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Four new palladium complexes containing a cyclometallated pinane ligand and l-amino acids (proline, tyrosine, serine, isoleucine) as coligands were synthesized and characterized. For the synthesis, we used the previously described binuclear palladacycle, the opening of the chloride bridges in which provides easy introduction of additional biogenic ligands and obtaining multimodal palladium complexes. All newly obtained compounds were characterized by NMR and IR spectroscopy and elemental analysis. We studied the antitumor activity of the synthesized complexes and reference compounds expressed in their toxic effect against a panel of tumor-derived cell lines A549, SH-SY5Y, Hep-2, and HeLa. It was established that the cytotoxic effect of the palladacycles may be due to the ability of these compounds to cause destruction of mitochondria by depolarizing the mitochondrial membrane. Some structure—activity correlations were revealed. [ABSTRACT FROM AUTHOR]

Six new chiral zinc(ii) complexes 1–6 based on ethylenediamine derivatives of terpenes were synthesized and characterized. The molecular structure of complex 2 was established by X-ray diffraction analysis. The modulating effect of complexes 1–6 on the functional state of mitochondria, which are organelles playing an utterly important role in maintaining the energy balance of cells, transfer of genetic material, and regulation of the processes of triggering the cell death by apoptosis, autophagy, and necrosis, was studied. It is shown that synthesized zinc complexes lead to depolarization of the mitochondrial membrane, an increase in the threshold of sensitivity of the organelles to calcium-induced opening of the mitochondrial permeability transition pores, and disruption of the operation of the respiratory chain complexes in these organelles. Such a dysfunctional state of mitochondria is one of the main causes of cell death through apoptosis due to the release of various proapoptotic factors into the intracellular space. In this regard, the newly synthesized zinc complexes 1–6 can be considered as destructive agents aimed at triggering cell death cascades by affecting mitochondrial functions. These properties are of paramount importance when searching for potential drugs with possible antitumor, antiprotozoal, or antifungal activity. [ABSTRACT FROM AUTHOR]

Background: Sesquiterpene lactones are secondary plant metabolites with a wide variety of biological activities. The process of lactone conjugation to other pharmacophores can increase the efficacy and specificity of the conjugated agent effect on molecular targets in various diseases, including brain pathologies. Derivatives of biogenic indoles, including neurotransmitter serotonin, are of considerable interest as potential pharmacophores. Most of these compounds have neurotropic activity and, therefore, can be used in the synthesis of new drugs with neuroprotective properties., Aim: The aim of this experimental synthesis was to generate potential treatment agents for Alzheimer's disease using serotonin conjugated with natural sesquiterpene lactones., Methods: Three novel compounds were obtained via the Michael reaction and used for biological testing. The obtained conjugates demonstrated complex neuroprotective activities. Serotonin conjugated to isoalantolactone exhibited strong antioxidant and mitoprotective activities., Results: The agent was also found to inhibit β-site amyloid precursor protein cleaving enzyme 1 (BACE-1), prevent the aggregation of β-amyloid peptide 1-42, and protect SH-SY5Y neuroblastoma cells from neurotoxins such as glutamate and H 2 O 2 . In a transgenic animal model of Alzheimer's disease (5xFAD line), the conjugated agent restored declined cognitive functions and improved learning and memory., Conclusion: In conclusion, the obtained results indicate that serotonin conjugates to sesquiterpene lactones are promising agents for the treatment of symptoms associated with Alzheimer's disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Parkinson's disease is the second most common neurodegenerative disease. Unfortunately, there is still no definitive disease-modifying therapy. In our work, the antiparkinsonian potential of trans-epoxide (1S,2S,3R,4S,6R)-1-methyl-4-(prop-1-en-2-yl)-7-oxabicyclo [4.1.0]heptan-2,3-diol (E-diol) was analyzed in a rotenone-induced neurotoxicity model using in vitro, in vivo and ex vivo approaches. It was conducted as part of the study of the mitoprotective properties of the compound. E-diol has been shown to have cytoprotective properties in the SH-SY5Y cell line exposed to rotenone, which is associated with its ability to prevent the loss of mitochondrial membrane potential and restore the oxygen consumption rate after inhibition of the complex I function. Under the conditions of rotenone modeling of Parkinson's disease in vivo, treatment with E-diol led to the leveling of both motor and non-motor disorders. The post-mortem analysis of brain samples from these animals demonstrated the ability of E-diol to prevent the loss of dopaminergic neurons. Moreover, that substance restored functioning of the mitochondrial respiratory chain complexes and significantly reduced the production of reactive oxygen species, preventing oxidative damage. Thus, E-diol can be considered as a new potential agent for the treatment of Parkinson's disease.

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 β-amyloid (Aβ) 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 Aβ expression and aggregation. In turn, oligomeric and aggregated Aβ cause mitochondrial disorders. In this review, we summarize available knowledge about the pathological effects of Aβ on mitochondria and the potential molecular targets associated with proteinopathy and mitochondrial dysfunction for the pharmacological treatment of Alzheimer's disease., (Copyright ® 2022 National Research University Higher School of Economics.)

Anthracycline antitumor antibiotics are one of the promising classes of chemotherapeutic agents for cancer treatment. The main deterrent to their use is high toxicity to a healthy environment, including cumulative cardiotoxicity. In our work, bipharmacophore molecules containing in their structure a fragment of the known anthracycline antibiotics daunorubicin and doxorubicin and natural sesquiterpene lactones were obtained for the first time. When studying the biological activity of the synthesized compounds, it was found that with equal and, in some cases, higher cytotoxicity and glycolysis inhibition by anthracycline antibiotics conjugates with sesquiterpene lactones in comparison with doxo- and daunorubicin, a reduced damaging effect on the functioning of rat heart mitochondria was observed. The results obtained allow us to confirm the assumption that the chemical modification of the anthracycline antibiotics molecules doxo- and daunorubicin by natural sesquiterpene lactones can be a promising strategy for creating potential antitumor chemotherapeutic drugs with a pronounced cytotoxic effect on tumor cells and a reduced damaging effect on healthy cells of the human organism.