Synthesis and biological activity of a 3,4,5-trimethoxybenzoyl ester analogue of epicatechin-3-gallate.
Despite presenting bioavailability problems, tea catechins have emerged as promising chemopreventive agents because of their observed efficacy in various animal models. To improve the stability and cellular absorption of tea polyphenols, we developed a new catechin-derived compound, 3- O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin (TMECG), which has shown significant antiproliferative activity against several cancer cell lines, especially melanoma. The presence of methoxy groups in its ester-bound gallyl moiety drastically decreased its antioxidant and prooxidant properties without affecting its cell-antiproliferative effects, and the data indicated that the 3-gallyl moiety was essential for its biological activity. As regards its action mechanism, we demonstrated that TMECG binds efficiently to human dihydrofolate reductase and down-regulates folate cycle gene expression in melanoma cells. Disruption of the folate cycle by TMECG is a plausible explanation for its observed biological effects and suggests that, like other antifolate compounds, TMECG could be of clinical value in cancer therapy.
Sánchez-del-Campo
Luís
L
Department of Biochemistry and Molecular Biology A, School of Biology, University of Murcia, Murcia, Spain.
Otón
Francisco
F
Tárraga
Alberto
A
Cabezas-Herrera
Juan
J
Chazarra
Soledad
S
Rodríguez-López
José Neptuno
JN
D000975:Antioxidants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005492:Folic Acid / Q000187:drug effects / Q000378:metabolism; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000187:drug effects / Q000235:genetics; D008958:Models, Molecular; D015394:Molecular Structure; D009249:NADP / Q000737:chemistry / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013662:Tea / Q000737:chemistry; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects / Q000235:genetics; D013940:Thymidylate Synthase / Q000187:drug effects / Q000235:genetics; D013997:Time Factors
C529447:3-O-(3,4,5-trimethoxybenzoyl)epicatechin; D000975:Antioxidants; D005493:Folic Acid Antagonists; D012333:RNA, Messenger; D013662:Tea; D009249:NADP; D002392:Catechin; D005492:Folic Acid; C045651:epigallocatechin gallate; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase