ABSTRACT
In the chalcone scaffold, it is thought that the double bond is an important structural linker but it is likely not essential for the interaction with tubulin. Yet, it may be a potential site of metabolic degradation and interaction with biological nucleophiles. In this letter, we have replaced this olefinic portion of chalcones with two metabolically stable and chemically inert heterocyclic rings, namely triazole or tetrazole. Yet, our biologic data suggest that, unlike in other antitubulinic structures, the olephinic ring might not be merely a structural linker.
Subject(s)
Chalcones/chemistry , Chalcones/pharmacology , Tetrazoles/chemistry , Tetrazoles/pharmacology , Triazoles/chemistry , Triazoles/pharmacology , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Chalcones/chemical synthesis , Humans , Models, Molecular , Neuroblastoma/drug therapy , Tetrazoles/chemical synthesis , Triazoles/chemical synthesis , Tubulin/metabolism , Tubulin Modulators/chemical synthesisABSTRACT
The potential interactions between rabeprazole, a widely used proton pump inhibitor, and anticancer drugs (5-fluorouracil, docetaxel, cyclophosphamide, gemcitabine, methotrexate, doxorubicin, etoposide) or drugs commonly present in the therapy of oncological patients (fluoxetine and ondansetron), were studied using in vitro human liver microsomes. The interactions between rabeprazole and the anticancer drugs were evaluated by measuring their concentrations in test and control incubations with HPLC-DAD-UV methods. To achieve this aim, nine HPLC-DAD-UV methods were developed using different stationary and mobile phases. The methods were then validated for the following parameters: selectivity, linearity, precision, and accuracy. As expected rabeprazole did not significantly inhibit the metabolism of the evaluated drugs in human liver microsomal preparations at the selected concentrations. These results shows that rabeprazole probably could be devoid of pharmacokinetic interactions with common drugs used during chemotherapy.
Subject(s)
2-Pyridinylmethylsulfinylbenzimidazoles/pharmacology , Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Microsomes, Liver/drug effects , Antibiotics, Antineoplastic/pharmacology , Antidepressive Agents, Second-Generation/pharmacology , Antiemetics/pharmacology , Antimetabolites, Antineoplastic/pharmacology , Antineoplastic Agents, Alkylating/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Chromatography, High Pressure Liquid , Cyclophosphamide/pharmacology , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Docetaxel , Doxorubicin/pharmacology , Etoposide/pharmacology , Female , Fluorouracil/pharmacology , Fluoxetine/pharmacology , Humans , In Vitro Techniques , Indicators and Reagents , Male , Methotrexate/pharmacology , Ondansetron/pharmacology , Rabeprazole , Reference Standards , Taxoids/pharmacology , GemcitabineABSTRACT
Here we demonstrate that pramipexole, an antiparkinsonian dopamine receptor agonist drug, exerts neuroprotective effects against beta-amyloid neurotoxicity. Using a specific protocol to test individually oligomers, fibrils, or unaggregated amyloid beta-peptide, we found pramipexole able to protect cells against oligomers and fibrils. Unaggregated amyloid beta-peptide was found unable to cause cell death. Fibrils and oligomers were also found to produce elevated amount of free radicals, and this effect was prevented by pramipexole. We propose pramipexole may become in the future a coadjuvant in the treatment of neuropathologies, besides Parkinson's disease, where amyloid beta-peptide-mediated oxidative injury exerts a relevant role.
