Anticancer properties of novel pyrazole-containing biguanide derivatives with activating the adenosine monophosphate-activated protein kinase signaling pathway
Sichun Zhou
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
Search for more papers by this authorLeichuan Xu
State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Sinochem Agrochemicals R&D Company Ltd., Shenyang, China
Search for more papers by this authorMengru Cao
TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
Search for more papers by this authorZhiren Wang
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
Search for more papers by this authorDi Xiao
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
Search for more papers by this authorSimeng Xu
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
Search for more papers by this authorJun Deng
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
Search for more papers by this authorXin Hu
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
Search for more papers by this authorCaimei He
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
Search for more papers by this authorTing Tao
Department of Pharmacy, Hunan Yueyang Maternal & Child Health-Care Hospital, Yueyang, China
Search for more papers by this authorCorresponding Author
Wei Wang
TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
Correspondence Wei Wang, TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, 410208 Changsha, China.
Email: [email protected]
Aiying Guan, State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Sinochem Agrochemicals R&D Company Ltd., 110021 Shenyang, China.
Email: [email protected]
Xiaoping Yang, Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Aiying Guan
State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Sinochem Agrochemicals R&D Company Ltd., Shenyang, China
Correspondence Wei Wang, TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, 410208 Changsha, China.
Email: [email protected]
Aiying Guan, State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Sinochem Agrochemicals R&D Company Ltd., 110021 Shenyang, China.
Email: [email protected]
Xiaoping Yang, Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Xiaoping Yang
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
Correspondence Wei Wang, TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, 410208 Changsha, China.
Email: [email protected]
Aiying Guan, State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Sinochem Agrochemicals R&D Company Ltd., 110021 Shenyang, China.
Email: [email protected]
Xiaoping Yang, Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China.
Email: [email protected]
Search for more papers by this authorSichun Zhou
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
Search for more papers by this authorLeichuan Xu
State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Sinochem Agrochemicals R&D Company Ltd., Shenyang, China
Search for more papers by this authorMengru Cao
TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
Search for more papers by this authorZhiren Wang
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
Search for more papers by this authorDi Xiao
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
Search for more papers by this authorSimeng Xu
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
Search for more papers by this authorJun Deng
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
Search for more papers by this authorXin Hu
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
Search for more papers by this authorCaimei He
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
Search for more papers by this authorTing Tao
Department of Pharmacy, Hunan Yueyang Maternal & Child Health-Care Hospital, Yueyang, China
Search for more papers by this authorCorresponding Author
Wei Wang
TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
Correspondence Wei Wang, TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, 410208 Changsha, China.
Email: [email protected]
Aiying Guan, State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Sinochem Agrochemicals R&D Company Ltd., 110021 Shenyang, China.
Email: [email protected]
Xiaoping Yang, Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Aiying Guan
State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Sinochem Agrochemicals R&D Company Ltd., Shenyang, China
Correspondence Wei Wang, TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, 410208 Changsha, China.
Email: [email protected]
Aiying Guan, State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Sinochem Agrochemicals R&D Company Ltd., 110021 Shenyang, China.
Email: [email protected]
Xiaoping Yang, Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Xiaoping Yang
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan, China
Correspondence Wei Wang, TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, 410208 Changsha, China.
Email: [email protected]
Aiying Guan, State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Sinochem Agrochemicals R&D Company Ltd., 110021 Shenyang, China.
Email: [email protected]
Xiaoping Yang, Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China.
Email: [email protected]
Search for more papers by this authorAbstract
Biguanides, including metformin and phenformin, have emerged as promising anticancer agents. However, the high dose needed for their efficient anticancer properties restricts their clinical application. In an attempt to obtain higher active compounds than these parent compounds, pyrazole-containing biguanide derivatives were synthesized and screened for in vitro cytotoxicity against human cancer cell lines. Clonogenic assays and scratch wound healing assays demonstrated that these new derivatives profoundly inhibit cell proliferation and migration. Compounds 10b and 10d exhibited strong potency with low IC50 values in the range of 6.9-28.3 μM, far superior to phenformin and metformin. Moreover, 20 μM 10b and 10d resulted in 72.3-88.2% (p < 0.001) inhibition of colony formation and 29.3-60.7% (p < 0.05) inhibition of cell migration. Mechanistically, 10b and 10d activated adenosine monophosphate-activated protein kinase, leading to inactivation of the mammalian target of rapamycin (mTOR) signaling pathway with the regulation of 4EBP1 and p70S6K. These results suggest the value of these novel biguanide derivatives as candidates with therapeutic potential for the treatment of bladder and ovarian cancer.
CONFLICT OF INTERESTS
The authors declare that there are no conflicts of interests.
Supporting Information
| Filename | Description |
|---|---|
| ardp201900075-sup-0001-ArchPharm_SupplMat_InChI.doc64.5 KB | Supporting information |
| ardp201900075-sup-0002-Supplementary_data.doc4.5 MB | Supporting information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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