title: Facile synthesis and in vitro properties of 1-alkyl- and 1-alkyl-N-propargyl-1,2,3,4-tetrahydroisoquinoline derivatives on PC12 cells.
abstract: The synthesis of several 1-alkyl-1,2,3,4-tetrahydroisoquinolines, which may play an important role in Parkinson's disease, has been achieved by modified Pictet-Spengler cyclization of the formyliminium ion. The direct cytotoxicity and preventative effects towards MPP(+)-mediated death of PC12 cells were estimated. The cytotoxicities of 1-alkyl-TIQs were apoptotic and depended on their lipophilic properties. Conversely, introducing the N-propargyl substituent reduced cytotoxicity. 1-Methyl-, 1-methyl-N-propargyl- and 1-cyclopropyl-TIQ partially inhibited MPP(+)-induced cell death, whereas relatively large alkyl substituents at the first position did not enhance the viability of PC12 cells. In summary, our findings suggest a crucial role for the N-propargyl functional group for the effective reduction of cytotoxicity, and show the importance of size and lipophilicity of substituents at the 1-position of 1-alkyl-TIQs.
authors.affiliation: Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors.forename: Michikazu
authors.initials: M
authors.lastname: Kitabatake
authors.forename: Junko
authors.initials: J
authors.lastname: Nagai
authors.forename: Kenji
authors.initials: K
authors.lastname: Abe
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Tsuchiya
authors.forename: Keita
authors.initials: K
authors.lastname: Ogawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Mohri
authors.forename: Kyoji
authors.initials: K
authors.lastname: Taguchi
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Horiguchi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D008995:Monoamine Oxidase / Q000378:metabolism; D009019:Morphinans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016716:PC12 Cells; D010300:Parkinson Disease / Q000188:drug therapy; D051381:Rats; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D061945:Caspase Inhibitors; D009019:Morphinans; C440369:N-propargyl; D044005:Tetrahydroisoquinolines; C014843:1,2,3,4-tetrahydroisoquinoline; D008995:Monoamine Oxidase; D020169:Caspases