propargylamine and Neuroblastoma

Twenty six propargylamine mycophenolate analogues were designed and synthesized from mycophenolic acid 1 employing a key step A

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Molecular Structure; Mycophenolic Acid; Neuroblastoma; Pargyline; Propylamines; Structure-Activity Relationship

The multifactorial pathophysiology of neurodegenerative disorders remains one of the main challenges in the design of a single molecule that may ultimately prevent the progression of these disorders in affected patients. In this article, we report on twelve novel polycyclic amine cage derivatives, synthesized with or without a propargylamine function, designed to possess inherent multifunctional neuroprotective activity. The MTT cytotoxicity assay results showed the SH-SY5Y human neuroblastoma cells to be viable with the twelve compounds, particularly at concentrations less than 10 μM. The compounds also showed significant neuroprotective activity, ranging from 31% to 61% at 1 μM, when assayed on SH-SY5Y human neuroblastoma cells in which neurodegeneration was induced by MPP

Topics: Cell Line, Tumor; Drug Design; Humans; Monoamine Oxidase; Neuroblastoma; Neuroprotective Agents; Pargyline; Propylamines; Protein Binding; Structure-Activity Relationship

In Parkinson's and other neurodegenerative diseases, a therapeutic strategy has been proposed to halt progressive cell death. Propargylamine derivatives, rasagiline and (-)deprenyl (selegiline), have been confirmed to protect neurons against cell death induced by various insults in cellular and animal models of neurodegenerative disorders. In this paper, the mechanism and the markers of the neuroprotection are reviewed. Propargylamines prevent the mitochondrial permeabilization, membrane potential decline, cytochrome c release, caspase activation and nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase. At the same time, rasagiline induces anti-apoptotic pro-survival proteins, Bcl-2 and glial cell-line derived neurotrophic factor, which is mediated by activated ERK-NF-kappaB signal pathway. DNA array studies indicate that rasagiline increases the expression of the genes coding mitochondrial energy synthesis, inhibitors of apoptosis, transcription factors, kinases and ubiquitin-proteasome system, sequentially in a time-dependent way. Products of cell survival-related gene induced by propargylamines may be applied as markers of neuroprotection in clinical samples.

Topics: Alkynes; Cell Death; Cell Line, Tumor; Energy Metabolism; Genetic Markers; Glial Cell Line-Derived Neurotrophic Factor; Humans; Indans; Membrane Potentials; Mitochondria; Neuroblastoma; Neuroprotective Agents; NF-kappa B; Oligonucleotide Array Sequence Analysis; Pargyline; Parkinson Disease; Propylamines; Proto-Oncogene Proteins c-bcl-2; Selegiline