Poszukiwanie nowych chelatorów żelaza dla terapii przeciwnowotworowych

Celem niniejszej pracy było poszukiwanie nowych chelatorów żelaza typu tiosemikarbazonów o potencjalnych zastosowaniach w terapiach przeciwnowotworowych. W zakres pracy wchodziło w szczególności badanie wpływu tytułowych związków na komórki ze zmianami nowotworowymi oraz bez tych zmian. Ponadto badano zastosowanie pochodnych tiosemikarbazonów w kombinowanej terapii ALA-PDT z chelatorami żelaza

Acid selective pro-dye for cellular compartments

A novel pro-dye approach for the acid-selective staining of the subcellular compartments for better permeability and selectivity was applied. The designed sensor has suitable physicochemical properties such as a large Stokes shift and a long-lived intracellular fluorescence. The Schiff base fragment was used for the acid-sensitive release of a fluorophore without affecting the overall stability of the biological systems. Due to the presence of an imine bond in its structure and its unique fluorescent properties, it can be presented as a “pro-dye” for acidic structures such as lysosomes. As a result of an imine bond cleavage, a new fluorescent compound is released, whose substantially shifted excitation and emission wavelengths enable a more selective and effective imaging of lysosomes and endosomes. The presented report provides the chemical, physicochemical and optical profiles as well as biological assays and theoretical calculations

The role of oxidative stress in activity of anticancer thiosemicarbazones

Thiosemicarbazones are chelators of transition metals such as iron or copper whose anticancer potency is intensively investigated. Although two compounds from this class have entered clinical trials, their precise mechanism of action is still unknown. Recent studies have suggested the mobilization of the iron ions from a cell, as well as the inhibition of ribonucleotide reductase, and the formation of reactive oxygen species. The complexity and vague nature of this mechanism not only impedes a more rational design of novel compounds, but also the further development of those that are highly active that are already in the preclinical phase. In the current work, a series of highly active thiosemicarbazones was studied for their antiproliferative activity in vitro. Our experiments indicate that these complexes have ionophoric properties and redox activity. They appeared to be very effective generating reactive oxygen species and deregulating the antioxidative potential of a cell. Moreover, the genes that are responsible for antioxidant capacity were considerably deregulated, which led to the induction of apoptosis and cell cycle arrest. On the other hand, good intercalating properties of the studied compounds may explain their ability to cleave DNA strands and to also poison related enzymes through the formation of reactive oxygen species. These findings may help to explain the particularly high selectivity that they have over normal cells, which generally have a stronger redox equilibrium

Theoretical and experimental investigations of large stokes shift fluorophores based on a quinoline scaffold

A series of novel styrylquinolines with the benzylidene imine moiety were synthesized and spectroscopically characterized for their applicability in cellular staining. The spectroscopic study revealed absorption in the ultraviolet–visible region (360–380 nm) and emission that covered the blue-green range of the light (above 500 nm). The fluorescence quantum yields were also determined, which amounted to 0.079 in the best-case scenario. The structural features that are behind these values are also discussed. An analysis of the spectroscopic properties and the theoretical calculations indicated the charge-transfer character of an emission, which was additionally evaluated using the Lippert–Mataga equation. Changes in geometry in the ground and excited states, which had a significant influence on the emission process, are also discussed. Additionally, the capability of the newly synthesized compounds for cellular staining was also investigated. These small molecules could effectively penetrate through the cellular membrane. Analyses of the images that were obtained with several of the tested styrylquinolines indicated their accumulation in organelles such as the mitochondria and the endoplasmic reticulum

Live cell imaging by 3-imino-(2-phenol)-1,8-naphthalimides : the effect of ex vivo hydrolysis

A series of 3-amino-N-substituted-1,8-naphthalimides and their salicylic Schiff base derivatives were synthesized. The structure of the obtained compounds was confirmed using 1H and 13C NMR, FT-IR spectroscopy and elemental analysis and COSY and HMQC for the representative molecules. The photophysical (UV–Vis, PL) and biological properties of all of the prepared compounds were studied. It was found that the amine with the nhexyl group in EtOH had the highest PL quantumyield (Ф=85%) compared to the others.Moreover, the chelating properties of the azomethines with the n-hexyl group (1a, 1b, 1c) were tested against various cations (Al3+, Ba2+, Co2+, Cu2+, Cr3+, Fe2+, Fe3+,Mn2+, Ni2+, Pb2+, Sr2+ and Zn2+) in an acetonitrile, acetone and PBS/AC mixture. Compounds that contained the electron withdrawing groups (-Br, -I) had the ability to chelate most of the studied cations, while the unsubstituted derivative chelated only the trivalent cations such as Al3+, Cr3+ and Fe3+ in acetonitrile. The effect of the environment on the keto-enol tautomeric equilibrium was also demonstrated, especially in the case of the derivativewith a bromine atom. The biological studies showed that the tested molecules had no cytotoxicity. Additionally, the ability to image intracellular organelles such as the mitochondria and endoplasmic reticulum was revealed. The crucial role of the hydrolysis of imines for cellular imaging was presented

Novel benzenesulfonate scaffolds with a high anticancer activity and G2/M cell cycle arrest

Sulfonates, unlike their derivatives, sulphonamides, have rarely been investigated for their anticancer activity. Unlike the well-known sulphonamides, esters are mainly used as conve-nient intermediates in a synthesis. Here, we present the first in-depth investigation of quinazoline sulfonates. A small series of derivatives were synthesized and tested for their anticancer activity. Based on their structural similarity, these compounds resemble tyrosine kinase inhibitors and the p53 reactivator CP-31398. Their biological activity profile, however, was more related to sulphonamides because there was a strong cell cycle arrest in the G2/M phase. Further investigation revealed a multitargeted mechanism of the action that corresponded to the p53 protein status in the cell. Al-though the compounds expressed a high submicromolar activity against leukemia and colon cancers, pancreatic cancer and glioblastoma were also susceptible. Apoptosis and autophagy were confirmed as the cell death modes that corresponded with the inhibition of metabolic activity and the activation of the p53-dependent and p53-independent pathways. Namely, there was a strong activation of the p62 protein and GADD44. Other proteins such as cdc2 were also expressed at a higher level. More-over, the classical caspase-dependent pathway in leukemia was observed at a lower concentration, which again confirmed a multitargeted mechanism. It can therefore be concluded that the sulfonates of quinazolines can be regarded as promising scaffolds for developing anticancer agents

Design, synthesis and in Vitro activity of anticancer styrylquinolines. The p53 Independent Mechanism of Action

A group of styrylquinolines were synthesized and tested for their anti-proliferative activity. Anti-proliferative activity was evaluated against the human colon carcinoma cell lines that had a normal expression of the p53 protein (HCT116 p53+/+) and mutants with a disabled TP53 gene (HCT116 p53-/-) and against the GM 07492 normal human fibroblast cell line. A SAR study revealed the importance of Cl and OH as substituents in the styryl moiety. Several of the compounds that were tested were found to have a marked anti-proliferative activity that was similar to or better than doxorubicin and were more active against the p53 null than the wild type cells. The cellular localization tests and caspase activity assays suggest a mechanism of action through the mitochondrial pathway of apoptosis in a p53-independent manner. The activity of the styrylquinoline compounds may be associated with their DNA intercalating ability

Bio-based nanofluids of extraordinary stability and enhanced thermal conductivity as sustainable green heat transfer media

Nanofluids (NFs) as a new generation of heat transfer media can be applied inter alia as engine coolants, in the microelectronic industry for the cooling of electronic components and systems, and in solar panels. In the present study, the extraordinarily, that is, more than 1 year, stable NFs composed of multi-walled carbon nanotubes (MWCNTs), biomass-derived 1,2- propanediol or 1,3-propanediol, and poly(N-vinylpyrrolidone) were created and studied. The thermal conductivity and density of NFs did not change over 8 months, and NFs did not sediment over 14 months. The real image of NFs determined using transmission electron cryo-microscopy allowed us to prove that the extraordinary stability and enhanced thermal conductivity were resulted by fully individualized MWCNTs in the continuous phase and MWCNTs stabilized in dispersions by shorter carbon nanoparticles and mostly homogenous poly(N-vinylpyrrolidone) coating. The maximum enhancement in thermal conductivity was 22 and 20% for NFs composed of 2 wt % MWCNTs in comparison with that of pure 1,2-propanediol and 1,3-propanediol, respectively. The improved thermal properties were accompanied by the practically Newtonian nature of all NFs. The cytotoxicity test on normal human dermal fibroblasts indicated that the use of diols diminished the toxicity of MWCNTs. Finally, the thermal conductivity and Prandtl number of bio-based NFsas compared with those of commercial heat transfer fluids DOWCAL 200 and DOWCAL Npredestine them as superb green heat transfer media in sustainable energy systems

Influence of the substituent D/A at the 1,2,3-triazole ring on novel terpyridine derivatives:synthesis and properties

In this study, we newly designed and developed a synthesis route based on the 1,3-dipolar cycloaddition of the derivatives of 40-(1,2,3-triazol-4-yl)phenyl-2,20:60,200-terpyridine with various (hetero)aryl substituents, differing in electronic character, on a triazol ring. The obtained compounds were comprehensively characterized by UV-Vis spectroscopy and electrochemical and thermal studies. Moreover, preliminary biological tests were conducted. The investigation allowed the selection of materials with the most promising properties with particular emphasis on the nature of the substituents. In addition, theoretical studies (DFT and TD-DFT) were performed to verify the comprehensive understanding of experimental results

Glycofullerenes as non-receptor tyrosine kinase inhibitors- towards better nanotherapeutics for pancreatic cancer treatment

The water-soluble glycofullerenes GF1 and GF2 were synthesized using two-step modified Bingel-Hirsch methodology. Interestingly, we identified buckyballs as a novel class of non-receptor Src kinases inhibitors. The evaluated compounds were found to inhibit Fyn A and BTK proteins with IC50 values in the low micromolar range, with the most active compound at 39 µM. Moreover, we have demonstrated that formation of protein corona on the surface of [60]fullerene derivatives is changing the landscape of their activity, tuning the selectivity of obtained carbon nanomaterials towards Fyn A and BTK kinases. The performed molecular biology studies revealed no cytotoxicity and no influence of engineered carbon nanomaterials on the cell cycle of PANC-1 and AsPC-1 cancer cell lines. Incubation with the tested compounds resulted in the cellular redox imbalance triggering the repair systems and influenced the changing of protein levels