title: Factors influencing the antifolate activity of synthetic tea-derived catechins.
abstract: Novel tea catechin derivatives have been synthesized, and a structure-activity study, related to the capacity of these and other polyphenols to bind dihydrofolate reductase (DHFR), has been performed. The data showed an effective binding between all molecules and the free enzyme, and the dissociation constants of the synthetic compounds and of the natural analogues were on the same order. Polyphenols with a catechin configuration were better DHFR inhibitors than those with an epicatechin configuration. Antiproliferative activity was also studied in cultured tumour cells, and the data showed that the activity of the novel derivatives was higher in catechin isomers. Derivatives with a hydroxyl group para on the ester-bonded gallate moiety presented a high in vitro binding to DHFR, but exhibited transport problems in cell culture due to ionization at physiologic pHs. The impact of the binding of catechins to serum albumin on their biological activity was also evaluated. The information provided in this study could be important for the design of novel medicinal active compounds derived from tea catechins. The data suggest that changes in their structure to avoid serum albumin interactions and to facilitate plasmatic membrane transport are essential for the intracellular functions of catechins.
authors.affiliation: Department of Biochemistry and Molecular Biology A, School of Biology, Regional Campus of International Excellence Campus Mare Nostrum, University of Murcia, 30100, Murcia, Spain. magali@um.es
authors.forename: Magalí
authors.initials: M
authors.lastname: Sáez-Ayala
authors.forename: María Piedad
authors.initials: MP
authors.lastname: Fernández-Pérez
authors.forename: Soledad
authors.initials: S
authors.lastname: Chazarra
authors.forename: Nani
authors.initials: N
authors.lastname: Mchedlishvili
authors.forename: Alberto
authors.initials: A
authors.lastname: Tárraga-Tomás
authors.forename: José Neptuno
authors.initials: JN
authors.lastname: Rodríguez-López
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002392:Catechin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D005419:Flavonoids / Q000032:analysis / Q000737:chemistry; D005492:Folic Acid / Q000737:chemistry / Q000378:metabolism; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D059808:Polyphenols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012709:Serum Albumin / Q000378:metabolism; D013662:Tea / Q000737:chemistry*; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D005493:Folic Acid Antagonists; D059808:Polyphenols; D012709:Serum Albumin; D013662:Tea; D002392:Catechin; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase