title: Acylated catechin derivatives: inhibitors of DNA polymerase and angiogenesis.
abstract: Catechins in green tea display anti-cancer and anti-angiogenesis activities. We previously found that some catechins, such as epigallocatechin-3-O-gallate (EGCG), inhibit the activities of eukaryotic DNA polymerases (pols) (Y. Mizushina et al.: Structural analysis of catechin derivatives as mammalian DNA polymerase inhibitors. Biochem Biophys Res Commun 333, 101-109 (2005)). In this study, we discuss the effects of chemical modifications of catechin and epicatechin that enhance their anti-cancer and anti-angiogenic activities based on pol inhibition. Catechins conjugated with fatty acid (3-O-acylcatechins) are stronger inhibitors of mammalian pol than epicatechins conjugated with fatty acid (3-O-acylepicatechins). Moreover, 3-O-acylcatechins are more potent inhibitors of cultured cell growth both of the human colon carcinoma cell line (HCT116 cells) and human umbilical vein endothelial cell (HUVEC) line, as well as angiogenesis by comparison with 3-O-acylepicatechins. Catechin conjugated with stearic acid ((2R,3S)-3',4',5,7-tetrahydroxyflavan-3-yl octadecanoate; C-C18) was the strongest inhibitor in replicative pol alpha and repair-related pol beta, as well as the cultured cell growth and angiogenesis assays in the compounds tested. C-C18 also suppressed HUVEC tube formation on reconstituted basement membrane suggesting that it affected not only pols but also signal transduction pathways in HUVECs. These data indicate that the acylated catechins target both pols and angiogenesis as anti-cancer agents. Moreover, the results suggest that acylation of catechin is an effective chemical modification to improve the anti-cancer activity of catechin.
authors.affiliation: Laboratory of Food and Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo, Japan. mizushin@nutr.kobegakuin.ac.jp
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Mizushina
authors.forename: Akiko
authors.initials: A
authors.lastname: Saito
authors.forename: Keiko
authors.initials: K
authors.lastname: Horikawa
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Nakajima
authors.forename: Akira
authors.initials: A
authors.lastname: Tanaka
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Kiminori
authors.initials: K
authors.lastname: Matsubara
mesh_terms: D000215:Acylation; D000818:Animals; D002392:Catechin / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D019384:Nucleic Acid Synthesis Inhibitors; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D002392:Catechin