title: Gastroprotective efficacy and safety evaluation of scoparone derivatives on experimentally induced gastric lesions in rodents.
abstract: This study investigated the gastroprotective efficacy of synthesized scoparone derivatives on experimentally induced gastritis and their toxicological safety. Six scoparone derivatives were synthesized and screened for gastroprotective activities against HCl/ethanol- and indomethacin-induced gastric ulcers in rats. Among these compounds, 5,6,7-trimethoxycoumarin and 6,7,8-trimethoxycoumarin were found to have gastroprotective activity greater than the standard drug rebamipide; 6-methoxy-7,8-methylenedioxycoumarin, 6-methoxy-7,8-(1-methoxy)-methylenedioxycoumarin, 6,7-methylenedioxycoumarin, and 6,7-(1-methoxy)-methylenedioxycoumarin were found to be equipotent or less potent that of rebamipide. Pharmacological studies suggest that the presence of a methoxy group at position C-5 or C-8 of the scoparone's phenyl ring significantly improves gastroprotective activity, whereas the presence of a dioxolane ring at C-6, C-7, or C-8 was found to have decreased activity. In order to assess toxicological safety, two of the potent gastroprotective scoparone derivatives-5,6,7-trimethoxycoumarin and 6,7,8-trimethoxycoumarin-were examined for their acute toxicity in mice as well as their effect on cytochrome P450 (CYP) enzyme activity. These two compounds showed low acute oral toxicity in adult male and female mice, and caused minimal changes to CYP3A4 and CYP2C9 enzyme activity. These results indicate that compared to other scoparone derivatives, 5,6,7-trimethoxycoumarin and 6,7,8-trimethoxycoumarin can improve gastroprotective effects, and they have low toxicity and minimal effects on drug-metabolizing enzymes.
authors.affiliation: School of Applied Bioscience, Kyungpook National University, Daegu 702-701, Korea. sondj1@hotmail.com.
authors.forename: Dong Ju
authors.initials: DJ
authors.lastname: Son
authors.affiliation: Department of Biotechnology, College of Natural Sciences, Soonchunhyang University, Asan, Chungnam 336-745, Korea. jjanglkr@nate.com.
authors.forename: Gyung Rak
authors.initials: GR
authors.lastname: Lee
authors.affiliation: Department of Biotechnology, College of Natural Sciences, Soonchunhyang University, Asan, Chungnam 336-745, Korea. jmosungil@naver.com.
authors.forename: Sungil
authors.initials: S
authors.lastname: Oh
authors.affiliation: School of Applied Bioscience, Kyungpook National University, Daegu 702-701, Korea. selpest@knu.ac.kr.
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Lee
authors.affiliation: Department of Biotechnology, College of Natural Sciences, Soonchunhyang University, Asan, Chungnam 336-745, Korea. wschoi@sch.ac.kr.
authors.forename: Won Sik
authors.initials: WS
authors.lastname: Choi
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019306:Artemisia / Q000737:chemistry*; D003374:Coumarins / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000431:Ethanol; D006851:Hydrochloric Acid; D007213:Indomethacin; D008297:Male; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D015363:Quinolones / Q000494:pharmacology / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: C404407:6,7,8-trimethoxycoumarin; D000897:Anti-Ulcer Agents; D003374:Coumarins; D010936:Plant Extracts; D015363:Quinolones; D000431:Ethanol; C018145:scoparone; C052785:rebamipide; D000409:Alanine; D006851:Hydrochloric Acid; D007213:Indomethacin