Azulene hydrazide-hydrazones for selective targeting of pancreatic cancer cells.

Dysregulation of iron homeostasis is one of the important processes in the development of many oncological diseases, such as pancreatic cancer. Targeting it with specific agents, such as an iron chelator, are promising therapeutic methods. In this study, we tested the cytotoxicity of novel azulene hydrazide-hydrazone-based chelators against pancreatic cancer cell lines (MIA PaCa-2, PANC-1, AsPC-1). All prepared chelators (compounds 4-6) showed strong cytotoxicity against pancreatic cancer cell lines and high selectivity for cancer cell lines compared to the healthy line. Their cytotoxicity is lower than thiosemicarbazone-based chelators Dp44mT and DpC, but significantly higher than hydroxamic acid-based chelator DFO. The chelator tested showed mitochondrial and lysosomal co-localization and its mechanism of action was based on the induction of hypoxia-inducible factor-1-alpha (HIF-1α), N-myc downstream-regulated gene-1 (NDRG1) and transferrin receptor 1 (TfR1). This strongly implies that the cytotoxic effect of tested chelators could be associated with mitophagy induction. Lipinski's rule of five analyses was performed to determine whether the prepared compounds had properties ensuring their bioavailability. In addition, the drug-likeness and drug-score were calculated and discussed.

Targeting of the Mitochondrial TET1 Protein by Pyrrolo[3,2-b]pyrrole Chelators.

Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies, including oncological disorders. Recent studies demonstrated that promising therapeutic strategies could potentially be based on the inhibition of the TET1 protein (ten-eleven translocation methylcytosine dioxygenase 1) by specific iron chelators. Therefore, in the present work, we prepared a series of pyrrolopyrrole derivatives with hydrazide (1) or hydrazone (2-6) iron-binding groups. As a result, we determined that the basic pyrrolo[3,2-b]pyrrole derivative 1 was a strong inhibitor of the TET1 protein (IC50 = 1.33 µM), supported by microscale thermophoresis and molecular docking. Pyrrolo[3,2-b]pyrroles 2-6, bearing substituted 2-hydroxybenzylidene moieties, displayed no significant inhibitory activity. In addition, in vitro studies demonstrated that derivative 1 exhibits potent anticancer activity and an exclusive mitochondrial localization, confirmed by Pearson's correlation coefficient of 0.92.

Non-psychotropic cannabinoids as inhibitors of TET1 protein.

Non-psychotropic cannabinoids (e.g., cannabidiol, cannabinol and cannabigerol) are contained in numerous alimentary and medicinal products. Therefore, predicting and studying their possible side effects, such as changes in DNA methylation, is an important task for assessing the safety of these products. Interference with TET enzymes by chelating ferrous ions can contribute to the altered methylation pattern. All tested cannabinoids displayed a strong affinity for Fe(II) ions. Cannabidiol and cannabinol exhibited potent inhibitory activities (IC50 = 4.8 and 6.27 µM, respectively) towards the TET1 protein, whereas cannabigerol had no effect on the enzyme activity. An in silico molecular docking study revealed marked binding potential within the catalytic cavity for CBD/CBN, but some affinity was also found for CBG, thus the total lack of activity remains unexplained. These results imply that cannabinoids could affect the activity of the TET1 protein not only due to their affinity for Fe(II) but also due to other types of interactions (e.g., hydrophobic interactions and hydrogen bonding).

Spectroscopic study of in situ-formed metallocomplexes of proton pump inhibitors in water.

Proton pump inhibitors, such as omeprazole, pantoprazole and lansoprazole, are an important group of clinically used drugs. Generally, they are considered safe without direct toxicity. Nevertheless, their long-term use can be associated with a higher risk of some serious pathological states (e.g. amnesia and oncological and neurodegenerative states). It is well known that dysregulation of the metabolism of transition metals (especially iron ions) plays a significant role in these pathological states and that the above drugs can form complexes with metal ions. However, to the best of our knowledge, this phenomenon has not yet been described in water systems. Therefore, we studied the interaction between these drugs and transition metal ions in the surrounding water environment (water/DMSO, 99:1, v/v) by absorption spectroscopy. In the presence of Fe(III), a strong redshift was observed, and more importantly, the affinities of the drugs (represented as binding constants) were strong enough, especially in the case of omeprazole, so that the formation of a metallocomplex cannot be excluded during the explanation of their side effects.

Role of mtDNA disturbances in the pathogenesis of Alzheimer's and Parkinson's disease.

Neurodegenerative diseases (e.g. Alzheimer's and Parkinson's disease) are becoming increasingly problematic to healthcare systems. Therefore, their underlying mechanisms are trending topics of study in medicinal research. Numerous studies have evidenced a strong association between mitochondrial DNA disturbances (e.g. oxidative damage, mutations, and methylation shifts) and the initiation and progression of neurodegenerative diseases. Therefore, this review discusses the risk and development of neurodegenerative diseases in terms of disturbances in mitochondrial DNA and as a part of a complex ecosystem that includes other important mechanisms (e.g. neuroinflammation and the misfolding and aggregation of amyloid-ß peptides, α-synuclein, and tau proteins). In addition, the influence of individual mitochondrial DNA haplogroups on the risk and development of neurodegenerative diseases is also described and discussed.