Search Results (64)

Background/Objectives: The dual targeting of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) represents an effective approach for cancer treatment. The current study involved the design, synthesis, and biological evaluation of a new series of purine-containing hydrazones, 6–24 (a,b), as anticancer agents targeting EGFR and HER2 kinases. Methods: The proposed compounds were initially screened in silico using molecular docking to investigate their binding affinity to the active sites of EGFR and HER2 kinase domains. Subsequently, the compounds were synthesized and evaluated in vitro for their antiproliferative activity, using the MTT assay, against the various cancer cell lines A549, SKOV-3, A2780, and SKBR-3, with lapatinib as the reference drug. The most active derivatives were then examined to determine their inhibitory activity against EGFR and HER2 kinases. Results: Among the assessed compounds, significant antiproliferative activity was demonstrated by 19a, 16b, and 22b. 19a exhibited substantial anticancer efficacy against A549 and SKBR-3, with IC₅₀ values of 0.81 µM and 1.41 µM, respectively. This activity surpassed lapatinib, which has an IC₅₀ of 11.57 µM on A549 and 8.54 µM on SKBR-3 cells. Furthermore, 19a, 16b, and 22b exhibited superior EGFR inhibitory efficacy compared with lapatinib (IC₅₀ = 0.13 µM), with IC₅₀ values of 0.08, 0.06, and 0.07 µM, respectively. Regarding HER2, 22b demonstrated the greatest potency with an IC₅₀ of 0.03 µM, equipotent to lapatinib (IC₅₀ = 0.03 µM). Flow cytometry analysis of A549 cells treated with 19a and 22b indicated their ability to arrest the cell cycle during the G1 phase and to trigger cellular apoptosis. Conclusions: Compounds 19a, 16b, and 22b represent intriguing candidates for the development of an anticancer agent targeting EGFR and HER2 kinases. Full article

Chitosan and technical cashew nutshell liquid (CNSLt) have emerged as promising natural compounds due to their antimicrobial, immunomodulatory, and fermentation-modulating properties. This study aimed to evaluate the inclusion of chitosan and CNSLt as potential substitutes for the ionophore monensin on feed intake, ruminal fermentation, nitrogen balance, and microbial protein synthesis in steers. Five crossbred steers (Bos taurus), 18 months old with an average body weight of approximately 350 kg and fitted with permanent ruminal cannulas, were assigned to a 5 × 5 Latin square design. The experimental diets consisted of: (1) control (CON), (2) monensin (MON; 25 mg/kg of dry matter [DM]), (3) chitosan (CHI; ≥850 g/kg deacetylation degree, 375 mg/kg DM), (4) CNSLt (500 mg/kg DM), and (5) CNSLt + CHI (500 + 375 mg/kg DM). Supplementation with CHI or CNSLt + CHI reduced the intake of dry matter, crude protein, and neutral detergent fiber. Additionally, fecal excretion of whole corn kernels increased in these treatments. Ruminal fermentation parameters were affected, with the CNSLt + CHI treatment promoting higher molar proportions of propionate and acetate, along with reduced estimated methane emissions. However, purine derivatives, microbial protein synthesis, and nitrogen balance were not significantly affected by any of the treatments. These results suggest that CNSLt and CHI, particularly when combined, may serve as effective natural alternatives to monensin in high-grain diets for ruminants. Full article

Cancer is a leading cause of death globally, claiming millions of lives each year. Despite the availability of numerous anticancer drugs, the need for new treatment options remains essential. Many current therapies come with significant toxicity, lead to various side effects, or do not consistently deliver the expected therapeutic results. Purines and pyrimidines are fundamental building blocks of nucleic acids and play crucial roles in cellular metabolism and signaling. Recent advances in medicinal chemistry have led to the development and synthesis of various derivatives that exhibit selective cytotoxic effects against cancer cells while minimizing toxicity to healthy tissues. Purine and pyrimidine scaffolds, due to their well-established biological roles and structural versatility, have emerged as key pharmacophoric fragments in anticancer drug discovery. In recent years, the rational design of hybrid molecules incorporating these heterocycles has shown promise in overcoming drug resistance, improving target selectivity, and enhancing pharmacological profiles. Purine and pyrimidines scaffolds hold significant potential as foundations for novel antitumor drugs, with established representatives in cancer treatment, including 5-fluorouracil, cladribine, capecitabine, and several others. In addition, the article discusses the challenges and future developments of purine and pyrimidine derivatives and hybrid molecules as antitumor drugs and emphasizes the need for continued research to optimize their effectiveness and reduce side effects. Overall, the innovative use of these compounds represents a major advance in targeted cancer therapy and holds promise for improving the therapeutic efficacy of malignant diseases. Full article

Background/Objectives: While various nucleoside and nucleotide analogs have been approved as anticancer and antiviral drugs, their limitations, including low bioavailability and chemotherapeutic resistance, encourage the development of novel structures. In this context, and motivated by our previous findings on bioactive 3′-O-substituted xylofuranosyl nucleosides and 5-guanidine xylofuranose derivatives, we present herein the synthesis and biological evaluation of 5′-guanidino furanosyl nucleosides comprising 6-chloropurine and uracil moieties and a 3-O-benzyl xylofuranosyl unit. Methods: The synthetic methodology was based on the N-glycosylation of a 5-azido 3-O-benzyl xylofuranosyl acetate donor with the silylated nucleobase and a subsequent one-pot sequential two-step protocol involving Staudinger reduction of the thus-obtained 5-azido uracil and N⁷/N⁹-linked purine nucleosides followed by guanidinylation with N,N′-bis(tert-butoxycarbonyl)-N′′-triflylguanidine. The molecules were evaluated for their anticancer and anti-neurodegenerative diseases potential. Results: 5′-Guanidino 6-chloropurine nucleosides revealed dual anticancer and butyrylcholinesterase (BChE)-inhibitory effects. Both N⁹/N⁷-linked nucleosides exhibited mixed-type and selective submicromolar/micromolar BChE inhibiton. The N⁹ regioisomer was the best inhibitor (K_i/K_i′ = 0.89 μM/2.96 μM), while showing low cytotoxicity to FL83B hepatocytes and no cytotoxicity to human neuroblastoma cells (SH-SY5Y). Moreover, the N⁹-linked nucleoside exhibited selective cytotoxicity to prostate cancer cells (DU-145; IC₅₀ = 27.63 μM), while its N⁷ regioisomer was active against all cancer cells tested [DU-145, IC₅₀ = 24.48 μM; colorectal adenocarcinoma (HCT-15, IC₅₀ = 64.07 μM); and breast adenocarcinoma (MCF-7, IC₅₀ = 43.67 μM)]. In turn, the 5′-guanidino uracil nucleoside displayed selective cytotoxicity to HCT-15 cells (IC₅₀ = 76.02 μM) and also showed neuroprotective potential in a Parkinson’s disease SH-SY5Y cells’ damage model. The active molecules exhibited IC₅₀ values close to or lower than those of standard drugs, and comparable, or not significant, neuro- and hepatotoxicity. Conclusions: These findings demonstrate the interest of combining guanidine moieties with nucleoside frameworks towards the search for new therapeutic agents. Full article

Benzimidazoles are considered a promising class of bioactive heterocyclic compounds that show a wide variety of useful biological properties due to their structural similarities to nucleotides such as purines. Among these properties, great attention has been given to the antibacterial activity exhibited by molecules containing a benzimidazole nucleus in their structure since recent research results have shown the potential of such molecules as alternatives in the fight against bacterial resistance. When these compounds have phenylsubstituted groups in the 2-position of the imidazole ring, a series of molecules can be obtained with generally improved pharmacological activity. These types of compounds are suitable for the formation of stable complexes with several transition metals, including nickel and copper; such compounds have also exhibited many biological properties in different reports. Accordingly, this brief review focuses on recent work on the synthesis and characterization of metal complexes of Ni(II) and Cu(II) with ligands derived from 2-(phenylsubstituted) benzimidazole that were subsequently evaluated for antibacterial activity. Full article

Xanthomonas oryzae pv. oryzae (Xoo) is a biotrophic bacterial pathogen, which causes devastating bacterial blight disease worldwide. In this study, we thoroughly investigated the antimicrobial effect of the plant-derived extract chelerythrine against Xanthomonas oryzae pv. oryzae (Xoo) and elucidated its mechanism. Chelerythrine is a quaternary ammonium alkaloid with a 2,3,7,8-tetrasubstituted phenanthridine structure, extracted from plants, such as the whole plant of Chelidonium majus, and the roots, stems, and leaves of Macleaya cordata. We found that chelerythrine significantly inhibited the growth of Xoo at a concentration of 1.25 μg/mL. Further experiments revealed that chelerythrine interfered with the division and reproduction of the bacterium, leading to its filamentous growth. Additionally, it increased the permeability of Xoo cell membranes and effectively decreased the pathogenicity of Xoo, including the inhibition of extracellular polysaccharide production, cellulase secretion, and biofilm formation. Chelerythrine induced the accumulation of reactive oxygen species in the bacterium, triggering oxidative stress. The result showed that chelerythrine inhibited the formation of the Z-ring of Xoo, interfered with the synthesis of pyrimidine and purine nucleotides, inhibited DNA damage repair, and inhibited the formation of peptidoglycan and lipid-like A, thus interfering with cell membrane permeability, inhibiting carbohydrate metabolism and phosphorylation of sugars, reducing pathogenicity, and ultimately inhibiting bacterial growth and leading to the destruction or lysis of bacterial cells. Altogether, our results suggest that the antimicrobial effect of chelerythrine on Xoo exhibits multi-target properties. Additionally, its effective inhibitory concentration is low. These findings provide a crucial theoretical basis and guidance for the development of novel and efficient plant-derived antimicrobial compounds. Full article

Tetrahydrofolate (THF), the biologically active form of folate, serves as a crucial carrier of one-carbon units essential for synthesizing cellular components such as amino acids and purine nucleotides in vivo. It also acts as an important precursor for the production of pharmaceuticals, including folinate and L-5-methyltetrahydrofolate (L-5-MTHF). In this study, we developed an efficient enzyme cascade system for the production tetrahydrofolate from folate, incorporating NADPH recycling, and explored its application in the synthesis of L-5-MTHF, a derivative of tetrahydrofolate. To achieve this, we first screened dihydrofolate reductases (DHFRs) from various organisms, identifying SmDHFR from Serratia marcescens as the enzyme with the highest catalytic activity. We then conducted a comparative analysis of formate dehydrogenases (FDHs) from different sources, successfully establishing an NADPH recycling system. To further enhance biocatalytic efficiency, we optimized key reaction parameters, including temperature, pH, enzyme ratio, and substrate concentration. To address the challenge of pH mismatch in dual-enzyme reactions, we employed an enzymatic microenvironment regulation strategy. This involved covalently conjugating SmDHFR with a superfolder green fluorescent protein mutant carrying 30 surface negative charges (−30sfGFP), using the SpyCatcher/SpyTag system. This modification resulted in a 2.16-fold increase in tetrahydrofolate production, achieving a final yield of 4223.4 µM. Finally, we extended the application of this tetrahydrofolate synthesis system to establish an enzyme cascade for L-5-MTHF production with NADH recycling. By incorporating methylenetetrahydrofolate reductase (MTHFR), we successfully produced 389.8 μM of L-5-MTHF from folate and formaldehyde. This work provides a novel and efficient pathway for the biosynthesis of L-5-MTHF and highlights the potential of enzyme cascade systems in the production of tetrahydrofolate-derived compounds. Full article

The aim of this study was to synthesize new racemic and optically pure aryl-substituted purine bioisosteres using ultrasound-assisted Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition. Regioselective synthesis of α-azido alcohols was applied to afford heterocycles with a 2-hydroxyeth-1-yl linker. Catalytic asymmetric synthesis using halohydrin dehalogenase in the ring-opening of epoxides gave enantioenriched azido alcohols, which subsequently afforded R- and S-enantiomers of purine and pyrrolo[2,3-d]pyrimidines with a 1-hydroxyeth-2-yl linker. The newly synthesized compounds were evaluated in vitro for their antiproliferative activity against four malignant tumor cell lines. The influence of regioisomerism and the stereochemistry of the hydroxyethyl group, as well as a N-heterocyclic scaffold linked to the aryl moiety on cytostatic activity was evaluated. Of all the compounds tested, purine 40a and pyrrolo[2,3-d]pyrimidine 45a derivatives with p-trifluoromethyl-substituted aryl connected to 1,2,3-triazole via a 2-hydroxyeth-1-yl spacer showed promising submicromolar antiproliferative activity. In addition, compound 45a exhibited selectivity towards the tumor cell line, with a selectivity index (SI) of 40, moderate clearance, and good membrane permeability. Full article

Parkinson’s disease (PD) represents a growing challenge to global health, as it involves millions of people. The high grade of disability is due to the loss of dopaminergic neuron activity, and levodopa is the gold-standard therapy used to restore dopamine in the dopamine-denervated regions. Another therapeutic approach is the use of A_2A adenosine receptor antagonists and, among them, istradefylline is the only one currently approved for therapy in association with levodopa. In this work, we synthesized A_2A adenosine receptor antagonists represented by 9-ethyl-2,8-disubstituted adenine derivatives, which were tested at human adenosine receptors in binding and functional assays. These compounds showed A_2A adenosine receptor-binding affinities in the low nanomolar range and 1, 4, and 5 exhibited good potency in the functional assays. Hence, they were evaluated in in vivo rat models of PD, where they were demonstrated to revert haloperidol-induced catalepsy and potentiate levodopa-induced contralateral rotations in 6-hydroxydopamine-lesioned rats. The most potent derivative, 4, was then evaluated in the tacrine model, where it reduced the tremulous jaw movements, therefore demonstrating an action on parkinsonian tremor. These data revealed 8-ethoxy-2-phenethoxy-9-ethyladenine (4) as an A_2A adenosine receptor antagonist endowed with antiparkinsonian effects and as a good candidate to treat the disease. Full article

Methylxanthines are ubiquitous purine alkaloids in nature and have rich biological activities and functions. Today, the demand for methylxanthine is increasing but its production is low. This issue prevents its widespread use in many industrial fields, such as pharmaceuticals, food manufacturing, and chemical engineering. To address these issues, this review provides a comprehensive and systematic exploration of methylxanthines, delving into their biological structures, detailed biosynthetic pathways, and the latest research trends. These findings serve as valuable references for researchers, fostering advancements in the optimization of synthesis processes for methylxanthines and their derivatives and promoting their application across diverse industrial fields, such as medicine, food, and chemical engineering. By bridging fundamental research and practical applications, this work aims to advance the understanding of methylxanthine compounds, enhance their production efficiency, and contribute to healthcare and technological progress. Full article

Post-exertional malaise (PEM) is a defining condition of myalgic encephalomyelitis (ME/CFS). The concept requires that a provocation causes disabling limitation of cognitive and functional effort (“fatigue”) that does not respond to rest. Cerebrospinal fluid was examined as a proxy for brain metabolite and lipid flux and to provide objective evidence of pathophysiological dysfunction. Two cohorts of ME/CFS and sedentary control subjects had lumbar punctures at baseline (non-exercise) or after submaximal exercise (post-exercise). Cerebrospinal fluid metabolites and lipids were quantified by targeted Biocrates mass spectrometry methods. Significant differences between ME/CFS and control, non-exercise vs. post-exercise, and by gender were examined by multivariate general linear regression and Bayesian regression methods. Differences were found at baseline between ME/CFS and control groups indicating disease-related pathologies, and between non-exercise and post-exercise groups implicating PEM-related pathologies. A new, novel finding was elevated serine and its derivatives sarcosine and phospholipids with a decrease in 5-methyltetrahydrofolate (5MTHF), which suggests general dysfunction of folate and one-carbon metabolism in ME/CFS. Exercise led to consumption of lipids in ME/CFS and controls while metabolites were consumed in ME/CFS but generated in controls. In general, the frequentist and Bayesian analyses generated complementary but not identical sets of analytes that matched the metabolic modules and pathway analysis. Cerebrospinal fluid is unique because it samples the choroid plexus, brain interstitial fluid, and cells of the brain parenchyma. The quantitative outcomes were placed into the context of the cell danger response hypothesis to explain shifts in serine and phospholipid synthesis; folate and one-carbon metabolism that affect sarcosine, creatine, purines, and thymidylate; aromatic and anaplerotic amino acids; glucose, TCA cycle, trans-aconitate, and coenzyme A in energy metabolism; and vitamin activities that may be altered by exertion. The metabolic and phospholipid profiles suggest the additional hypothesis that white matter dysfunction may contribute to the cognitive dysfunction in ME/CFS. Full article

(1) Background: Humulus lupulus L. plants constitute a rich source of bioactive compounds. The synthesis of bioactive compounds in plants is often triggered by the activation of secondary metabolism, which can be induced by biotic or abiotic elicitors. In vitro, the effect of the elicitors can be studied in a controlled environment and in a small space, independently of seasonal variations. Cytokinins are frequently used in plant tissue culture for bud regeneration, branching and shoot elongation due to their role in cell division enhancement. This study aimed to investigate the effects of different cytokinins on the growth parameters, total (poly)phenolic content and antioxidant capacity of in vitro-grown hop plants to evaluate hop vitro-derived biomass as a potential source of bioactive compounds. (2) Methods: unimodal hop (cvs. Cascade and Columbus) explants were cultured on media enriched with four cytokinins (kinetin, 6-benzylaminopurine, meta-topolin and 6-(γ,γ-dimethylallylamino)-purine) at four concentrations. (3) Results: A genotype-dependent response to different cytokinins was encountered. (4) Conclusions Columbus explants could root in culture media auxin-free, providing valuable opportunities for commercial nurseries. Moreover, cytokinins were confirmed to be valuable elicitors to stimulate the bioactive compound biosynthesis in micropropagated hop plants, making them a precious source for various industries. Full article

Marine-derived foods, often called blue foods, are promising sustainable alternatives to conventional food sources owing to their abundant amino acids and high protein content. Current treatments for hyperuricemia, a chronic condition attributed to purine metabolism disorders, are associated with various side effects. Novel peptide xanthine oxidase inhibitors have been discovered in the hydrolyzed products of marine fish and invertebrate proteins, which have demonstrated promising therapeutic potential by reducing uric acid levels in vitro and in vivo. This review explores the potential therapeutic effects of xanthine oxidase inhibitors derived from marine fish and invertebrates, summarizes the methods for extracting bioactive peptides from marine organisms, and emphasizes the impact of different proteases on the structure–activity relationship of bioactive peptides. The hypouricemic effects of these bioactive peptides warrant further verification. There is consensus on the in vitro chemical methods used to verify the xanthine oxidase inhibitory effects of these peptides. Considering several cell and animal model development strategies, this review summarizes several highly recognized modeling methods, proposes strategies to improve the bioavailability of bioactive peptides, and advocates for a diversified evaluation system. Although the screening and evaluation methods for antihyperuricemic peptides have been shown to be feasible across numerous studies, they are not optimal. This review examines the deficiencies in bioavailability, synthesis efficiency, and evaluation mechanisms in terms of their future development and proposes potential solutions to address these issues. This review provides a novel perspective for the exploration and application of marine-derived hypouricemic bioactive peptides. Full article

Tomato is an economically and nutritionally important crop and is vulnerable to drought. Under drought, soil microbes provide beneficial effects to plants and alleviate stress. We suggest a reconstruction of the soil microbiome using biofumigation, an organic farming method, to protect tomatoes. In this study, we treated soil in four ways with varied concentrations: biofumigation (BF0.5, BF1.0, and BF1.5), green manure treatment (GM0.5, GM1.0, and GM1.5), autoclaving (AT), and non-treatment (NT). Tomatoes were grown in each treated soil, subjected to water shortages, and were rewatered. We investigated plant phenotypes and soil properties, focused on microbial communities using the Illumina MiSeq^® System. Relative Water Content and malondialdehyde were measured as plant stress. The results showed that the 1% biofumigation treatment had 105% and 108.8% RWC during drought and after rewatering, compared to the non-treated soil. The highest concentration, the 1.5% treatment, lowered RWC due to an excess of NO₃⁻, K⁺, Ca²⁺, and decreased alpha diversity. Through PLS-PM, bacterial alpha diversity was found to be the largest factor in the increase in RWC (coefficient = 0.3397), and both biofumigant and green manure significantly increased the Shannon index and observed species. In addition, biofumigation increased beneficial functional genes (purine metabolism, pyrimidine metabolism, carbon fixation pathways, and zeatin bio-synthesis) of soil microorganisms (p value < 0.05, <0.01, >0.05, and <0.05, respectively). The 1% biofumigation treatment enriched the core five genera of the fungal network (Enterocarpus, Aspergillus, Leucothecium, Peniophora, and Wallemia) of the fungal network which might suppress the most dominant pathogen, Plectosphaerella. In conclusion, biofumigation-derived soil microbiome alterations have the potential to lower plant stress under drought. Full article

The enzymatic synthesis of nucleoside derivatives is an important alternative to multi-step chemical methods traditionally used for this purpose. Despite several undeniable advantages of the enzymatic approach, there are a number of factors limiting its application, such as the limited substrate specificity of enzymes, the need to work at fairly low concentrations, and the physicochemical properties of substrates—for example, low solubility. This research conducted by our group is dedicated to the advantages and limitations of using purine nucleoside phosphorylases (PNPs), the main enzymes for the metabolic reutilization of purines, in the synthesis of modified nucleoside analogues. In our work, the substrate specificity of PNP from various bacterial sources (mesophilic and thermophilic) was studied, and the effect of substrate, increased temperature, and the presence of organic solvents on the conversion rate was investigated. Full article