Zhixian Shi, Li Chen* and Jianbo Sun* Pages 1774 - 1782 ( 9 )
Background: Natural products and their molecular frameworks have been explored as invaluable sources of inspiration for drug design by means of structural modification, computer aided drug design, and so on. Scopoletin extracting from multiple herbs exhibits potential anticancer activity in vitro and vivo without toxicity towards normal cells.
Objective: To obtain new scopoletin derivatives with enhanced anticancer activity, we performed the chemical structure modification and researched the mechanism of anti-tumor activity.
Methods: In this study, we take regard scopoletin as lead compound, designed and synthesized a series of scopoletin derivatives via introducing different heterocyclic fragments, and their chemical structures were characterized by NMR spectra (1H NMR and 13C NMR) and HRMS(ESI). The antiproliferative activity of target compounds in four cancer cell lines (MDA-MB-231, MCF-7, HepG2, and A549) were determined by the MTT assay. Compound 11b was treated with Ac-cys under different reaction condition to explore the thiol addition activity of it. The Annexin V/PI and JC-1 staining assay were performed to investigate the anti-tumor mechanism of 11b.
Results: Novel compounds 8a-h and 11a-h derivatives of scopoletin were synthesized. Most of target compounds exhibited enhanced antiproliferative activity against different cancer cells and reduced toxicity towards normal cells. In particular, 11b displayed the optimal antitumor ability against breast cancer MDA-MB-231 cells with an IC50 value of 4.46 μM. 11b also cannot react with Ac-cys under the experimental condition. When treated with 11b for 24 h, the total apoptotic cells increased from 10.8% to 79.3%. Besides, 11b induced the depolarization of mitochondrial membrane potential.
Conclusion: 11b was more active than other derivatives, indicating that the introduction of thiophene fragment was beneficial for the enhancement of antitumor effect, and it was also not an irreversible inhibitor basing on the result that the α, β-unsaturated ketones of 11b cannot undergo Michael addition reactions with Ac-cys. Furthermore, studies on the pharmacological mechanism showed that 11b induced the mitochondrial depolarization and apoptosis, which indicated 11b killed cancer cells via mitochondrial apoptotic pathway. Therefore, an in-depth research and structure optimization of this compound is warranted.
Scopoletin, heterocycle, anti-cancer, mitochondrial apoptotic pathway, apoptosis, NMR spectra.
Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009