Facile synthesis and in vitro properties of 1-alkyl- and 1-alkyl-N-propargyl-1,2,3,4-tetrahydroisoquinoline derivatives on PC12 cells
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- 作者：Michikazu Kitabatake ; Junko Nagai ; Kenji Abe ; Yukihiro Tsuchiya ; Keita Ogawa ; Takashi Yokoyama ; Kunihiko Mohri ; Kyoji Taguchi ; Yoshie Horiguchi
- 关键词：Pictet– ; Spengler reaction ; 1 ; 2 ; 3 ; 4-Tetrahydroisoquinoline ; Structure– ; activity relationships ; Cytotoxicity ; Parkinson's disease ; Cell protective effect ; Propargyl group
- 刊名：European Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：October 2009
- 年：2009
- 卷：44
- 期：10
- 页码：4034-4043
- 全文大小：698 K
文摘
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.