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Medicinal Chemistry


ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Synthesis of Chiral 3-Methyl- and 3-Methyl-N-propargyl-1,2,3,4- tetrahydroisoquinoline and Prevention of MPP+-Induced Cytotoxicity

Author(s): Toshiaki Saitoh, Aki Yamashita, Kenji Abe, Keita Ogawa, Michikazu Kitabatake, Kyoji Taguchi and Yoshie Horiguchi

Volume 4 , Issue 6 , 2008

Page: [531 - 538] Pages: 8

DOI: 10.2174/157340608786242043

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The chemical structure of selegiline, a commercially available drug for Parkinsons disease (PD), resembles that of 1,2,3,4-tetrahydroisoquinoline (TIQ), an endogenous parkinsonism-inducing compound. In the present study, we evaluated the direct cytotoxicity of (R)- and (S)-3-methyl-TIQ (3-MeTIQ) and (R)- and (S)-3-methyl-N-propargyl-TIQ (3- Me-N-propargyl-TIQ), as selegiline-mimetic TIQ derivatives, and their ability to prevent 1-methyl-4-phenylpyridinium iodide (MPP+)-induced cell death. Synthesis of optically-pure 3-MeTIQs was achieved via the super acid-induced cyclization of chiral N-benzyl-N-[1-methyl-2-(phenylsulfinyl)ethyl]formamide using a Pummerer-type cyclization reaction as the key step in producing excellent yields. Subsequent N-propargylation of chiral 3-MeTIQs using propynylbromide gave the corresponding 3-Me-N-propargyl-TIQs. In our in vitro experiments, the direct cytotoxicity of chiral 3-MeTIQs and 3-Me- N-propargyl-TIQs was almost identical, with no relationship to optical chirality except for (S)-3-Me-N-propargyl-TIQ, which had significantly weaker direct cytotoxicity than the other 3-MeTIQ derivatives. However, the decreased viability of PC12 cells induced by treatment with MPP+ was accelerated by the coexistence of 3-MeTIQs and inhibited by 3-Me-Npropargyl- TIQs without any participation of the stereochemistry at the 3-postion. These results suggest that the Npropargyl group is necessary for protection of cells against the toxicity of MPP+. Furthermore, the stereochemistry of the 3-position appears to partially participate in the direct cytotoxicity of 3-Me-N-propargyl-TIQs.

Keywords: 1,2,3,4-tetrahydroisoquinoline, selegiline, structure-activity relationships, cytotoxicity, Parkinson's disease

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