ABSTRACT
In recent years, researchers have often encountered the significance of the aberrant metabolism of tumor cells in the pathogenesis of malignant neoplasms. This phenomenon, known as the Warburg effect, provides a number of advantages in the survival of neoplastic cells, and its application is considered a potential strategy in the search for antitumor agents. With the aim of developing a promising platform for designing antitumor therapeutics, we synthesized a library of conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones. To gain insight into the determinants of the biological activity of the prepared compounds, we showed that the conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones, which are cytotoxic agents, demonstrate selective activity toward a number of tumor cell lines with glycolysis-inhibiting ability. Moreover, the results of molecular and in silico screening allowed us to identify these compounds as potential inhibitors of the pyruvate kinase M2 oncoprotein, which is the rate-determining enzyme of glycolysis. Thus, the results of our work indicate that the synthesized conjugates of 3,5-bis(arylidene)-4-piperidone and sesquiterpene lactones can be considered a promising platform for designing selective cytotoxic agents against the glycolysis process, which opens new possibilities for researchers involved in the search for antitumor therapeutics among compounds containing piperidone platforms.
Subject(s)
Antineoplastic Agents , Lactones , Piperidones , Sesquiterpenes , Humans , Sesquiterpenes/pharmacology , Sesquiterpenes/chemistry , Lactones/chemistry , Lactones/pharmacology , Lactones/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Piperidones/pharmacology , Piperidones/chemistry , Glycolysis/drug effects , Cell Proliferation/drug effects , Molecular Docking Simulation , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Drug Screening Assays, AntitumorABSTRACT
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases in existence. It is characterized by an impaired cognitive function that is due to a progressive loss of neurons in the brain. Extracellular ß-amyloid (Aß) plaques are the main pathological features of the disease. In addition to abnormal protein aggregation, increased mitochondrial fragmentation, altered expression of the genes involved in mitochondrial biogenesis, disruptions in the ER-mitochondria interaction, and mitophagy are observed. Reactive oxygen species are known to affect Aß expression and aggregation. In turn, oligomeric and aggregated Aß cause mitochondrial disorders. In this review, we summarize available knowledge about the pathological effects of Aß on mitochondria and the potential molecular targets associated with proteinopathy and mitochondrial dysfunction for the pharmacological treatment of Alzheimer's disease.
ABSTRACT
Drug development for the treatment of neurodegenerative diseases has to confront numerous problems occurring, in particular, because of attempts to address only one of the causes of the pathogenesis of neurological disorders. Recent advances in multitarget therapy research are gaining momentum by utilizing pharmacophores that simultaneously affect different pathological pathways in the neurodegeneration process. The application of such a therapeutic strategy not only involves the treatment of symptoms, but also mainly addresses prevention of the fundamental pathological processes of neurodegenerative diseases and the reduction of cognitive abilities. Neuroinflammation and oxidative stress, mitochondrial dysfunction, dysregulation of the expression of histone deacetylases, and aggregation of pathogenic forms of proteins are among the most common and significant pathological features of neurodegenerative diseases. In this review, we focus on the molecular mechanisms and highlight the main aspects, including reactive oxygen species, the cell endogenous antioxidant system, neuroinflammation triggers, metalloproteinases, α-synuclein, tau proteins, neuromelanin, histone deacetylases, presenilins, etc. The processes and molecular targets discussed in this review could serve as a starting point for screening leader compounds that could help prevent or slow down the development of neurodegenerative diseases.
ABSTRACT
Cyclic hydroxamic acids based on quinazoline-4(3H)-one and dihydroquinazoline-4(1H)-one have been synthesized. The antioxidant and iron-chelating properties of these compounds, their effect on the activity of the histone deacetylase enzyme, and their cytotoxic effect on cells of various tumor lines have been investigated. We have identified two compounds-hits, which exhibit the multipharmacological type of the antineoplastic activity. Their cytotoxic effect on cells of human lung carcinoma A549 and breast adenocarcinoma MCF-7 is obviously associated with their ability to modulate the level of reactive oxygen species and to chelate Fe(II) ions, as well as to inhibit the metalloenzymes, histone deacetylases, involved in the epigenetic regulation of tumor genesis. Thus, the synthesized hydroxamic acids may be considered as a promising basis for creating potential oncolytics.
Subject(s)
Antineoplastic Agents , Histone Deacetylase Inhibitors , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Epigenesis, Genetic , Histone Deacetylase Inhibitors/pharmacology , Humans , Hydroxamic Acids/pharmacology , Structure-Activity RelationshipABSTRACT
Antioxidant activity of a pharmaceutical substance hypocard was compared with activity of nitromalic acid and well-known agents nicorandil and Mexidol. The ability of these substances to inhibit spontaneous and oxidant-induced LPO process in rat brain homogenate was analyzed. The mechanisms of these effects were studied. The antioxidant properties of hypocard manifested in the inhibition of Fe(II)-induced LPO were significantly more pronounced in comparison with Mexidol and nicorandil.
Subject(s)
Antioxidants/metabolism , Animals , Brain/drug effects , Brain/metabolism , Lipid Peroxidation/drug effects , Male , Nicorandil/pharmacology , Oxidative Stress/drug effects , Oxidative Stress/physiology , Picolines/pharmacology , RatsABSTRACT
Iron-chelating activity of synthesized spirocyclic hydroxamic acids, their toxicity, and effects on mitochondrial function were studied using primary culture of cerebral cortical neurons from newborn rats. All tested compounds effectively chelated Fe(II) ions. Activity of spirocyclic hydroxamic acids more strictly depended on the structure their piperidine, but not imidazolidine fragment. All compounds were non-toxic for normal neuronal culture.
Subject(s)
Hydroxamic Acids/pharmacology , Iron Chelating Agents/pharmacology , Iron/metabolism , Mitochondria, Liver/drug effects , Neurons/drug effects , Spiro Compounds/pharmacology , Animals , Animals, Newborn , Animals, Outbred Strains , Cations, Divalent , Cell Survival/drug effects , Cerebral Cortex/cytology , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Ferrozine/chemistry , Hydroxamic Acids/chemical synthesis , Iron Chelating Agents/chemical synthesis , Male , Membrane Potential, Mitochondrial/drug effects , Mitochondria, Liver/metabolism , Mitochondrial Swelling/drug effects , Neurons/metabolism , Primary Cell Culture , Rats , Spiro Compounds/chemical synthesis , Structure-Activity RelationshipABSTRACT
Analysis of antioxidant activity of synthesized selenourea derivatives showed that N,N'-substituted selenoureas inhibited Fe(III)-induced LPO in rat brain homogenate. On the other hand, oxygen- and sulfur-containing analogs exhibited no antioxidant activity or even slight prooxidant activity. Intramolecular alkylation of selenium atom also led to loss of antioxidant activity. Thus, antioxidant activity of the compounds was due to the presence of a nonalkylated selenium atom in N,N'-substituted selenourea analogs.
Subject(s)
Antioxidants/pharmacology , Ferric Compounds/pharmacology , Organoselenium Compounds/pharmacology , Urea/analogs & derivatives , Animals , Lipid Peroxidation/drug effects , Oxidation-Reduction/drug effects , Rats , Reactive Oxygen Species/metabolism , Urea/pharmacologyABSTRACT
We performed screening of potential antioxidants among natural lactone and alkaloid derivatives and characterized their antioxidant effects. The substances exhibiting antioxidant and metal-chelating potential, in particular, tryptamine derivatives, are promising neuroprotector agents.