Inclusion-dependent mechanism of modification of cyclodextrins with heterocycles

Mono(6-deoxy-dimethylpyridinium)- -cyclodextrins have been synthesized in reaction of mono (p-toluenesulfonyl) derivative of –cyclodextrin with the appropriate lutidine under microwave irradiation and conventional conditions. The results indicate that the mechanism consists of inclusion complex formation

The Landscape of the Anti-Kinase Activity of the IDH1 Inhibitors

Isocitrate dehydrogenases constitute a class of enzymes that are crucial for cellular metabolism. The overexpression or mutation of isocitrate dehydrogenases are often found in leukemias, glioblastomas, lung cancers, and ductal pancreatic cancer among others. Mutation R132H, which changes the functionality of an enzyme to produce mutagenic 2-hydroxyglutarate instead of a normal product, is particularly important in this field. A series of inhibitors were described for these enzymes of which ivosidenib was the first to be approved for treating leukemia and bile duct cancers in 2018. Here, we investigated the polypharmacological landscape of the activity for known sulfamoyl derivatives that are inhibitors, which are selective towards IDH1 R132H. These compounds appeared to be effective inhibitors of several non-receptor kinases at a similar level as imatinib and axitinib. The antiproliferative activity of these compounds against a panel of cancer cells was tested and is explained based on the relative expression levels of the investigated proteins. The multitargeted activity of these compounds makes them valuable agents against a wide range of cancers, regardless of the status of IDH1

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

Blocking and dislocation of Candida albicans Cdr1p transporter bystyrylquinolines

Styrylquinolines are a novel group of quinoline drugs that are known to have p53-independent antiproliferative activity and antiviral properties. This study evaluated the antifungal activity of these drugs more deeply, particularly their activity modulation towards Cdr1p, the main multidrug transporter of Candida albicans. Styrylquinolines were found to have antifungal activity and to work synergistically with fluconazole. Additionally, they decreased the extracellular concentration of rhodamine 6G in ABC-transporter-expressing cells. The cellular localization of GFP-tagged Cdr1p was assessed by epifluorescent microscopy. Styrylquinolines induce expression of Cdr1p, as confirmed by Western blotting. Three of four drugs tested caused the partial delocalization of transport protein to the cytoplasm. These results show the first evidence that styrylquinolines decrease the activity of ABC multidrug transporters in C. albicans

Interactions between modified fullerenes and proteins in cancer nanotechnology

Fullerenes have numerous properties that fill the gap between small molecules and nanomaterials. Several types of chemical reaction allow their surface to be ornamented with functional groups designed to change them into ‘ideal’ nanodelivery systems. Improved stability, and bioavailability are important, but chemical modifications can render them practically soluble in water. ‘Buckyball’ fullerene scaffolds can interact with many biological targets and inhibit several proteins essential for tumorigeneses. Herein, we focus on the inhibitory properties of fullerene nanomaterials against essential proteins in cancer nanotechnology, as well as the use of dedicated proteins to improve the bioavailability of these promising nanomaterials

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

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

Antifungal styryloquinolines as Candida albicans efflux pump inhibitors : styryloquinolines are ABC transporter inhibitors

Styrylquinolines are heterocyclic compounds that are known for their antifungal and antimicrobial activity. Metal complexation through hydroxyl groups has been claimed to be a plausible mechanism of action for these types of compounds. A series of novel structures with protected hydroxyl groups have been designed and synthesized to verify the literature data. Their antifungal activity against wild-type Candida albicans strain and mutants with silenced efflux pumps activity has been determined. Combinations with fluconazole revealed synergistic interactions that were dependent on the substitution pattern. These results open a new route for designing active antifungal agents on a styrylquinoline scaffold

Electrolytic copper as cheap and effective catalyst for one-pot triazole synthesis

Electrolytic copper is a well-known form of pure, oxygen free copper that is used for industrial applications. In this work, the catalytic potential of this relatively cheap material was studied. The addition of less than 0.015 mol equivalent of copper powder effectively catalysed the one-pot synthesis of triazoles from a diverse range of organic halides and alkynes. Quantitative conversions in aqueous solvents can be achieved within minutes. The heterogenous nature of the catalyst afforded a low level of copper contamination in the products, thus meeting the rigorous criteria of the pharmaceutical industry

A [60]fullerene nanoconjugate with gemcitabine : synthesis, biophysical properties and biological evaluation for treating pancreatic cancer

Background:The first‑line chemotherapy drug that is used to treat pancreatic ductal adenocarcinoma is gemcitabine. Unfortunately, its effectiveness is hampered by its chemo‑resistance, low vascularization and drug biodistribution limitations in the tumor microenvironment. Novel nanotherapeutics must be developed in order to improve the prognosis for patients with pancreatic cancer.Results:We developed a synthetic methodology for obtaining a water‑soluble nano‑conjugate of a [60]fullerene‑glycine derivative with the FDA‑approved drug gemcit‑abine (nanoC60GEM). The proposed synthetic protocol enables a highly water‑soluble [60]fullerene‑glycine derivative (6) to be obtained, which was next successfully conju‑gated with gemcitabine using the EDCI/NHS carbodiimide protocol. The desired nano‑conjugate was characterized using mass spectrometry and DLS, IR and XPS techniques. The photogeneration of singlet oxygen and the superoxide anion radical were studied by measuring 1O2 near‑infrared luminescence at 1270 nm, followed by spin trapping of the DMPO adducts by EPR spectroscopy. The biological assays that were performed indicate that there is an inhibition of the cell cycle in the S phase and the induction of apoptosis by nanoC60GEM.Conclusion:In this paper, we present a robust approach for synthesizing a highly water‑soluble [60]fullerene nanoconjugate with gemcitabine. The performed biological assays on pancreatic cancer cell lines demonstrated cytotoxic effects of nanoC60GEM, which were enhanced by the generation of reactive oxygen species after blue LED irradiation of synthesized fullerene nanomaterial