Abstract
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
Medicinal Chemistry
Title: Synthesis of Chiral 3-Methyl- and 3-Methyl-N-propargyl-1,2,3,4- tetrahydroisoquinoline and Prevention of MPP+-Induced Cytotoxicity
Volume: 4 Issue: 6
Author(s): Toshiaki Saitoh, Aki Yamashita, Kenji Abe, Keita Ogawa, Michikazu Kitabatake, Kyoji Taguchi and Yoshie Horiguchi
Affiliation:
Keywords: 1,2,3,4-tetrahydroisoquinoline, selegiline, structure-activity relationships, cytotoxicity, Parkinson's disease
Abstract: 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.
Export Options
About this article
Cite this article as:
Saitoh Toshiaki, Yamashita Aki, Abe Kenji, Ogawa Keita, Kitabatake Michikazu, Taguchi Kyoji and Horiguchi Yoshie, Synthesis of Chiral 3-Methyl- and 3-Methyl-N-propargyl-1,2,3,4- tetrahydroisoquinoline and Prevention of MPP+-Induced Cytotoxicity, Medicinal Chemistry 2008; 4 (6) . https://dx.doi.org/10.2174/157340608786242043
DOI https://dx.doi.org/10.2174/157340608786242043 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
Call for Papers in Thematic Issues
Carbohydrates in Computational and Medicinal Chemistry
Carbohydrates are the most essential organic molecules and are involved in the maintenance of various physiological and metabolic processes in living organisms. Carbohydrate-based compounds have come to the attention of researchers because of their significant contributions to biological functions, such as cell development and cell proliferation, connections between several cells, ...read more
Recent Advances in the Medicinal Chemistry of Cancer
Scope of the Thematic Issue: Correlation between structure and function is one of the important aspects of the success of anti-cancer compounds associated with their structure-activity interactions, physiology, biochemical, molecular, and genetic processes. Overcoming these obstacles is key to obtaining further insights into developments in rational drug design, bioorganic chemistry, ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
A Role for Leptin in the Systemic Inflammatory Response Syndrome (SIRS) and in Immune Response, an Update
Current Medicinal Chemistry Meldrum's Acid in Organic Synthesis, an Outlook to Reaction Media
Current Organic Chemistry Advancements in the Understanding of Paclitaxel Metabolism in Tissue Culture
Current Pharmaceutical Biotechnology Aetiology, Diagnosis and Treatment of Hydrops Foetalis
Current Pediatric Reviews Deep Tissue Optical and Optoacoustic Molecular Imaging Technologies for Pre-Clinical Research and Drug Discovery
Current Pharmaceutical Biotechnology A Systems Biology Approach for miRNA-mRNA Expression Patterns Analysis in Rheumatoid Arthritis
Combinatorial Chemistry & High Throughput Screening Ethnobotanical Treatment Strategies Against Alzheimers Disease
Current Alzheimer Research Ca2+ Signaling, Mitochondria and Cell Death
Current Molecular Medicine Directions for Enhancement of the Therapeutic Efficacy of Mesenchymal Stem Cells in Different Neurodegenerative and Cardiovascular Diseases: Current Status and Future Perspectives
Current Stem Cell Research & Therapy Editorial [Hot Topic: Conformational Diseases (Guest Editor: Paolo Zatta)]
Current Alzheimer Research Childhood and Adulthood Rural Residence Increases the Risk of Dementia: NEDICES Study
Current Alzheimer Research Oligonucleotides and G-quadruplex Stabilizers: Targeting Telomeres and Telomerase in Cancer Therapy
Current Pharmaceutical Design A RasMol study of the Mechanism of Inhibition of Cysteine Endopeptidase Enzyme Papain
Current Proteomics Simulation of Microgravity for Studies in Gravitational Biology: Principles, Devices and Applications
Current Biotechnology Management of Adult Active Tuberculosis Disease in Era of HIV Pandemic, Current Practices and Future Perspectives
Infectious Disorders - Drug Targets Chemo-botanical and Neurological Accounts of Some Ayurvedic Plants Useful in Mental Health
The Natural Products Journal Selective Antagonism at Dopamine D3 Receptors as a Target for Drug Addiction Pharmacotherapy: A Review of Preclinical Evidence
CNS & Neurological Disorders - Drug Targets Preface
CNS & Neurological Disorders - Drug Targets Modulating the Amyloidogenesis of α-Synuclein
Current Neuropharmacology Ruthenium Complexes as Anticancer Agents
Current Medicinal Chemistry