Identification of a Potent Oridonin Analogue for Treatment of Triple-Negative Breast Cancer

被引：37

作者：

Yao, Hong ^{[1
,2
]}

Xie, Shaowen ^{[1
,2
]}

Ma, Xiaoqian ^{[1
,2
]}

Liu, Junkai ^{[1
,2
]}

Wu, Hongyu ^{[1
,2
]}

Lin, Aijun ^{[1
,2
]}

Yao, Hequan ^{[1
,2
]}

Li, Dahong ^{[3
]}

Xu, Shengtao ^{[1
,2
]}

Yang, Dong-Hua ^{[4
]}

Chen, Zhe-Sheng ^{[4
]}

Xu, Jinyi ^{[1
,2
]}

机构：

[1] China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Peoples R China

[2] China Pharmaceut Univ, Dept Med Chem, Nanjing 210009, Peoples R China

[3] Shenyang Pharmaceut Univ, Sch Tradit Chinese Mat Med, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Peoples R China

[4] St Johns Univ, Coll Pharm & Hlth Sci, Queens, NY 11439 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 15期

基金：

中国国家自然科学基金; 中国博士后科学基金;

关键词：

KAURENE-TYPE ORIDONIN; BIOLOGICAL EVALUATION; NATURAL-PRODUCTS; STRUCTURAL MODIFICATION; DITERPENOID ANALOGS; NITROGEN MUSTARDS; SPIROLACTONE-TYPE; ANTICANCER; DERIVATIVES; APOPTOSIS;

D O I：

10.1021/acs.jmedchem.0c00408

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Triple-negative breast cancer (TNBC) is one of the most highly invasive and metastatic breast cancers without safe and effective therapeutic drugs. The natural product oridonin is reported to be a potential anti-TNBC agent. However, its moderate activity and complex structure hampered its clinical application. In this study, the novel oridonin analogues were first identified by removal of multiple hydroxyl groups and structural simplification of oridonin. The representative analogue 20 exhibited potent anticancer effects. Further structural modification on 20 generated the most potent derivative 56, which possessed 120-fold more potent antiproliferative activity than oridonin in the TNBC cell line HCC1806. Importantly, compound 56 exhibited more potent anticancer activity than paclitaxel in TNBC xenograft nude mice. Moreover, 56 could attenuate the expression of MMP-2, MMP-9, p-FAK, and integrin beta 1 to inhibit TNBC cell metastasis. All results suggest that compound 56 may warrant further investigation as a promising candidate agent for the treatment of TNBC.

引用

页码：8157 / 8178

页数：22

共 46 条

[1] Discovery and resupply of pharmacologically active plant-derived natural products: A review [J].

Atanasov, Atanas G. ;

Waltenberger, Birgit ;

Pferschy-Wenzig, Eva-Maria ;

Linder, Thomas ;

Wawrosch, Christoph ;

Uhrin, Pavel ;

Temml, Veronika ;

Wang, Limei ;

Schwaiger, Stefan ;

Heiss, Elke H. ;

Rollinger, Judith M. ;

Schuster, Daniela ;

Breuss, Johannes M. ;

Bochkov, Valery ;

Mihovilovic, Marko D. ;

Kopp, Brigitte ;

Bauer, Rudolf ;

Dirsch, Verena M. ;

Stuppner, Hermann .

BIOTECHNOLOGY ADVANCES, 2015, 33 (08) :1582-1614

[2] Cell cycle molecular targets in novel anticancer drug discovery [J].

Buolamwini, JK .

CURRENT PHARMACEUTICAL DESIGN, 2000, 6 (04) :379-392

[3] Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer [J].

Costa, Ana ;

Kieffer, Yann ;

Scholer-Dahirel, Alix ;

Pelon, Floriane ;

Bourachot, Brigitte ;

Cardon, Melissa ;

Sirven, Philemon ;

Magagna, Ilaria ;

Fuhrmann, Laetitia ;

Bernard, Charles ;

Bonneau, Claire ;

Kondratova, Maria ;

Kuperstein, Inna ;

Zinovyev, Andrei ;

Givel, Anne-Marie ;

Parrini, Maria-Carla ;

Soumelis, Vassili ;

Vincent-Salomon, Anne ;

Mechta-Grigoriou, Fatima .

CANCER CELL, 2018, 33 (03) :463-+

[4] Hydroxyl Groups in Synthetic and Natural-Product-Derived Therapeutics: A Perspective on a Common Functional Group [J].

Cramer, Jonathan ;

Sager, Christoph P. ;

Ernst, Beat .

JOURNAL OF MEDICINAL CHEMISTRY, 2019, 62 (20) :8915-8930

[5] Oridonin Ring A-Based Diverse Constructions of Enone Functionality: Identification of Novel Dienone Analogues Effective for Highly Aggressive Breast Cancer by Inducing Apoptosis [J].

Ding, Chunyong ;

Zhang, Yusong ;

Chen, Haijun ;

Yang, Zhengduo ;

Wild, Christopher ;

Ye, Na ;

Ester, Corbin D. ;

Xiong, Ailian ;

White, Mark A. ;

Shen, Qiang ;

Zhou, Jia .

JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (21) :8814-8825

[6] Overcoming Synthetic Challenges of Oridonin A-Ring Structural Diversification: Regio- and Stereoselective Installation of Azides and 1,2,3-Triazoles at the C-1, C-2, or C-3 Position [J].

Ding, Chunyong ;

Zhang, Yusong ;

Chen, Haijun ;

Wild, Christopher ;

Wang, Tianzhi ;

White, Mark A. ;

Shen, Qiang ;

Zhou, Jia .

ORGANIC LETTERS, 2013, 15 (14) :3718-3721

[7] Novel Nitrogen-Enriched Oridonin Analogues with Thiazole-Fused A-Ring: Protecting Group-Free Synthesis, Enhanced Anticancer Profile, and Improved Aqueous Solubility [J].

Ding, Chunyong ;

Zhang, Yusong ;

Chen, Haijun ;

Yang, Zhengduo ;

Wild, Christopher ;

Chu, Lili ;

Liu, Huiling ;

Shen, Qiang ;

Zhou, Jia .

JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (12) :5048-5058

[8] Regio- and Stereospecific Synthesis of Oridonin D-Ring Aziridinated Analogues for the Treatment of Triple-Negative Breast Cancer via Mediated Irreversible Covalent Warheads [J].

Ding, Ye ;

Li, Dengfeng ;

Ding, Chunyong ;

Wang, Pingyuan ;

Liu, Zhiqing ;

Wold, Eric A. ;

Ye, Na ;

Chen, Haiying ;

White, Mark A. ;

Shen, Qiang ;

Zhou, Jia .

JOURNAL OF MEDICINAL CHEMISTRY, 2018, 61 (07) :2737-2752

[9] Discovery and development of natural product oridonin-inspired anticancer agents [J].

Ding, Ye ;

Ding, Chunyong ;

Ye, Na ;

Liu, Zhiqing ;

Wold, Eric A. ;

Chen, Haiying ;

Wild, Christopher ;

Shen, Qiang ;

Zhou, Jia .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2016, 122 :102-117

[10] Novel enmein-type diterpenoid hybrids coupled with nitrogen mustards: Synthesis of promising candidates for anticancer therapeutics [J].

Gao, Xiang ;

Li, Jia ;

Wang, Mingying ;

Xu, Shengtao ;

Liu, Weiwei ;

Zang, Linghe ;

Li, Zhanlin ;

Hua, Huiming ;

Xu, Jinyi ;

Li, Dahong .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2018, 146 :588-598

← 1 2 3 4 5 →