]. Chemistry and Industry of Forest Products, 2020, 40(6): 77-84.
[2]	Can LIU, Yu REN, Xin LI, Jianxiang LIU, Zhengjun SHI, Zhifeng ZHENG. Preparation of High-ortho Phenolic Resin Fiber from Eucalyptus Residue [J]. Chemistry and Industry of Forest Products, 2020, 40(6): 70-76.
[3]	Chunliu LIANG, Limin ZANG, Xin LIU, Wusheng ZUO, Qifan LIU. Preparation and Properties of Flexible Supercapacitor from Polypyrrole@Manganese Dioxide@Sisal Microcrystalline Cellulose [J]. Chemistry and Industry of Forest Products, 2020, 40(6): 61-69.
[4]	Xian CHENG, Liangwu BI, Weixing ZENG, Zhendong ZHAO, Yuxiang CHEN, Zuohui ZHANG. Chemical Constituents of Distillation Residues from Cinnamon Twigs and Leaves by Using UHPLC-QTOF MS [J]. Chemistry and Industry of Forest Products, 2020, 40(6): 50-60.
[5]	Qian YANG, Guifeng LIU, Can JIN, Zhenwu KONG. Synergetic Effects of Pt/ZrO₂ and Lewis Acid on Reductive Depolymerization of Alkali Lignin to Phenolic Oligomers [J]. Chemistry and Industry of Forest Products, 2020, 40(6): 37-49.
[6]	Yiwei JIANG, Na GUO, Zhiguo LIU, Chunjian ZHAO, Yujie FU, Xiqing WANG. Optimization of Extraction Technology of Blue Honeysuckle Seed Oil and Analysis of Its Fatty Acid Composition [J]. Chemistry and Industry of Forest Products, 2020, 40(6): 30-36.
[7]	Sansan BAO, Xiqing WANG, Yuchun YANG, Xiaodan WU, Chunjian ZHAO, Yujie FU. Enrichment and Purification Technology of Pinolenic Acid from Pinus koraiensis Seed Oil [J]. Chemistry and Industry of Forest Products, 2020, 40(6): 23-29.
[8]	Haibo ZHANG, Jiali XU, Shufeng YAO, Hong GAO, Shibin SHANG. Study on Preservation Effect of Maleric Rosin Pentaerythritol on Ponkan [J]. Chemistry and Industry of Forest Products, 2020, 40(6): 15-22.
[9]	Shitao YU, Haoxue ZOU, Yaya LI, Huimin ZHANG, Yujing WANG. Preparation of Rosin Glyceride Catalyzed by Fe₃O₄ Supported ZnO [J]. Chemistry and Industry of Forest Products, 2020, 40(6): 8-14.
[10]	Jianxin JIANG, Liwei ZHU, Wei ZHANG, Xianping LI. Effect of Baking Temperature on Preparation and Properties of Gleditsia sinensis Polysaccharide Gum [J]. Chemistry and Industry of Forest Products, 2020, 40(6): 1-7.
[11]	WU Chunhua, WANG Ruiling, LIN Xu, LIU Xiangyi, ZHENG Zhifeng. Increasing Resin Effect of Pinus kesiya Royle ex Gordonby Chemical and Biological Compound Tapping Irritant Agent [J]. Chemistry and Industry of Forest Products, 2020, 40(6): 93-98.
[12]	FANG Xianying, XIE Yingying, ZHANG Yiwei, CAO Fuliang, ZHAO Linguo. Toxic and Side Effects of Ginkgolic Acid and Effect of Celtis sinensis Extracts on Detoxification of Ginkgolic Acid [J]. Chemistry and Industry of Forest Products, 2020, 40(6): 99-106.
[13]	ZHANG Weiwei, ZHANG Bo, ZHANG Leping, JIANG Jianxin. Progress on Production of Xylo-oligosaccharides from Lignocellulosic Materials by Non-enzymatic Catalysis [J]. Chemistry and Industry of Forest Products, 2020, 40(6): 118-128.
[14]	Zhiwen QI,Hao ZHOU,Hongxia CHEN,Changwei ZHANG,Tao DENG,Chengzhang WANG. pH Responsiveness and Their in vitro Properties of Urushiol-based BPAU-NH₂-Gal Paclitaxel-loaded Micelle [J]. Chemistry and Industry of Forest Products, 2020, 40(5): 121-128.
[15]	Tianjiao TONG,Junhai LIU,Yan LIU,Rui CAO,Lingling WEI. Extraction of Myricetin from Myrica rubra Leaves and Its Antioxidant Activity [J]. Chemistry and Industry of Forest Products, 2020, 40(5): 114-120.

Semi-synthesis of (5R)-5-Hydroxyltripthiocyanatolide and Their Biological Activities in vitro

RichHTML

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 4

References 16

Related Articles 15

Recommended Articles

Metrics

Comments