ABSTRACT
To develop novel neuroprotective agents, a library of novel arylalkenylpropargylamines was synthesized and tested for inhibitory activities against monoamine oxidases. From this, a number of highly potent and selective monoamine oxidase B inhibitors were identified. Selected compounds were also tested for neuroprotection in in vitro studies with PC-12 cells treated with 6-OHDA and rotenone, respectively. It was observed that some of the compounds tested yielded a marked increase in survival in PC-12 cells treated with the neurotoxins. This indicates that these propargylamines are able to confer protection against the effects of the toxins and may also be considered as novel disease-modifying anti-Parkinsonian agents, which are much needed for the therapy of Parkinson's disease.
Subject(s)
Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Neuroprotective Agents/pharmacology , Pargyline/analogs & derivatives , Parkinson Disease/drug therapy , Propylamines/pharmacology , Animals , Cell Survival/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Humans , Mice , Molecular Structure , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/chemistry , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , PC12 Cells , Pargyline/chemical synthesis , Pargyline/chemistry , Pargyline/pharmacology , Parkinson Disease/enzymology , Parkinson Disease/metabolism , Propylamines/chemical synthesis , Propylamines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
3-Deazaneplanocinâ A (DzNep) is a potential epigenetic drug for the treatment of various cancers. DzNep has been reported to deplete histone methylations, including oncogenic EZH2 complex, giving rise to epigenetic modifications that reactivate many silenced tumor suppressors in cancer cells. Despite its promise as an anticancer drug, little is known about the structure-activity relationships of DzNep in the context of epigenetic modifications and apoptosis induction. In this study, a number of analogues of DzNep were examined for DzNep-like ability to induce synergistic apoptosis in cancer cells in combination with trichostatinâ A, a known histone deacetylase (HDAC) inhibitor. The structure-activity relationship data thus obtained provide valuable information on the structural requirements for biological activity. The studies identified three compounds that show similar activities to DzNep. Two of these compounds show good pharmacokinetics and safety profiles. Attempts to correlate the observed synergistic apoptotic activities with measured S-adenosylhomocysteine hydrolase (SAHH) inhibitory activities suggest that the apoptotic activity of DzNep might not be directly due to its inhibition of SAHH.
