Synthesis and Structure–Activity Relationship of Salvinal Derivatives as Potent Microtubule Inhibitors

Author:

Chang Chi-I1,Hsieh Cheng-Chih23,Wein Yung-Shung4,Kuo Ching-Chuan56,Chang Chi-Yen7,Lung Jrhau8ORCID,Cherng Jong-Yuh9,Chu Po-Chen10,Chang Jang-Yang51112,Kuo Yueh-Hsiung131415ORCID

Affiliation:

1. Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 912, Taiwan

2. Department of Pharmacy, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan

3. School of Pharmacy and Institute of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan

4. Department of Chemistry, National Taiwan University, Taipei 114, Taiwan

5. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 350, Taiwan

6. Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan

7. National Institute of Cancer Research, National Health Research Institutes, Miaoli 350, Taiwan

8. Department of Medical Research and Development, Chiayi Chang Gung Memorial Hospital, Chiayi Branch, Chiayi 613, Taiwan

9. Department of Chemistry and Biochemistry, National Chung Cheng University, Chiayi 613, Taiwan

10. Department of Cosmeceutics and Graduate Institute of Cosmeceutic, China Medical University, Taichung 404, Taiwan

11. Taipei Cancer Center, Taipei Medical University Hospital, Taipei 110, Taiwan

12. TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110, Taiwan

13. Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Pharmacy, China Medical University, Taichung 404, Taiwan

14. Department of Biotechnology, Asia University, Taichung 413, Taiwan

15. Chinese Medicine Research Center, China Medical University, Taichung 404, Taiwan

Abstract

Salvinal is a natural lignan isolated from the roots of Salvia mitorrhiza Bunge (Danshen). Previous studies have demonstrated its anti-proliferative activity in both drug-sensitive and -resistant cancer cell lines, with IC50 values ranging from 4–17 µM. In this study, a series of salvinal derivatives was synthesized and evaluated for the structure–activity relationship. Among the twenty-four salvinal derivatives, six compounds showed better anticancer activity than salvinal. Compound 25 displayed excellent anticancer activity, with IC50 values of 0.13–0.14 µM against KB, KB-Vin10 (overexpress MDR/Pgp), and KB-7D (overexpress MRP) human carcinoma cell lines. Based on our in vitro microtubule depolymerization assay, compound 25 showed depolymerization activity in a dose-dependent manner. Our findings indicate that compound 25 is a promising anticancer agent with depolymerization activity that has potential for the management of malignance.

Funder

National Health Research Institutes

National Science Council

Tri-Service General Hospital

Ministry of Education, Taiwan

Department of Health Clinical Trial and Research Center of Excellence

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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