title: (-)-Neocaryachine, an Antiproliferative Pavine Alkaloid from Cryptocarya laevigata, Induces DNA Double-Strand Breaks.
abstract: Twelve benzylisoquinoline alkaloids, including pavine and phenanthroindolizidine types, were isolated from a MeOH/CH2Cl2extract of Cryptocarya laevigata (stem bark) through bioactivity-guided fractionation for antitumor effects. Selected compounds were evaluated for antiproliferative activity against five human tumor cell lines, including a multidrug-resistant subline. Since more common 2,3,8,9-tetrasubstituted pavine alkaloids, such as crychine (3), exhibit very mild or no cytotoxicity, this compound type has not been well investigated for antitumor activity. Thus, this report is the first discovery of a 7-hydroxylated pavine alkaloid, (-)-neocaryachine (1), to demonstrate strong antiproliferative activity, with IC50values of 0.06 to 0.41 μM against five tested tumor cell lines, including an MDR subline. Further mechanism of action studies revealed that 1 impacts the cellular S-phase by inducing DNA double-strand breaks.
authors.affiliation: School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University , Kanazawa, 920-1192, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University , Kanazawa, 920-1192, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599-7568, United States.
authors.forename: Masuo
authors.initials: M
authors.lastname: Goto
authors.affiliation: NIH Special Volunteer, Wayne, Pennsylvania 19087, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Newman
authors.forename: Barry R
authors.initials: BR
authors.lastname: O'Keefe
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599-7568, United States.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599-7295, United States.|Chinese Medicine Research and Development Center, China Medical University and Hospital , 2 Yuh-Der Road, Taichung, 40447, Taiwan.
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.affiliation: School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University , Kanazawa, 920-1192, Japan.|Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599-7568, United States.
authors.forename: Kyoko
authors.identifier: 0000-0002-1642-6538
authors.initials: K
authors.lastname: Nakagawa-Goto
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D031369:Cryptocarya / Q000737:chemistry*; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004149:Dioxoles / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D006801:Humans; D007212:Indolizines / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D015394:Molecular Structure; D010618:Phenanthrolines / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology
chemical_list: D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D004149:Dioxoles; D007212:Indolizines; D010618:Phenanthrolines; C521640:phenanthroindolizidine; C084233:crychine; D004247:DNA