title: Synthesis of chiral 3-methyl- and 3-methyl-N-propargyl-1,2,3,4-tetrahydroisoquinoline and prevention of MPP+ -induced cytotoxicity.
abstract: The chemical structure of selegiline, a commercially available drug for Parkinson's 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-N-propargyl-TIQs without any participation of the stereochemistry at the 3-position. These results suggest that the N-propargyl 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.
authors.affiliation: Department of Organic Reaction Chemistry and Showa Pharmaceutical University, Machida, Tokyo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Saitoh
authors.forename: Aki
authors.initials: A
authors.lastname: Yamashita
authors.forename: Kenji
authors.initials: K
authors.lastname: Abe
authors.forename: Keita
authors.initials: K
authors.lastname: Ogawa
authors.forename: Michikazu
authors.initials: M
authors.lastname: Kitabatake
authors.forename: Kyoji
authors.initials: K
authors.lastname: Taguchi
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Horiguchi
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003627:Data Interpretation, Statistical; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D008958:Models, Molecular; D016716:PC12 Cells; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: C534538:3-methyl-1,2,3,4-tetrahydroisoquinoline; C534539:3-methyl-N-propargyl-1,2,3,4-tetrahydroisoquinoline; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D044005:Tetrahydroisoquinolines; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue; D015655:1-Methyl-4-phenylpyridinium