title: Artepillin C isoprenomics: design and synthesis of artepillin C isoprene analogues as lipid peroxidation inhibitor having low mitochondrial toxicity.
abstract: We designed and synthesized isoprene analogues of artepillin C, a major component of Brazilian propolis, and investigated the inhibitory activity on lipid peroxidation of rat liver mitochondria (RLM) and RLM toxicity based on isoprenomics. We succeeded in the synthesis of artepillin C isoprene analogues using regioselective prenylation within the range from 22% to 53% total yield. Reactivity of artepillin C and its isoprene analogues with ABTS (2,2'-Azinobis(3-ethylbenzothiazoline-6-sulfonate)) radical cations showed only a slight difference among the molecules. The isoprene side-chain elongation analogues of artepillin C showed almost the same inhibitory activity against RLM lipid peroxidation as artepillin C. Artepillin C and its isoprene analogues had very weak RLM uncoupling activity. Moreover, artepillin C and its isoprene analogues exhibited a lower inhibitory activity against adenosine 5'-triphosphate (ATP) synthesis by about two orders of magnitude than the effective inhibitory activity against RLM lipid peroxidation. From these results we conclude that artepillin C isoprene analogues could be potent lipid peroxidation inhibitors having low mitochondrial toxicity. We also conclude that elongation of the isoprene side chain of artepillin C to increase lipophilicity had little influence on the inhibitory activity toward RLM lipid peroxidation.
authors.affiliation: Department of Biological Science and Technology, Faculty of Engineering, The University of Tokushima, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Uto
authors.forename: Shutaro
authors.initials: S
authors.lastname: Ae
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koyama
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Sakakibara
authors.forename: Naoki
authors.initials: N
authors.lastname: Otomo
authors.forename: Mamoru
authors.initials: M
authors.lastname: Otsuki
authors.forename: Hideko
authors.initials: H
authors.lastname: Nagasawa
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Kirk
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hori
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002070:Butadienes / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D005227:Fatty Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D045782:Hemiterpenes / Q000138:chemical synthesis / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects*; D008956:Models, Chemical; D010420:Pentanes / Q000138:chemical synthesis / Q000494:pharmacology*; D010666:Phenylpropionates / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002070:Butadienes; D005227:Fatty Acids; D045782:Hemiterpenes; D010420:Pentanes; D010666:Phenylpropionates; C013584:lipid peroxidation inhibitor; C005059:isoprene; C102259:artepillin C; D000255:Adenosine Triphosphate