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


METHODS
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.


CONCLUSIONS
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.
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.
Ri-Zhen
RZ
Huang
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.
Shi-Xian
SX
Hua
College of Chemical and Material Science, Hebei Normal University, Shijiazhuang 050024, China.
Cai-Yi
CY
Wang
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.
Ying-Ming
YM
Pan
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.
Jian-Mei
JM
Qin
College of Chemistry, Nankai University, Weijin Road 15 of Nankai district, Tianjin 300071, China.
Zhan-Yu
ZY
Ding
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.
Ye
Y
Zhang
State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Science of Guangxi Normal University, Yucai Road 15, Guilin 541004, Guangxi, China.
Heng-Shan
HS
Wang
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006923:Hymecromone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D006923:Hymecromone; D002118:Calcium
4-Methylumbelliferones; apoptosis; cell cycle; cytotoxicity; urea/thioureas piperazine