Novel Coumarin-Containing Aminophosphonatesas Antitumor Agent: Synthesis, Cytotoxicity, DNA-Binding and Apoptosis Evaluation.
A series of novel coumarin-containing α-aminophosphonates were synthesized and evaluated for their antitumor activities against Human colorectal (HCT-116), human nasopharyngeal carcinoma (human KB) and human lung adenocarcinoma (MGC-803) cell lines in vitro. Compared with 7-hydroxy-4-methylcoumarin (4-MU), most of the derivatives showed an improved antitumor activity. Compound 8j (diethyl 1-(3-(4-methyl-2-oxo-2H-chromen-7-yloxy) propanamido)-1-phenylethyl-Phosphonate), with IC50 value of 8.68 μM against HCT-116 cell lines, was about 12 fold than that of unsubstituted parent compound. The mechanism investigation proved that 8c, 8d, 8f and 8j were achieved through the induction of cell apoptosis by G1 cell-cycle arrest. In addition, the further mechanisms of compound 8j-induced apoptosis in HCT-116 cells demonstrated that compound 8j induced the activations of caspase-9 and caspase-3 for causing cell apoptosis, and altered anti- and pro-apoptotic proteins. DNA-binding experiments suggested that some derivatives bind to DNA through intercalation. The results seem to imply the presence of an important synergistic effect between coumarin and aminophosphonate, which could contribute to the strong chelating properties of aminophosphonate moiety.
State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Chemical Engineering of Guangxi Normal University, Guilin 541004, China. liyajungxnu@163.com.|College of Medicine and Pharmacy, Hunan Polytechnic of Environment and Biology, Hengyang 421000, China. liyajungxnu@163.com.
Ya-Jun
YJ
Li
College of Chemical and Material Science, Hebei Normal University, Shijiazhuang 050024, China. wangcaiyigxnu@163.com.
Cai-Yi
CY
Wang
State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Chemical Engineering of Guangxi Normal University, Guilin 541004, China. baobei_mayu@163.com.
Man-Yi
MY
Ye
State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Chemical Engineering of Guangxi Normal University, Guilin 541004, China. yaoguiyangmayu@126.com.
Gui-Yang
GY
Yao
State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Chemical Engineering of Guangxi Normal University, Guilin 541004, China. whengshan@163.com.
Heng-Shan
HS
Wang
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013050:Spectrometry, Fluorescence; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D003374:Coumarins; D063065:Organophosphonates; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D004247:DNA; C427203:calf thymus DNA; C030123:coumarin; D020169:Caspases
7-hydroxy-4-methylcoumarin; DNA binding; cell cycle; cytotoxicity; synthesis; α-aminophosphonates