Discovery of Novel Anti-Breast-Cancer Inhibitors by Synergistically Antagonizing Microtubule Polymerization and Aryl Hydrocarbon Receptor Expression

被引：20

作者：

Wang, Kun ^{[1
]}

Zhong, Hui ^{[2
]}

Li, Na ^{[1
]}

Yu, Nairong ^{[1
]}

Wang, Yujin ^{[1
]}

Chen, Li ^{[1
]}

Sun, Jianbo ^{[1
]}

机构：

[1] China Pharmaceut Univ, Sch Tradit Chinese Pharm, Dept Nat Med Chem, State Key Lab Nat Med, Nanjing 210009, Peoples R China

[2] China Pharmaceut Univ, Sch Tradit Chinese Pharm, Dept Pharmacol Tradit Chinese Med, Nanjing 210009, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 17期

基金：

中国国家自然科学基金;

关键词：

TARGETS; BINDING; TUBULIN; LIFE; AHR;

D O I：

10.1021/acs.jmedchem.1c01099

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of unreported dual-receptor inhibitors targeting both the tubulin colchicine site and AhR were designed and synthesized, and their anti-breast-cancer activities were evaluated. Compound 12 showed the strongest activity with an IC50 of 0.9 nM in MCF-7 cell lines. Besides, 12 could significantly inhibit cancer growth in MCF-7 xenograft tumor models with no obvious toxic effects and was more effective than the positive control (combretastatin A-4). With the in-depth study, it was found that 12 could induce apoptosis in breast cancer cells by making arrest in G2/M phase, depolarizing mitochondria and inducing intracellular reactive oxygen generation. This evident anticancer effect and the ability to inhibit cell migration were attributed to the synergistic antagonism of 12 on tubulin and AhR. In general, 12 was worthy of further research as an effective and safe anti-breast-cancer drug.

引用

页码：12964 / 12977

页数：14

共 26 条

[1] A review on anticancer potential of bioactive heterocycle quinoline [J].

Afzal, Obaid ;

Kumar, Suresh ;

Haider, Md Rafi ;

Ali, Md Rahmat ;

Kumar, Rajiv ;

Jaggi, Manu ;

Bawa, Sandhya .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2015, 97 :871-910

[2] Aryl hydrocarbon receptor/cytochrome P450 1A1 pathway mediates breast cancer stem cells expansion through PTEN inhibition and β-Catenin and Akt activation [J].

Al-Dhfyan, Abdullah ;

Alhoshani, Ali ;

Korashy, Hesham M. .

MOLECULAR CANCER, 2017, 16

[3] Design, synthesis and molecular modeling of new 4-phenylcoumarin derivatives as tubulin polymerization inhibitors targeting MCF-7 breast cancer cells [J].

Batran, Rasha Z. ;

Kassem, Asmaa F. ;

Abbas, Eman M. H. ;

Elseginy, Samia A. ;

Mounier, Marwa M. .

BIOORGANIC & MEDICINAL CHEMISTRY, 2018, 26 (12) :3474-3490

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

Buolamwini, JK .

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

[5] Reactive oxygen species, cellular redox systems, and apoptosis [J].

Circu, Magdalena L. ;

Aw, Tak Yee .

FREE RADICAL BIOLOGY AND MEDICINE, 2010, 48 (06) :749-762

[6] Cell-cycle control in the face of damage - a matter of life or death [J].

Clarke, Paul R. ;

Allan, Lindsey A. .

TRENDS IN CELL BIOLOGY, 2009, 19 (03) :89-98

[7] The aryl hydrocarbon receptor (AhR) in the regulation of cell-cell contact and tumor growth [J].

Dietrich, Cornelia ;

Kaina, Bernd .

CARCINOGENESIS, 2010, 31 (08) :1319-1328

[8] In vivo effects of the pure aryl hydrocarbon receptor antagonist GNF-351 after oral administration are limited to the gastrointestinal tract [J].

Fang, Zhong-Ze ;

Krausz, Kristopher W. ;

Nagaoka, Kenjiro ;

Tanaka, Naoki ;

Gowda, Krishne ;

Amin, Shantu G. ;

Perdew, Gary H. ;

Gonzalez, Frank J. .

BRITISH JOURNAL OF PHARMACOLOGY, 2014, 171 (07) :1735-1746

[9] Quick and Simple Detection Technique to Assess the Binding of Antimicrotubule Agents to the Colchicine-Binding Site [J].

Fortin, Sebastien ;

Lacroix, Jacques ;

Cote, Marie-France ;

Moreau, Emmanuel ;

Petitclerc, Eric ;

Gaudreault, Rene C. .

BIOLOGICAL PROCEDURES ONLINE, 2010, 12 (01) :113-117

[10] Structural Basis of cis- and trans-Combretastatin Binding to Tubulin [J].

Gaspari, Roberto ;

Prota, Andrea E. ;

Bargsten, Katja ;

Cavalli, Andrea ;

Steinmetz, Michel O. .

CHEM, 2017, 2 (01) :102-113

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