Facile synthesis and in vitro properties of 1-alkyl- and 1-alkyl-N-propargyl-1,2,3,4-tetrahydroisoquinoline derivatives on PC12 cells.
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.
Kitabatake
Michikazu
M
Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
Nagai
Junko
J
Abe
Kenji
K
Tsuchiya
Yukihiro
Y
Ogawa
Keita
K
Yokoyama
Takashi
T
Mohri
Kunihiko
K
Taguchi
Kyoji
K
Horiguchi
Yoshie
Y
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*
D061945:Caspase Inhibitors; D009019:Morphinans; C440369:N-propargyl; D044005:Tetrahydroisoquinolines; C014843:1,2,3,4-tetrahydroisoquinoline; D008995:Monoamine Oxidase; D020169:Caspases