Search Results (48)

Epigenetics garnered significant scientific interest in recent decades, with histone acetylation emerging as the most prevalent epigenetic deregulation process observed in malignancies. The clinical application of histone deacetylase (HDAC) inhibitors faced challenges, including complex therapeutic mechanisms and inconsistent treatment outcomes. In Acute Lymphoblastic Leukemia (ALL), the dysregulation of HDAC activity presents a promising therapeutic target. To investigate cellular-level tumor suppression by HDAC inhibitors possessing potent target engagement, we developed two novel azetidine-hydroxamic acid conjugates. Compared to N-hydroxy-4-((quinolin-4-ylamino)methyl)benzamide (NBU-1), N-hydroxy-6-((5-methyl-4-nitro-9-oxo-9,10-dihydroacridin-1-yl)amino)hexanamide (NBU-2) demonstrated enhanced inhibitory activity against HDAC1 (class I) and HDAC6 (class II) with IC₅₀ values of 7.75 nM and 7.34 nM, respectively, consistent with binding mode analysis and docking energy calculations. In vitro evaluation across 12 tumor cell lines revealed NBU-2’s potent antiproliferative effects, particularly against the ALL-derived Jurkat cells (IC₅₀ = 0.86 μM). Subsequent mechanistic studies were therefore conducted in this ALL model. Proteomic profiling indicated its potential involvement in modulating AKT signaling and histone modification pathways in Jurkat cells. Mechanistic investigations demonstrated that NBU-2 elevated histone acetylation while suppressing AKT phosphorylation. This compound altered apoptotic regulators by downregulating Bcl-2 and Bcl-XL expression while upregulating BAX, ultimately activating Caspase-9 and Caspase-3 to induce apoptosis. Cell cycle analysis revealed NBU-2-mediated G0/G1 arrest through reduced expression of Cyclin D1 and CDK4, diminished Rb protein phosphorylation, and increased p21 expression. These findings propose a strategic framework for developing next-generation HDAC inhibitors for ALL treatment and elucidating their mechanism-specific anti-cancer actions. Full article

Previously, we have described a successful molecular switch (8-(benzo[d]thiazol-2-yl)quinolin-7-ol), working on the basis of long-range proton transfer. Bearing in mind that its switching efficiency in low-polarity aprotic solvents is not sufficient, in the current communication, we investigate in detail the effect of the substitution in the benzothiazole ring. By using the DFT approach, the ground-state stability of the tautomeric forms, involved in the switching process, is modeled with the aim of finding conditions where clean switching could be possible in variety of aprotic solvents. The results indicate that the substitution with electron-acceptor substituents could increase the switching efficiency, but the overall improvement depends on the positions and electronic effect of the particular substituent. Full article

Long-range proton transfer in several conjugated proton cranes, originating from 7-hydroxy quinoline as a proton transfer platform, has been investigated theoretically by means of DFT and TD-DFT methodology. Major emphasis was given to their applicability to provide clean switching upon irradiation. The border conditions require the existence of a single enol tautomer in the ground state, which under excitation through a series of consecutive exited and ground state intramolecular proton transfer steps is transferred to the keto tautomer. It was shown that the most suitable candidates are based on using iso-quinoline, pyrimidine and 4-nitropyridine as proton crane units. Their suitability is a function of aromaticity changes, the basicity of the nitrogen atom from the proton crane unit and the structural effects originating from their conjugation with 7-hydroxy quinoline. Full article

A series of new unique acetylene derivatives of 8-hydroxy- and 8-methoxyquinoline- 5-sulfonamide 3a–f and 6a–f were prepared by reactions of 8-hydroxy- and 8-methoxyquinoline- 5-sulfonyl chlorides with acetylene derivatives of amine. A series of new hybrid systems containing quinoline and 1,2,3-triazole systems 7a–h were obtained by reactions of acetylene derivatives of quinoline-5-sulfonamide 6a–d with organic azides. The structures of the obtained compounds were confirmed by ¹H and ¹³C NMR spectroscopy and HR-MS spectrometry. The obtained quinoline derivatives 3a–f and 6a–f and 1,2,3-triazole derivatives 7a–h were tested for their anticancer and antimicrobial activity. Human amelanotic melanoma cells (C-32), human breast adenocarcinoma cells (MDA-MB-231), and human lung adenocarcinoma cells (A549) were selected as tested cancer lines, while cytotoxicity was investigated on normal human dermal fibroblasts (HFF-1). All the compounds were also tested against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 and representatives of multidrug-resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis. Only the acetylene derivatives of 8-hydroxyquinoline-5-sulfonamide 3a–f were shown to be biologically active, and 8-hydroxy-N-methyl-N-(prop-2-yn-1-yl)quinoline-5-sulfonamide (3c) showed the highest activity against all three cancer lines and MRSA isolates. Its efficacies were comparable to those of cisplatin/doxorubicin and oxacillin/ciprofloxacin. In the non-cancer HFF-1 line, the compound showed no toxicity up to an IC₅₀ of 100 µM. In additional tests, compound 3c decreased the expression of H3, increased the transcriptional activity of cell cycle regulators (P53 and P21 proteins), and altered the expression of BCL-2 and BAX genes in all cancer lines. The unsubstituted phenolic group at position 8 of the quinoline is the key structural fragment necessary for biological activity. Full article

Human exposure to PM2.5 and PM10 has been linked to respiratory and cardiovascular diseases through inflammation activation. The kynurenine pathway is associated with inflammation, and it is necessary to investigate the effects of long-term PM2.5 and PM10 exposure on this pathway. This study aimed to conduct a cross-sectional analysis of long-term PM2.5 and PM10 exposure’s impact on the kynurenine pathway using proton NMR spectroscopy (¹H-NMR). The participants were divided into a low-PM-exposure group (LG; n = 98), and a high-PM-exposure group (HG; n = 92). The metabolites of tryptophan were determined in blood by ¹H-NMR. Serotonin, cinnabarinic acid, xanthurenic acid, 5-hydroxytryptophan, indoleacetic acid, tryptamine, melatonin, L-tryptophan, 5-hydroxy-L-tryptophol, indoxyl, 2-aminobenzoic acid, 5-HTOL, hydroxykynurenine, L-3-hydroxykynurenine, N-formyl kynurenine, 3-hydroxy anthranilic acid, kynurenic acid, and picolinic acid significantly increased (p < 0.05) in the HG group. Conversely, NAD and quinolinic acid significantly decreased in the HG group compared to the LG group. The enzyme activities of indoleamine 2,3-dioxygenase and formamidase significantly decreased, while kynureninase and kynurenine monooxygenase significantly increased. The kynurenine pathway is linked to inflammation and non-communicable diseases. Disruption of the kynurenine pathway from particulate matter might promote diseases. Reducing exposure to the particulate matter is crucial for preventing adverse health effects. Full article

Kynurenic acid (KYNA) is an antioxidant degradation product of tryptophan that has been shown to have a variety of cytoprotective, neuroprotective and neuronal signalling properties. However, mammalian transporters and receptors display micromolar binding constants; these are consistent with its typically micromolar tissue concentrations but far above its serum/plasma concentration (normally tens of nanomolar), suggesting large gaps in our knowledge of its transport and mechanisms of action, in that the main influx transporters characterized to date are equilibrative, not concentrative. In addition, it is a substrate of a known anion efflux pump (ABCC4), whose in vivo activity is largely unknown. Exogeneous addition of L-tryptophan or L-kynurenine leads to the production of KYNA but also to that of many other co-metabolites (including some such as 3-hydroxy-L-kynurenine and quinolinic acid that may be toxic). With the exception of chestnut honey, KYNA exists at relatively low levels in natural foodstuffs. However, its bioavailability is reasonable, and as the terminal element of an irreversible reaction of most tryptophan degradation pathways, it might be added exogenously without disturbing upstream metabolism significantly. Many examples, which we review, show that it has valuable bioactivity. Given the above, we review its potential utility as a nutraceutical, finding it significantly worthy of further study and development. Full article

A novel quinophthalone derivative, 4,5,6,7-tetrachloro-2-(2-(3-hydroxy-1-oxo-1H-cyclopenta[b]naphthalen-2-yl)quinolin-4-yl)isoindoline-1,3-dione (TCHCQ), was designed and synthesized as a yellow colorant additive for green color filters in image sensors. The characteristics of the new material were evaluated in terms of optical, thermal, and chemical properties under solution and color filter film conditions. TCHCQ exhibited a significantly enhanced molar extinction coefficient in solution, being 1.21 times higher than that of the commercially used yellow colorant Y138. It also demonstrated excellent thermal stability, with a decomposition temperature (T_d) exceeding 450 °C. Utilizing the nano-pigmentation process, TCHCQ was used to prepare nano-sized particles with an excellent average size of 35 nm. This enabled the fabrication of a color filter film with outstanding properties. The optical properties of the produced film revealed outstanding yellow colorant transmittance of 0.97% at 435 nm and 91.2% at 530 nm. The color filter film exhibited similar optical and thermal stability to Y138, with an improved chemical stability, as evidenced by a ΔE_ab value of 0.52. The newly synthesized TCHCQ is considered a promising candidate for use as a yellow colorant additive in image sensor color filters, demonstrating superior optical, thermal, and chemical stability. Full article

New amide conjugates of hydroxycinnamic acids (HCAs) and the known antineoplastic 5,11-dimethyl-5H-indolo[2,3-b]quinoline (DiMIQ), an analog of the natural alkaloid neocryptolepine, were synthesized and tested in vitro for anticancer activity. The compound 9-[((2-hydroxy)cinnamoyl)amino]-5,11-dimethyl-5H-indolo[2,3-b]quinoline (2), which contains the ortho-coumaric acid fragment, demonstrated dose-dependent effectiveness against both normal BxPC-3 and metastatic AsPC-1 pancreatic cancer cells. The IC₅₀ values for AsPC-1 and BxPC-3 were 336.5 nM and 347.5 nM, respectively, with a selectivity index of approximately 5 for both pancreatic cancer cells compared to normal dermal fibroblasts. Conjugate 2 did not exhibit any hemolytic activity against human erythrocytes at the tested concentration. Computational studies were performed to predict the pharmacokinetic profile and potential mechanism of action of the synthesized conjugates. These studies focused on the ADME properties of the conjugates and their interactions with DNA, as well as DNA–topoisomerase alpha and beta complexes. All of the conjugates studied showed approximately one order of magnitude stronger binding to DNA compared to the reference DiMIQ, and approximately two orders of magnitude stronger binding to the topoisomerase II–DNA complex compared to DiMIQ. Conjugate 2 was predicted to have the strongest binding to the enzyme–DNA complex, with a Ki value of 2.8 nM. Full article

A study was conducted to investigate the effects of different doses of 6-hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline (HTHQ) on motor coordination scores, brain tissue morphology, the expression of tyrosine hydroxylase, the severity of oxidative stress parameters, the levels of the p65 subunit of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) factor, and the inflammatory response in rats during the development of rotenone-induced Parkinsonism. The findings indicate that HTHQ, with its antioxidant attributes, reduced the levels of 8-isoprostane, lipid oxidation products, and protein oxidation products. The decrease in oxidative stress due to HTHQ led to a reduction in the mRNA content of proinflammatory cytokines and myeloperoxidase activity, accompanying the drop in the expression of the factor NF-κB. These alterations promoted an improvement in motor coordination scores and increased tyrosine hydroxylase levels, whereas histopathological changes in the brain tissue of the experimental animals were attenuated. HTHQ exhibited greater effectiveness than the comparative drug rasagiline based on the majority of variables. Full article

Neuropathic pain is a well-documented phenomenon in experimental and clinical diabetes; however, current treatment is unsatisfactory. Serotoninergic-containing neurons are key components of the descending autoinhibitory pathway, and a decrease in their activity may contribute at least in part to diabetic neuropathic pain (DNP). A streptozotocin (STZ)-treated rat was used as a model for type 1 diabetes mellitus (T1DM). Pain transmission was evaluated using well-established nociceptive-based techniques, including the Hargreaves apparatus, cold plate and dynamic plantar aesthesiometer. Using qRT-PCR, Western blotting, immunohistochemistry, and HPLC-based techniques, we also measured in the central nervous system and peripheral nervous system of diabetic animals the expression and localization of 5-HT1A receptors (5-HT1AR), levels of key enzymes involved in the synthesis and degradation of tryptophan and 5-HT, including tryptophan hydroxylase-2 (Tph-2), tryptophan 2,3-dioxygenase (Tdo), indoleamine 2,3-dioxygenase 1 (Ido1) and Ido2. Moreover, spinal concentrations of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA, a metabolite of 5-HT) and quinolinic acid (QA, a metabolite of tryptophan) were also quantified. Diabetic rats developed thermal hyperalgesia and cold/mechanical allodynia, and these behavioral abnormalities appear to be associated with the upregulation in the levels of expression of critical molecules related to the serotoninergic nervous system, including presynaptic 5-HT1AR and the enzymes Tph-2, Tdo, Ido1 and Ido2. Interestingly, the level of postsynaptic 5-HT1AR remains unaltered in STZ-induced T1DM. Chronic treatment of diabetic animals with 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT), a selective 5-HT1AR agonist, downregulated the upregulation of neuronal presynaptic 5-HT1AR, increased spinal release of 5-HT (↑ 5-HIAA/5-HT) and reduced the concentration of QA, decreased mRNA expression of Tdo, Ido1 and Ido2, arrested neuronal degeneration and ameliorated pain-related behavior as exemplified by thermal hyperalgesia and cold/mechanical allodynia. These data show that 8-OH-DPAT alleviates DNP and other components of the serotoninergic system, including the ratio of 5-HIAA/5-HT and 5-HT1AR, and could be a useful therapeutic agent for managing DNP. Full article

Among the pathogenic free-living amoebae (FLA), Naegleria fowleri is the etiological agent of a fatal disease known as primary amoebic meningoencephalitis (PAM). Once infection begins, the lesions generated in the central nervous system (CNS) result in the onset of symptoms leading to death in a short period of time. Currently, there is no standardized treatment against the infection, which, due to the high virulence of the parasite, results in a high case fatality rate (>97%). Therefore, it is essential to search for new therapeutic sources that can generate a rapid elimination of the parasite. In recent years, there have already been several successful examples of drug repurposing, such as Nitroxoline, for which, in addition to its known bioactive properties, anti-Balamuthia activity has recently been described. Following this approach, the anti-Naegleria activity of Nitroxoline was tested. Nitroxoline displayed low micromolar activity against two different strains of N. fowleri trophozoites (IC₅₀ values of 1.63 ± 0.37 µM and 1.17 ± 0.21 µM) and against cyst stages (IC₅₀ of 1.26 ± 0.42 μM). The potent anti-parasitic activity compared to the toxicity produced (selectivity index of 3.78 and 5.25, respectively) in murine macrophages and human cell lines (reported in previous studies), together with the induction of programmed cell death (PCD)-related events in N. fowleri make Nitroxoline a great candidate for an alternative PAM treatment. Full article

The isoelectronic relationship of 1,2-azaborinine (B=N structural motif) and benzene (C=C) is well documented. Upon deprotonation of the former, the anionic 1,2-azaboratabenzene is obtained, which is isosteric with pyridine (C=N) and has a similar capability as an aromatic N-donor. We present the complexation of boron and aluminum precursors with a κ²-N,O-donating 8-hydroxy-BN-naphthalene ligand (H₂(BQ), 1). Six chelate complexes with 1:1 and 2:1 stoichiometries were isolated and characterized by X-ray diffraction analysis and NMR spectroscopy. Comparing the isosteric dimethylaluminum complexes of H₂(BQ) and an 8-hydroxyquinoline (HQ’, 2) as a reference allowed us to quantify the influence of a formal substitution of carbon by boron on the structure and the electronic properties: While the structural parameters of the ligands were similar, the electropositive boron atom affected the electron density distributions within the complexes substantially. As the consequence, the Al–N bond was significantly shortened, and the aluminum atom showed a different coordination geometry than in the quinoline analog. Moreover, strong hypsochromic shifts of both the absorption and the emission were observed. The results highlight that the differences between CN and BN polyaromatic complexes are more distinct than between equally charged BN and CC congeners. Full article

Sustainable functionalization of renewable aromatics is a key step to supply our present needs for specialty chemicals and pursuing the transition to a circular, fossil-free economy. In the present work, three typically stable aromatic compounds, representative of products abundantly obtainable from biomass or recycling processes, were functionalized in one-pot oxidation reactions at room temperature, using H₂O₂ as a green oxidant and ethanol as a green solvent in the presence of a highly electron withdrawing iron porphyrin catalyst. The results show unusual initial epoxidation of the aromatic ring by the green catalytic system. The epoxides were isolated or evolved through rearrangement, ring opening by nucleophiles, and oxidation. Acridine was oxidized to mono- and di-oxides in the peripheral ring: 1:2-epoxy-1,2-dihydroacridine and anti-1:2,3:4-diepoxy-1,2,3,4-tetrahydroacridine, with TON of 285. o-Xylene was oxidized to 4-hydroxy-3,4-dimethylcyclohexa-2,5-dienone, an attractive building block for synthesis, and 3,4-dimethylphenol as an intermediate, with TON of 237. Quinoline was directly functionalized to 4-quinolone or 3-substituted-4-quinolones (3-ethoxy-4-quinolone or 3-hydroxy-4-quinolone) and corresponding hydroxy-tautomers, with TON of 61. Full article

The effects of two anticancer active copper(II) mixed-ligand complexes of the type [Cu(qui)(mphen)]Y·H₂O, where Hqui = 2-phenyl-3-hydroxy- 1H-quinolin-4-one, mphen = bathophenanthroline, and Y = NO₃ (complex 1) or BF₄ (complex 2) on the activities of different isoenzymes of cytochrome P450 (CYP) have been evaluated. The screening revealed significant inhibitory effects of the complexes on CYP3A4/5 (IC₅₀ values were 2.46 and 4.88 μM), CYP2C9 (IC₅₀ values were 16.34 and 37.25 μM), and CYP2C19 (IC₅₀ values were 61.21 and 77.07 μM). Further, the analysis of mechanisms of action uncovered a non-competitive type of inhibition for both the studied compounds. Consequent studies of pharmacokinetic properties proved good stability of both the complexes in phosphate buffer saline (>96% stability) and human plasma (>91% stability) after 2 h of incubation. Both compounds are moderately metabolised by human liver microsomes (<30% after 1 h of incubation), and over 90% of the complexes bind to plasma proteins. The obtained results showed the potential of complexes 1 and 2 to interact with major metabolic pathways of drugs and, as a consequence of this finding, their apparent incompatibility in combination therapy with most chemotherapeutic agents. Full article

Iodine deficiency impacts on the development of thyroid disease. Vegetables and fruits usually have a low iodine content; hence, it makes sense to increase their iodine content. Potato is consumed daily by millions of consumers and would, therefore, be a good target for biofortification with iodine programs. The aim of this study was to determine the effects of biofortification via the application of soil solutions of two iodoquinolines [8-hydroxy-7-iodo-5-quinolinic acid (8-OH-7-I-5QSA) and 5-chloro-7-iodo-8-quinoline (5-Cl-7-I-8-Q)] and KIO₃ (as an iodine positive control) on the iodine content and basic chemical composition, macro and micronutrient content, nitrogen compounds, vitamin C, and antioxidant potential of potato tubers Solanum tuberosum L. The biofortification process had no significant effect on the tuber weight in yield. The application of I in forms of KIO₃, 8-OH-7-I-5QSA, 5-Cl-7-I-8-Q resulted in an increase in the I content of tubers (1400.15; 693.65; 502.79, respectively, compared with control, 24.96 µg·kg⁻¹ d.w.). This also resulted in a decrease in elements that are harmful to consumers, such as: Al, Ni, Cr, Ag, Pb and Tl. The enrichment of tubers with 8-OH-7-I-5QSA and 5-Cl-7-I-8-Q resulted in a significant reduction in the content of ammonium ions (from 19.16 to 14.96; 13.52 mg∙kg⁻¹ f.w.) and chlorides (from 423.59 to 264.92; 265.31 mg∙kg⁻¹ f.w.). Biofortification with 8-OH-7-I-5QSA improved the polyphenolic profile of the potato tuber from 197.31 to 233.33 mg GAE·100 g⁻¹ f.w. A significant reduction in the carotenoid content of tubers after the enrichment of the plant with iodine in KIO₃, 8-OH-7-I-5QSA and 5-Cl-7-I-8-Q (from 3.46 to 2.96, 2.45, and 1.47 mg∙100 g⁻¹ d.w., respectively) was observed. It can be postulated that the production of potatoes enriched with iodoquinolines and/or KIO₃ is worthwhile, as it can provide a good source of I in the diet and simultaneously reduce the risk of developing deficiencies. Full article