Search Results (51)

This study investigates the cytotoxic properties of metal complexes incorporating thio-uracil derivatives, specifically 2,4-dithiouracil and 6-propyl-2-thiouracil. The research focuses on the cytotoxic effects of Cu(II) and Pd(II) complexes with 6-propyl-2-thiouracil, as well as mixed-ligand transition metal Cu(II) and Au(III) complexes of 2,4-dithiouracil with 2-thiouracil and uracil. Cytotoxic activity was assessed against human cervical carcinoma cells (HeLa) and normal kidney cells from the African green monkey. The results demonstrated that incorporating Cu(II) and Au(III) into the compound structures significantly enhanced their cytotoxic effects. Notably, all tested complexes exhibited a stronger inhibitory effect on cancer cell proliferation compared to normal cells, with the palladium(II) complex of 6-propyl-2-thiouracil showing the lowest CD₅₀ value against the tumor cell line (0.00064 mM), which were 149 times lower than that of the ligand (0.0955 mM). These findings suggest that thio-uracil-based metal complexes, particularly those containing palladium (II) and gold(III), hold significant potential for further development as anticancer agents. Full article

The synthesis of various heterocyclic base modifications of nucleic acids has been thoroughly investigated; however, much less is known about their catabolism. Also, little is known about the transport of such compounds across the microbial cell membranes. Using the Saccharomyces cerevisiae single-gene deletion library, we performed genome-wide screening for genes affecting the growth of yeast in minimal media supplemented with N⁴-acetylcytosine as a source of uracil. We found that Fcy1, Fcy21, Bud16, Gnd1, and Fur4 proteins are required for efficient growth in the tested medium. Additionally, we used several heterocyclic pyrimidine bases and Fcy homolog mutants to test their growth in respective minimal media. We found that tested permeases differently affect the growth of yeast that is dependent on the heterocyclic pyrimidine bases used as a source of uracil. The most pronounced effect was observed for the ∆fur4 mutant, which was growing much slower than the corresponding wild-type strain in the media supplemented with N⁴-acetylcytosine, 4-methylthiouracil, N⁴-methylcytosine, N⁴,N⁴-dimethylcytosine, 2-thiouracil, or 4-thiouracil. We suggest that Fur4 protein is the major yeast transporter of modified heterocyclic pyrimidine bases. Our observations might be helpful when investigating the actions of various heterocyclic base-based antifungal, anticancer, and antiviral drugs. Full article

Houttuynia cordata Thunb. holds a longstanding reputation as a traditional folk remedy in East Asia, where it has been employed to treat a variety of inflammatory conditions, nephritis, hepatitis and cancer. Despite its extensive use, there exists a paucity of research examining its efficacy in managing thyroid disorders and diabetes. Moreover, the bioactive components responsible for modulating the molecular pathways remain elusive. Objectives: This research aimed to determine the key bioactive components in the ethanolic extract of H. cordata Thunb. (HCEE) responsible for its thyroid-modifying properties and examine its effects on rats with experimentally induced hypothyroidism and diabetes. Methods: Molecular docking was performed to investigate the possible mechanisms of thyroid regulation of HCEE constituents. Researchers induced hypothyroidism in rats by adding 6-propyl-2-thiouracil to their drinking water for a period of four weeks. To induce diabetes, the rats received an intraperitoneal injection of streptozotocin. The animals were then given daily oral doses of HCEE (500 mg/kg b.w.), levothyroxine (50 mg/kg b.w.), or glibenclamide (5 mg/kg b.w.) for 28 days. Following this treatment, standard methods were employed to measure biochemical parameters in the rats’ serum. Results: The results demonstrate that HCEE ameliorated hypothyroidism by increasing serum T3 (14.38%) and T4 (125.96%) levels and decreasing TSH (p < 0.01; −41.75%) levels. In diabetic rats with induced hypothyroidism, HCEE significantly (p < 0.001) increased T3 (149.51%) and T4 (73.54%) levels with reduced TSH (−64.39%) levels. In silico analysis demonstrated that the identified bioactive compounds from HCEE may enhance thyroid hormone function through interaction with the thyroid hormone receptor protein TRβ1 (PDB:3GWS), similar to the conventional pharmaceuticals levothyroxine and triiodothyronine (T3). Conclusions: HCEE exhibits potential as a natural alternative to synthetic medications in the prevention and treatment of thyroid dysfunctions. Full article

This study explores the formation and properties of new complexes involving gallium(III) and thiouracil derivatives—2-thiouracil (TU), 6-methyl-2-thiouracil (MTU), 6-propyl-2-thiouracil (PTU), 5-carboxy-2-thiouracil (CTU), and 6-methoxymethyl-2-thiouracil (MMTU). Conducted in aqueous solutions at relatively low concentrations, this research enabled the formation of soluble complexes, identified and described here for the first time. The influence of metal-to-ligand ratios on species distribution and their fluorescence properties was examined through potentiometric titration, alongside visible and fluorescence spectroscopy. Stability constants were determined, revealing that coordination mode and complex stability are pH-dependent, and nitrogen, sulfur, and oxygen atoms are involved in higher pH coordination. Additionally, the structure of the ligand 6-methoxymethyl-2-thiouracil was characterized. The findings suggest that these complexes hold potential for future biomedical applications, particularly as antibacterial and anticancer agents, warranting further studies under physiological conditions. Full article

Τhyreostats (TSs) are veterinary drugs used in livestock farming for fattening. Their administration is banned in the European Union since 1981, and their monitoring for food quality and safety control requires sensitive and confirmatory methods. The present study describes the development and validation of a hydrophilic interaction liquid chromatography tandem mass spectrometry (HILIC-MS/MS) method for the simultaneous determination of 2-thiouracil (TU), 6-methyl-2-thiouracil (MTU), 6-propyl-2-thiouracil (PTU), 6-phenyl-2-thiouracil (PhTU), tapazole (TAP), and 2-mercaptobenzimidazole (MBI) in bovine muscle tissues. Investigation of the retention mechanism of the six analytes on the selected amide-based stationary phase showed that hydrophilic partition was the dominant interaction. The sample preparation included extraction with ACN/H₂O (80/20), followed by dispersive solid-phase extraction (d-SPE) with C18 sorbent and hexane partitioning. The method was validated according to European guidelines using internal standards, including isotopically labelled ones. The method’s LODs ranged between 2.8 ng g⁻¹ (6-phenyl-2-thiouracil) and 4.1 ng g⁻¹ (2-thiouracil). Application of the proposed method to 48 bovine tissue samples showed non-detectable results. Full article

This article describes the synthesis of a new metal complex using 6-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one. The compound was analyzed using several methods, including determining its melting point and employing UV-Vis, IR, ATR, ¹H NMR, HSQC, and Raman spectroscopy for the free ligand. The metal complex was formed by combining aqueous solutions of metal salts with the ligand dissolved in DMSO and water, along with NaOH in a metal-to-ligand-to-base ratio of 1:4:2. The NMR signals of the ligand were assigned using ¹H-¹H COSY, DEPT-135, HMBC, and HMQC spectra. Furthermore, the compound’s antimicrobial activity against Gram-positive and Gram-negative bacteria, as well as yeasts, was assessed. Full article

The thionamide antithyroid agents were discovered largely through observations carried out by various researchers in the 1940s that found that sulfhydryl-containing substances were goitrogenic in animals. Prof. Edwin B. Astwood started using these drugs to treat hyperthyroidism. In the current paper, we summarize the development background of these agents and the coordination possibility of 2-thiouracil and its derivatives, as well as the biological activities of some of its complexes. Some of them are used as agents for the treatment of tuberculosis, and arthritis, others have bactericidal and fungicidal activity, the third cytotoxic properties, and could be used to treat various types of cancer. Full article

Hypothyroidism compromises the testicular redox status and is associated with reduced sperm quality and infertility in men. In this regard, studies have demonstrated the antioxidant potential of kisspeptin in reproductive and metabolic diseases. In this study, we evaluate the effects of kisspeptin-10 (Kp10) on the testicular redox, as well as mediators of the unfolded protein response (UPR) in adult rats with hypothyroidism. Adult male Wistar rats were randomly separated into the Control (n = 15), Hypo (n = 13) and Hypo + Kp10 (n = 14) groups, and hypothyroidism was induced with 6-propyl-2-thiouracil (PTU) for three months. In the last month, half of the hypothyroid animals received Kp10. Testis samples were collected for enzymatic, immunohistochemical and/or gene evaluation of mediators of oxidative stress (TBARs, lipid hydroperoxides (LOOH), ROS, peroxynitrite, SOD, CAT and GPX), endoplasmic reticulum stress (GRP78, ATF6, PERK, CHOP, HO-1 and sXBP1) and antiapoptocytes (BCL-2). Hypothyroidism increased apoptosis index, TBARS and LOOH concentrations, and reduced testicular gene expression of Sod1, Sod2 and Gpx1, as well as the expression of Grp78, Atf6, Ho1 and Chop. Treatment with Kp10, in turn, reduced testicular apoptosis and the production of peroxynitrite, while increased SOD1 and GPX ½ expression, and enzymatic activity of CAT, but did not affect the lower expression of UPR mediators caused by hypothyroidism. This study demonstrated that hypothyroidism causes oxidative stress and dysregulated the UPR pathway in rat testes and that, although Kp10 does not influence the low expression of UPR mediators, it improves the testicular redox status, configuring it as an important antioxidant factor in situations of thyroid dysfunction. Full article

This study demonstrated the capability of two readily available optical spectroscopy tools, namely UV-Vis absorption spectrophotometry and Raman/surface-enhanced Raman spectroscopy, to select in a rapid and noninvasive manner the most homogenous gold nanoparticle (AuNP) models and to identify their chemical binding mechanism to 2-thiouracil (2-TU). 2-TU is an anticancer drug of great promise in the antiproliferative and photothermal therapies of cancer. The citrate-capped AuNPs emerged as the most stable as well as time- and cost-effective AuNP model out of the three widely used colloidal nanocores (citrate-, borohydride-citrate-, and sodium dodecyl sulfate (SDS)-capped AuNPs) that were examined. 2-TU chemically attached to the relatively monodispersed AuNPs via a chemisorption mechanism. The 2-TU-AuNPs complex formed through the covalent bonding of the S atom of 2-TU to the nanosurface in a vertical orientation. The spectroscopic results were then confirmed with the help of density functional theory (DFT) calculations and other physicochemical characterization tools for nanomaterials such as transmission electron microscopy (TEM), dynamic light scattering (DLS), and zeta potential. Overall, the purified 2-TU-AuNPs were found to be spherical, had an average diameter of 25 ± 2 nm, a narrow size distribution (1–30 nm), a sharp localized surface plasmon resonance (LSPR) peak at 525 nm, and a negative surface charge (−14 mV). Full article

The aim of the present study is to synthesize new metal complexes of 6-methyl-2-thiouracil and 6-propyl-2-thiouracil, elucidate their structures, and investigate their biological properties. All metal complexes were obtained after mixing water solutions of the corresponding metal salts and the ligand dissolved in DMSO and water solutions of NaOH in a metal-to-ligand ratio of 1:4:2. The structures of the new compounds are discussed based on melting point analysis (MP-AES) for Cu and Pd, UV-Vis, IR, ATR, ¹H NMR, ¹³C NMR, and Raman spectroscopy. The interpretation of complex spectra is assisted by the data for 6-methyl-2-thiouracil and 6-propyl-2-thiouracil obtained from ¹H-¹H COSY, DEPT-135, HMBC and HMQC spectra. In addition, the antimicrobial activity of these complexes and the free ligands are assessed against both Gram-positive and Gram-negative bacteria, as well as yeasts. In general, the addition of metal ions improved the antimicrobial activity of both 6-methyl-2-thiouracil and 6-propyl-2-thiouracil. The Cu(II) complex with 6-methyl-2-thiouracil and the Pd(II) complex with 6-propyl-2-thiouracil exhibited the highest activity against the test microorganisms. Full article

Histone deacetylases (HDACs) are an attractive drug target for the treatment of human breast cancer (BC), and therefore, HDAC inhibitors (HDACis) are being used in preclinical and clinical studies. The need to understand the scope of the mode of action of HDACis, as well as the report of the co-crystal structure of HDAC6/SS-208 at the catalytic site, provoked us to develop an isoxazole-based lead structure called 4-(2-(((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)thio) pyrimidin-4-yl) morpholine (5h) and 1-(2-(((3-(p-tolyl) isoxazol-5-yl)methyl)thio) pyrimidin-4-yl) piperidin-4-one (6l) that targets HDACs in human BC cells. We found that the compound 5h or 6l could inhibit the proliferation of BC cells with an IC₅₀ value of 8.754 and 11.71 µM, respectively. Our detailed in silico analysis showed that 5h or 6l compounds could target HDAC in MCF-7 cells. In conclusion, we identified a new structure bearing triazole, isoxazole, and thiouracil moiety, which could target HDAC in MCF-7 cells and serve as a base to make new drugs against cancer. Full article

Background: Histone deacetylase inhibitors (HDACIs) are a relatively new class of potential drugs for treating cancer. Aim: Discovery of new anticancer agents targeting HDAC. Methods: New uracil and thiouracil derivatives panels were designed and synthesized as HDAC inhibitors. The synthesized compounds were tested against MCF-7, HepG2, and HCT-116. HDAC1 and HDAC4 inhibitory activities of these compounds were tested. The most active member was tested for its potential against cell cycle, apoptosis, caspase-3, and caspase-8. Docking studies were carried out against HDAC1. Results: Compounds 5a, 5b, 5f, 5i, 5k, and 5m exhibited promising cytotoxic activities. HDAC1 and HDAC4 inhibitory activities of these compounds were tested. Regarding the HDAC1 inhibitory activity, compound 5m was the most potent member (IC₅₀ = 0.05 µg/mL) compared to trichostatin A (IC₅₀ = 0.0349 µg/mL). For HDAC4, compound 5m showed superior activity (IC₅₀ = 2.83 µg/mL) than trichostatin A (IC₅₀ = 3.349 µg/mL). Compound 5m showed a high potential to arrest the HCT116 cell cycle at the G0-G1 phase. In addition, it showed an almost 17 times apoptotic effect (37.59%) compared to the control cells (2.17%). Furthermore, Compound 5m showed significant increases in the levels of caspase-3 and caspase-8. Finally, the uracil and thiouracil derivatives showed accepted binding mods against HDAC. Conclusions: Compound 5m has potential anticancer activity targeting HDAC with a significant apoptotic effect. Full article

Nanoparticles have been used to transport drugs to various body parts to treat cancer. Our interest is in gold nanoparticles (AuNPs) since they have the capacity to absorb light and convert it to heat, inducing cellular damage. This property is known as photothermal therapy (PTT) and has been studied in cancer treatment. In the present study, biocompatible citrate-reduced AuNPs were functionalized with a biologically active compound, 2-thiouracil (2-TU), of potential anticancer activity. Both the unfunctionalized (AuNPs) and functionalized (2-TU-AuNPs) were purified and characterized by UV–Vis absorption spectrophotometry, Zeta potential, and Transmission Electron Microscopy. Results showed monodispersed, spherical AuNPs with a mean core diameter of 20 ± 2 nm, a surface charge of −38 ± 5 mV, and a localized surface plasmon resonance peak at 520 nm. As a result of functionalization, the mean core diameter of 2-TU-AuNPs increased to 24 ± 4 nm, and the surface charge increased to −14 ± 1 mV. The functionalization of AuNPs and the load efficiency were further established through Raman spectroscopy and UV–Vis absorption spectrophotometry. The antiproliferative activities of AuNPs, 2-TU and 2-TU-AuNPs were examined by a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay in the MDA-MB-231 breast cancer cell line. It was established that AuNPs significantly enhanced the antiproliferative activity of 2-TU. Furthermore, the irradiation of the samples with visible light at 520 nm decreased the half-maximal inhibitory concentration by a factor of 2. Thus, the 2-TU drug concentration and its side effect during treatments could be significantly reduced by synergistically exploiting the antiproliferative activity of 2-TU loaded onto AuNPs and the PTT effect of AuNPs. Full article

When modified uridine derivatives are incorporated into DNA, radical species may form that cause DNA damage. This category of molecules has been proposed as radiosensitizers and is currently being researched. Here, we study electron attachment to 5-bromo-4-thiouracil (BrSU), a uracil derivative, and 5-bromo-4-thio-2′-deoxyuridine (BrSdU), with an attached deoxyribose moiety via the N-glycosidic (N1-C) bond. Quadrupole mass spectrometry was used to detect the anionic products of dissociative electron attachment (DEA), and the experimental results were supported by quantum chemical calculations performed at the M062X/aug-cc-pVTZ level of theory. Experimentally, we found that BrSU predominantly captures low-energy electrons with kinetic energies near 0 eV, though the abundance of bromine anions was rather low compared to a similar experiment with bromouracil. We suggest that, for this reaction channel, proton-transfer reactions in the transient negative ions limit the release of bromine anions. Full article

In this work, we investigate the relaxation processes of 2-thiouracil after UV photoexcitation to the S₂ state through the use of ultrafast, single-colour, pump-probe UV/UV spectroscopy. We place focus on investigating the appearance and subsequent decay signals of ionized fragments. We complement this with VUV-induced dissociative photoionisation studies collected at a synchrotron, allowing us to better understand and assign the ionisation channels involved in the appearance of the fragments. We find that all fragments appear when single photons with energy > 11 eV are used in the VUV experiments and hence appear through 3+ photon-order processes when 266 nm light is used. We also observe three major decays for the fragment ions: a sub-autocorrelation decay (i.e., sub-370 fs), a secondary ultrafast decay on the order of 300–400 fs, and a long decay on the order of 220 to 400 ps (all fragment dependent). These decays agree well with the previously established S₂ → S₁ → Triplet → Ground decay process. Results from the VUV study also suggest that some of the fragments may be created by dynamics occurring in the excited cationic state. Full article