4-Methylumbelliferones Analogues as Anticancer Agents: Synthesis and in Cell Pharmacological Studies

Title:4-Methylumbelliferones Analogues as Anticancer Agents: Synthesis and in Cell Pharmacological Studies

Volume: 17 Issue: 4

Author(s): Ri-Zhen Huang, Shi-Xian Hua, Cai-Yi Wang, Ying-Ming Pan, Jian-Mei Qin, Zhan-Yu Ding, Ye Zhang*Heng-Shan Wang*

Affiliation:

• State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Yucai Road 15, Guilin 541004, Guangxi,China

• State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry&Pharmaceutical Science of Guangxi Normal University, Yucai Road 15, Guilin 541004, Guangxi,China

Keywords: 4-Methylumbelliferones, urea/thioureas piperazine, cytotoxicity, apoptosis, cell cycle.

Abstract: Background: Cancer is one of the most serious clinical problems worldwide, and considerable efforts have been devoted to discovering therapeutic agents with novel modes of action. Natural and synthetic coumarin derivatives have attracted intense research interest due to their diverse structural features and remarkable array of biological properties.

Objective: In the present study, we synthesized a series of 4-MU derivatives containing urea-piperazine and thioureapiperazine moieties and evaluated their antitumor activities to find efficacy antitumor drugs.

Method: Cell proliferation, apoptosis, cell cycle, the generation of reactive oxygen species and calcium were measured using MTT assay and flow cytometry, respectively. The expression of apoptosis- and proliferation-related proteins was determined by western blotting. The effect of 4l on apoptosis-related mRNA expression in NCI-H460 cells was detected by RT-PCR.

Results: Most of the target compounds exhibited potential anticancer activities against tested cancer cells but had low cytotoxicity to normal cells. Compound 4l inhibited the growth and proliferation of NCI-H460 cells and resulted in apoptosis. Successive studies conducted with 4l in NCI-H460 cells demonstrated that this compound induced the intracellular reactive oxygen species generation and calcium overload, suppressed nuclear factor-κB (NF-κB) activity and regulated anti- and pro-apoptotic proteins. In addition, compound 4l effectively arrested NCI-H460 cells in G2 phase and altered the cell cycle regulatory proteins especially cyclin B1.

Conclusion: Compound 4l exerts significant anticancer effects on NCI-H460 cells in vitro through targeting of mitochondria-dependent apoptotic pathway. These results indicate that the strategy for rational design of 4-MU derivatives may identify potential anticancer agents.

Cite this article as:

Huang Ri-Zhen, Hua Shi-Xian, Wang Cai-Yi, Pan Ying-Ming, Qin Jian-Mei, Ding Zhan-Yu, Zhang Ye*, Wang Heng-Shan*, 4-Methylumbelliferones Analogues as Anticancer Agents: Synthesis and in Cell Pharmacological Studies, Anti-Cancer Agents in Medicinal Chemistry 2017; 17 (4) . https://dx.doi.org/10.2174/1871520616666160926113109

DOI https://dx.doi.org/10.2174/1871520616666160926113109	Print ISSN 1871-5206
Publisher Name Bentham Science Publisher	Online ISSN 1875-5992