Design, synthesis, biological evaluation and computational studies of 4-Aminopiperidine-3, 4-dihyroquinazoline-2-uracil derivatives as promising antidiabetic agents.

A novel series of 4-aminopiperidin-3,4-dihyroquinazoline-2-uracil derivatives (9a-9 L) were logically designed and synthesized as potent DPP4 inhibitors as antidiabetic agents. Chemical structure of all new compounds were confirmed by different spectroscopic methods. The designed compounds were evaluated using a MAK 203 kit as DPP4 inhibitors in comparison with Sitagliptin. The biological evaluation revealed that compound 9i bearing chloro substitution on phenyl moiety of 6-bromo quinazoline ring had promising inhibitory activity with IC50 = 9.25 ± 0.57 µM. The toxicity test of all compounds confirmed safety profile of them. Kinetic studies showed that compound 9i exhibited a competitive-type inhibition with a Ki value of 12.01 µM. Computational approach supported the rationality of our design strategy, as 9i represented appropriate binding interactions with the active sites of DPP4 target. MD simulation outputs validated the stability of ligand 9i at DPP4 active site. Also, Density functional theory (DFT) including HOMO-LUMO energies, ESP map, thermochemical parameters, and theoretical IR spectrum was employed to study the reactivity descriptors of 9i and 9a as the most and least potent compounds respectively. Based on the DFT study, compound 9i was softer and, as a result, more reactive than 9a. Taken together, our results showed the potential of 4-aminopiperidin-3,4-dihyroquinazoline-2-uracil derivatives as promising candidates for developing some novel DPP4 inhibitors for managing of type 2 diabetes.

PIDA as an Iodinating Reagent: Visible-Light-Induced Iodination of Pyrazolo[1,5-a]pyrimidines and Other Heteroarenes.

We have developed a visible-light-mediated convenient and efficient strategy for the iodination of heteroarenes using diacetoxyiodobenzene (PIDA) under photocatalyst-free conditions. This unique approach is the first report on photocatalytic C-H iodination employing PIDA as the iodinating agent. The new photocatalyst-free strategy is applicable to a wide range of pyrazolo[1,5-a]pyrimidine derivatives with various functionalities. Iodination of other electron-rich heterocycles like imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrimidine, imidazo[2,1-b]thiazole, benzo[d]imidazo[2,1-b]thiazole, and pyrazoles has been accomplished employing this benign protocol. The usefulness of 3-iodo pyrazolo[1,5-a]pyrimidine as a synthetic intermediate in synthesizing various functionalized pyrazolo[1,5-a]pyrimidines has been demonstrated.

Tumor-associated macrophages confer resistance to chemotherapy (Trifluridine/Tipiracil) in digestive cancers by overexpressing thymidine phosphorylase.

Pyrimidine analogs are part of the first-line chemotherapy regimen for gastrointestinal cancers. Trifluridine combined with tipiracil, a specific thymidine phosphorylase inhibitor, in TAS-102 has recently emerged as a potential alternative in the face of primary or secondary chemoresistance to 5-fluorouracil. Despite its promise, we report that macrophage-specific overexpression of thymidine phosphorylase results in macrophage-induced chemoresistance to TAS-102 that is insensitive to tipiracil inhibition. Furthermore, we illustrate the human-specific nature of this mechanism, as mouse macrophages do not express substantial levels of thymidine phosphorylase, which constrains the applicability of mouse models. To study the importance of macrophages in chemoresistance to trifluridine, we developed a humanized mouse model with tumor-implanted human macrophages and demonstrated their important role in treatment resistance to pyrimidine analogs. Additionally, our findings revealed that macrophages represent a significant source of thymidine phosphorylase expression, comprising over 40 % of the expressing cells, in human colorectal cancer, thereby contributing to chemoresistance.

Synthesis of pyridyl pyrimidine hedgehog signaling pathway inhibitors and their antitumor activity in human pancreatic cancer.

Pancreatic cancer (PC) is an extremely lethal malignant tumor. The Hedgehog (Hh) signaling pathway is implicated in embryonic development, regulation of tumor stem cells, and modulation of the tumor microenvironment. Aberrant activation of Hh pathway leads to the development of multiple malignant tumors, especially Hh-driven PC. Targeting the molecular regulation of the Hh signaling pathway presents a promising therapeutic strategy for PC treatment. Hence, there is a high demand for novel molecules that inhibit the Hh pathway. In this study, the Hh pathway inhibitors bearing pyridyl pyrimidine skeleton were designed, synthesized, and characterized. Among them, N-(4-((dimethylamino)methyl)phenyl)-4-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)benzamide (B31) emerged as the most potent analog following screening with a Gli luciferase reporter assay, competing with cyclopamine in the binding site of Smo protein. Molecular simulation revealed that B31 interacts with Smo through hydrogen bonds, hydrophobic interactions, and electrostatic forces. B31 inhibited PC cell proliferation, migration, and induced apoptosis by suppressing Gli1 expression at both the transcriptional and translational levels. Moreover, B31 significantly regressed subcutaneous tumors formed by BxPC-3 cells in nude mice without inducing toxic effects. These results underscore the enhanced efficacy of B31 in the PC model and offer a new avenue for developing effective Hh pathway inhibitors for clinical PC treatment.

Identification of furo[2,3-d]pyrimidin-4-ylsulfanyl-1,3,4-thiadiazole derivatives as novel FLT3-ITD inhibitors.

Given the significant prevalence of FLT3 receptor and its mutations in acute myeloid leukemia (AML) pathogenesis, we present a novel series of furo[2,3-d]pyrimidin-1,3,4-thiadiazole-urea derivatives, designed to exhibit FLT3-ITD inhibitory activity. These compounds demonstrated cytotoxicity in FLT3-ITD expressing AML cell lines MOLM-13 and MV4-11 in the nanomolar range, with significant selectivity over the K562 cell line. In-depth evaluations of example compound 49 revealed its efficacy in suppressing FLT3 phosphorylation and the downstream signaling molecules, including STAT5 and ERK1/2. Notably, compound 49 demonstrated cytotoxic effects in Ba/F3 cells expressing FLT3-ITD or FLT3-ITD-F691L mutant, exceeding the potency of both sorafenib and quizartinib. Molecular docking studies suggest that this compound binds to the active site of FLT3 in a type II manner. The study suggests that substituted furo[2,3-d]pyrimidines could be useful additions to the growing field of FLT3-targeted therapy for AML. These compounds have the potential to serve as novel FLT3-ITD inhibitors and may offer insights for developing future therapeutic strategies in AML.

New S-substituted-3-phenyltetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one scaffold with promising anticancer activity profile through the regulation and inhibition of mutated B-RAF signaling pathway.

Novel 3-phenyltetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives were synthesized and screened for their antiproliferative activity against a panel of 60 cancer cell lines. Derivatives 5b, 5f, and 9c showed significant antitumor activity at a single dose with mean growth inhibition of 55.62%, 55.79%, and 71.40%, respectively. These compounds were further investigated against HCT-116, colon cancer cell line, and FHC, normal colon cell line. Compound 9c showed the highest activity with IC50 = 0.904 ± 0.03 µM and SI = 20.42 excelling doxorubicin which scored IC50 = 2.556 ± 0.09 µM and SI = 6.19. Compound 9c was also the most potent against B-RAFWT and mutated B-RAFV600E with IC50 = 0.145 ± 0.005 and 0.042 ± 0.002 µM, respectively in comparison with vemurafenib with IC50 = 0.229 ± 0.008 and 0.038 ± 0.001 µM, respectively. The cell cycle analysis showed that 9c increased the cell population and induced an arrest in the cell cycle of HCT-116 cancer cells at the G0-G1 stage with 1.23-fold. Apoptosis evaluation showed that compound 9c displayed an 18.18-fold elevation in total apoptosis of HCT-116 cancer cells in comparison to the control. Compound 9c increased the content of caspase-3 by 3.52-fold versus the control. A molecular modeling study determined the binding profile and interaction of 9c with the B-RAF active site.

New Pyrazole/Pyrimidine-Based Scaffolds as Inhibitors of Heat Shock Protein 90 Endowed with Apoptotic Anti-Breast Cancer Activity.

Background/Objectives: Supported by a comparative study between conventional, grinding, and microwave techniques, a mild and versatile method based on the [1 + 3] cycloaddition of 2-((3-nitrophenyl)diazenyl)malononitrile to tether pyrazole and pyrimidine derivatives in good yields was used. Methods: The newly synthesized compounds were analyzed with IR, 13C NMR, 1H NMR, mass, and elemental analysis methods. The products show interesting precursors for their antiproliferative anti-breast cancer activity. Results: Pyrimidine-containing scaffold compounds 9 and 10 were the most active, achieving IC50 = 26.07 and 4.72 µM against the breast cancer MCF-7 cell line, and 10.64 and 7.64 µM against breast cancer MDA-MB231-tested cell lines, respectively. Also, compounds 9 and 10 showed a remarkable inhibitory activity against the Hsp90 protein with IC50 values of 2.44 and 7.30 µM, respectively, in comparison to the reference novobiocin (IC50 = 1.14 µM). Moreover, there were possible apoptosis and cell cycle arrest in the G1 phase for both tested compounds (supported by CD1, caspase-3,8, BAX, and Bcl-2 studies). Also, the binding interactions of compound 9 were confirmed through molecular docking, and simulation studies displayed a complete overlay into the Hsp90 protein pocket. Conclusions: Compounds 9 and 10 may have apoptotic antiproliferative action as Hsp90 inhibitors.

A mild skeletal phenotype with overlapping features of Miller syndrome and functional characterisation of two new variants of human dihydroorotate dehydrogenase.

Dihydroorotate dehydrogenase (DHODH) catalyzes the fourth enzymatic reaction of the pyrimidine biosynthesis pathway. Miller syndrome, also known as postaxial acrofacial dysostosis, is caused by biallelic pathogenic variants in DHODH. We present a patient with a relatively mild skeletal phenotype carrying a novel variant of unknown significance in DHODH: c.829G > A, p.(D277N), in combination with a known variant, c.403C > T, p.(R135C). We functionally characterized the DHODH variant D277N in comparison to a very recently reported, but functionally uncharacterized variant P43L, that was found in a patient with more pronounced Miller syndrome features. Because both cases share the same DHODH variant R135C, we aimed to study the effect on enzyme activity of the two variants D277N and P43L to determine pathogenicity and possibly a genotype-phenotype relationship on the R135C background. We found a significant reduction in enzyme activity for both variants. The variant P43L showed a more pronounced loss of function in all assays compatible with other pathogenic variants reported in Miller, whereas the D277N variant showed milder changes that could reflect the mild phenotypic features in our patient. Yet due to a lack of a known threshold of residual enzyme activity to determine pathogenicity, this needs to be confirmed in further studies.

Pyrimidine metabolism reshapes immune microenvironment and implies poor prognosis in glioma.

BACKGROUND: The metabolic environment of glioma is extremely complex. Pyrimidine metabolism can significantly influence malignant progression of multiple kinds of cancer cells. In this study, we intend to explore the relationship between pyrimidine metabolism and malignant progression of glioma. METHODS: We analyzed two glioma RNA-sequencing databases to construct a pyrimidine metabolism-related risk signature. An individualized prognosis prediction model based on this risk signature was established. Functional analysis and in vitro experiments were conducted to assess the role of pyrimidine metabolism in the tumor-immune microenvironment and malignant progress of gliomas. RESULTS: The high-risk group, as predicted by the pyrimidine metabolism-related risk score, showed a tendency toward more malignant entities and poorer survival outcomes. Functional analysis revealed that pyrimidine metabolism significantly regulates the tumor-immune microenvironment. In vitro experiments confirmed that targeting pyrimidine metabolism-related genes can inhibit malignancy of glioma cell. CONCLUSION: In short, the pyrimidine metabolism-related signature we established could serve as an independent prognostic biomarker in diffuse gliomas and has a close association with regulation of the tumor-immune microenvironment.

On the chemistry of sunlight-induced DNA lesions: A perspective on the alkaline chemical-induced reactivities of photo-damaged pyrimidine intra-strand dimers.

Photoexcitation of cellular as well as isolated DNAs upon exposure to the UV portion of sunlight or other UV sources can lead to the covalent dimerization of adjacent intra-strand stacked pyrimidine nucleobase rings (i.e., at 5'-Py-p-Py-3' sites). These modifications generate, in mammalian DNA as well as the DNA of all other forms of life, lesions such as cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs); and, in bacterial endospores, spore photoproducts (SPs). Importantly, the lesions formed in higher organisms can lead to disease states including cancer. While the formation, structure, and biological outcomes of pyrimidine dimer lesions have been the focus of much research, less has been known about their fundamental chemical properties until recently. Such an understanding of these lesions may lead to novel means to chemically identify and quantitate their presence in the genome. This review is intended to provide an overview of intra-strand pyrimidine dimer lesions derived from 5'-T-p-T sites with a focus on presenting what is currently known about their individual in vitro alkaline chemical reactivities. Included here are descriptions of investigations of the DNA lesions CPD, 6-4PP, and SP, and, for comparison, the monomeric pyrimidine lesion 5,6-dihydo-2'-deoxyuridine (dHdU). Of interest, the alkaline hydrolyses of these various lesions are all found to be centered on the loss of aromaticity of a lesion Py ring (T) leading to a carbonyl "hot spot," the focal point of initial hydrolytic attack.

Pyrrolo[2,3-d]pyrimidines as potential kinase inhibitors in cancer drug discovery: A critical review.

Pyrrolo[2,3-d]pyrimidine-based kinase inhibitors have emerged as an important class of targeted therapeutics to combat various types of cancer. The distinctive structural feature of pyrrolopyrimidine ring system offers an adaptable platform for designing potent inhibitors of various kinases, crucial in regulating cellular processes. The deazapurine framework inherent to pyrrolopyrimidines bears a conspicuous resemblance to adenine, the natural ligand ATP. The structural mimicry enhances their appeal as potent inhibitors of key kinases. This review reconnoitres the intricate process of designing and developing pyrrolopyrimidine based derivatives, accentuating their structural diversity and the strategic modifications employed to enhance selectivity, potency, and pharmacokinetic properties. The discussion delves into medicinal chemistry strategies, highlighting successful examples that have been progressed to clinical evaluation. Furthermore, the review highlights the promise of pyrrolopyrimidine scaffolds in revolutionizing targeted cancer therapy and provides a pioneering perspective on future directions.

Discovery of pyrazolo[1,5-a]pyrimidine derivatives targeting TLR4-TLR4∗ homodimerization via AI-powered next-generation screening.

TLR4 signaling is instrumental in orchestrating multiple aspects of innate immunity. Developing small molecule inhibitors targeting the TLR4 pathway holds potential therapeutic promise for TLR4-related disorders. Herein, an artificial intelligence (AI)-powered next-generation screening approach, employing HelixVS and HelixDock, was utilized to focus on the TLR4-TLR4∗ (a second copy of TLR4) homodimerization surface, leading to the identification of a potent pyrazolo[1,5-a]pyrimidine derivative, designated as compound 1. An extensive structure-activity relationship (SAR) exploration culminated in the discovery of the lead compound TH023, which effectively blocked the LPS-stimulated NF-κB activation and nitric oxide overproduction in HEK-Blue hTLR4 and RAW264.7 cells, with IC50 values of 0.354 and 1.61 µM, respectively. Molecular dynamic (MD) simulations indicated that TH023 stabilized TLR4-MD-2 and disrupted its association with TLR4∗. Moreover, TH023 alleviated the lung injury and decreased pro-inflammatory cytokine levels in LPS-induced septic mice. These findings not only illuminated the strategic advantage of HelixDock in advancing the frontiers of AI-driven drug discovery, but also provided valuable structural insights for the rational design of TLR4-TLR4∗ protein-protein interaction (PPI) inhibitors based on the pyrazolo[1,5-a]pyrimidine scaffold. Overall, this study validated a new strategy for TLR4 signaling regulation by targeting its dimerization, thereby underscoring the therapeutic promise of TH023 in treating TLR4-mediated inflammatory diseases.

Construction of pyrimidine derivatives-copper enzyme mimics as colorimetric sensing elements for efficient detection of phenolic compounds and hydrogen peroxide.

As concerns about environmental pollution grow, the rapid identification and quantification of pollutants have become increasingly vital. In this work, a series of pyrimidine derivatives-Cu enzyme mimics (Cytosine-Cu, Cytidine-Cu, and CMP-Cu) with laccase- and peroxidase-like activity were prepared through the coordination of Cu2+ with different pyrimidine derivatives (PDs). The PDs-Cu enzyme mimics contain high levels of Cu+ and N - Cu coordination structures, which provide sufficient catalytic sites for the substrates. Compared with natural enzymes and other nanozymes, PDs-Cu demonstrate superior substrate affinity, catalytic efficiency, stability, and resistance to interference. It was found that PDs-Cu enzyme mimics have different catalytic activities towards different phenolic compounds. Therefore, a three-channel colorimetric sensor array (CSA) was successfully developed utilizing PDs-Cu as the sensing elements. The CSA can accurately identify different phenolic compounds and their mixtures in seawater and simulated wastewater. Additionally, a colorimetric method for detecting H2O2 in eye drops was developed, featuring a detection range of 0.1-10.0 µM and a limit of quantification of 0.1 µM. This research not only provides a flexible protocol for regulating the catalytic activity of enzyme mimics, but also provides important inspiration for the development of methods for rapid identification and detection of contaminants in the environmental water.

Alterations in purine and pyrimidine metabolism associated with latent tuberculosis infection: insights from gut microbiome and metabolomics analyses.

Individuals with latent tuberculosis infection (LTBI) account for almost 30% of the population worldwide and have the potential to develop active tuberculosis (ATB). Despite this, the current understanding of the pathogenesis of LTBI is limited. The gut microbiome can be altered in tuberculosis patients, and an understanding of the changes associated with the progression from good health to LTBI to ATB can provide novel perspectives for understanding the pathogenesis of LTBI by identifying microbial and molecular biomarkers associated therewith. In this study, fecal samples from healthy controls (HC), individuals with LTBI and ATB patients were collected for gut microbiome and metabolomics analyses. Compared to HC and LTBI subjects, participants with ATB showed a significant decrease in gut bacterial α-diversity. Additionally, there were significant differences in gut microbial communities and metabolism among the HC, LTBI, and ATB groups. PICRUSt2 analysis revealed that microbiota metabolic pathways involving the degradation of purine and pyrimidine metabolites were upregulated in LTBI and ATB individuals relative to HCs. Metabolomic profiling similarly revealed that purine and pyrimidine metabolite levels were decreased in LTBI and ATB samples relative to those from HCs. Further correlation analyses revealed that the levels of purine and pyrimidine metabolites were negatively correlated with those of gut microbial genera represented by Ruminococcus_gnavus_group (R. gnavus), and the levels of R. gnavus were also positively correlated with adenosine nucleotide degradation II, which is a purine degradation pathway. Moreover, a combined signature including hypoxanthine and xanthine was found to effectively distinguish between LTBI and HC samples (area under the curve [AUC] of training set = 0.796; AUC of testing set = 0.924). Therefore, through gut microbiome and metabolomic analyses, these findings provide valuable clues regarding how alterations in gut purine and pyrimidine metabolism are linked to the pathogenesis of LTBI.IMPORTANCEThis study provides valuable insight into alterations in the gut microbiome and metabolomic profiles in a cohort of adults with LTBI and ATB. Perturbed gut purine and pyrimidine metabolism in LTBI was associated with the compositional alterations of gut microbiota, which may be an impetus for developing novel diagnostic strategies and interventions targeting LTBI.

Anticancer and Antibacterial Activeness of Fused Pyrimidines: Newfangled Updates.

Pyrimidine-based heterocyclic compounds are garnering substantial interest due to their essential role as a class of natural and synthetic molecules. These compounds show a diverse array of biologically relevant activities, making them highly prospective candidates for clinical translation as therapeutic agents in combating various diseases. Pyrimidine derivatives and their fused analogues, such as thienopyrimidines, pyrazolopyrimidines, pyridopyrimidines, and pyrimidopyrimidines, hold immense possibility in both anticancer and antibacterial research. These compounds exhibit notable efficacy by targeting protein kinases, which are crucial enzymes regulating fundamental cellular processes like metabolism, migration, division, and growth. Through enzyme inhibition, these derivatives disrupt key cellular signaling pathways, thereby affecting critical cellular functions and viability. The advantage lies in the ubiquity of the pyrimidine structure across various natural compounds, enabling interactions with enzymes, genetic material, and cellular components pivotal for chemical and biological processes. This interaction plays a central role in modulating vital biological activities, making pyrimidine-containing compounds indispensable in drug discovery. In the realm of anticancer therapy, these compounds strategically target key proteins like EGFR, important for aberrant cell growth. Fused pyrimidine motifs, exemplified by various drugs, are designed to inhibit EGFR, thereby impeding tumor progression. Moreover, these compounds influence potent antibacterial activity, interfering with microbial growth through mechanisms ranging from DNA replication inhibition to other vital cellular functions. This dual activity, targeting both cancer cells and microbial pathogens, underscores the versatility and potential of pyrimidine derivatives in medical applications. This review provides insights into the structural characteristics, synthesis methods, and significant medicinal applications of fused pyrimidine derivatives, highlighting their double role in combating cancer and bacterial infections.

Discovery and structure - activity relationships of 2,4,5-trimethoxyphenyl pyrimidine derivatives as selective D5 receptor partial agonists.

Dopamine receptors are therapeutic targets for the treatment of various neurological and psychiatric disorders, including Parkinson's and Alzheimer's. Previously, PF-06649751 (tavapadon), PF-2562 and PW0464 have been discovered as potent and selective G protein-biased D1/D5 receptor agonists with optimal pharmacokinetic properties. However, no selective D5R agonist has been reported yet. In this context, we designed and synthesized forty non-catecholamines-based pyrimidine derivatives and identified four pyrimidine derivatives as selective D5R partial agonists. Using cAMP-based GloSensor assay in transiently transfected HEK293T cells with human D1 or D5 receptors, we discovered that compound 5c (4-(4-bromophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-amine) exhibited modest D5R agonist activity. This leads us to explore various modifications of this scaffold to improve the D5 agonist potency and efficacy. Using molecular docking, and rational design followed by their evaluation at D1 and D5 receptors for agonist activity, we identified three new derivatives, 5j, 5h, and 5e. The most potent compound of this series 5j (4-(4-iodophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-amine), exhibited EC50 of 269.7 ± 6.6 nM. Mice microsomal stability studies revealed that 5j is quite stable (>70 % at 1 hr). Furthermore, pharmacokinetic analysis of 5j (20 mg/kg, p.o) in C57BL/6j mice showed that 5j is readily absorbed via oral route of dosing and also enters into the brain (plasma Tmax: 1 h, Cmax: 51.10 ± 13.51 ng/ml; Brain Tmax: 0.5 h, Cmax: 22.54 ± 4.08 ng/ml). We further determined the in-vivo effect of 5j on cognition in scopolamine-induced amnesia in C57BL/6j mice. We observed that 5j (10 mg/kg, p.o) alleviated scopolamine-induced impairment in short-term memory and social recognition, which were blocked by D1/D5 antagonist SCH23390 (0.1 mg/kg, i.p.). Furthermore, 5j did not exhibit any cytotoxicity (up to 10 µM) or in vivo acute toxicity up to 200 mg/kg (p.o). These results strongly suggest that 5j could be further developed for treating neurological disorders wherein the D5 receptors play pivotal roles.

circE2F1-encoded peptide inhibits circadian machinery essential for nucleotide biosynthesis and tumor progression via repressing SPIB/E2F1 axis.

Circadian clock dominates a variety of biological activities, while its roles and regulatory mechanisms in neuroblastoma (NB), a pediatric extracranial malignancy, still remain largely elusive. Herein, through comprehensive analyses of public datasets, E2F transcription factor 1 (E2F1) and its circular RNA (circE2F1)-encoded 99-amino acid peptide (E2F1-99aa) were identified as vital regulators of circadian machinery essential for purine and pyrimidine biosynthesis during NB progression. Mechanistically, through interaction with Spi-B transcription factor (SPIB), E2F1 was transactivated to up-regulate circadian machinery genes (CRY1 and TIMELESS), resulting in relief of CLOCK/BMAL1-repressed transcription of enzymes (DHODH, PAICS, or PPAT) essential for de novo purine and pyrimidine biosynthesis. The biogenesis of circE2F1 was repressed by eukaryotic translation initiation factor 4A3 (EIF4A3), while E2F1-99aa or its truncated peptide competitively bound to SPIB, leading to decrease in SPIB-E2F1 interaction, circadian machinery and nucleotide biosynthetic gene expression, purine or pyrimidine biosynthesis, tumorigenesis, and aggresiveness of NB cells. In clinical NB cases, high EIF4A3, E2F1 or SPIB expression was correlated with low survival possibility of patients, while lower circE2F1 or E2F1-99aa levels were associated with advanced stages and tumor progression. These results indicate that circE2F1-encoded peptide inhibits circadian machinery essential for nucleotide biosynthesis and tumor progression via repressing SPIB/E2F1 axis.

Harnessing nucleotide metabolism and immunity in cancer: a tumour microenvironment perspective.

The tumour microenvironment (TME) is a dynamic nexus where cancer cell metabolism and the immune system intricately converge, with nucleotide metabolism (NM) playing a pivotal role. This review explores the critical function of NM in cancer cell proliferation and its profound influence on the TME and immune landscape. NM is essential for DNA and RNA synthesis and is markedly upregulated in cancer cells to meet the demands of rapid growth. This metabolic rewiring fuels cancer progression, but also shapes the TME, impacting the function and viability of immune cells. The altered nucleotide milieu in the TME can suppress immune response, aiding cancer cell evasion from immune surveillance. Drug discoveries in the field of NM have revealed different therapeutic strategies, including inhibitors of nucleotide synthesis and drugs targeting salvage pathways, which are discussed thoroughly in this review. Furthermore, the emerging strategy of combining NM-targeted therapies with immunotherapies is emphasised, particularly their effect on sensitising tumours to immune checkpoint inhibitors and enhancing overall treatment efficacy. The Human Genome Project paved the way for personalised medicine, countering the established 'one size fits all' approach to cancer treatment. Advances in understanding the TME and NM have spurred interest in personalised therapeutic strategies. This review highlights the potential of leveraging individual tumour metabolic profiles to guide treatment selection, aiming to optimise efficacy and minimise adverse effects. The strategic importance of targeting NM in cancer therapy and its synergistic potential with immunotherapies offers a path towards more effective and personalised cancer treatments.

Derivatives of Pyrimidine Nucleosides Affect Artificial Membranes Enriched with Mycobacterial Lipids.

The mechanisms of action of pyrimidine nucleoside derivatives on model lipid membranes of various compositions were studied. A systematic analysis of the tested agents' effects on the membrane physicochemical properties was performed. Differential scanning microcalorimetry data indicated that the ability of nucleoside derivatives to disorder membrane lipids depended on the types of nucleoside bases and membrane-forming lipids. The 5'-norcarbocyclic uracil derivatives were found to be ineffective, while N4-alkylcytidines demonstrated the most pronounced effects, significantly decreasing the dipalmitoylphosphocholine melting temperature and cooperativity of phase transition. The elongation of hydrophobic acyl radicals potentiated the disordering action of N4-alkylcytidines, while an increase in hydrophilicity due to replacing deoxyribose with ribose inhibited this effect. The ability of compounds to form transmembrane pores was also tested. It was found that 5-alkyluridines produced single, ion-permeable pores in phosphatidylglycerol membranes, and that methoxy-mycolic acid and trehalose monooleate potentiated the pore-forming activity of alkyloxymethyldeoxyuridines. The results obtained open up perspectives for the development of innovative highly selective anti-tuberculosis agents, which may be characterized by a low risk of developing drug resistance due to the direct action on the membranes of the pathogen.

Synthesis of Ethyl Pyrimidine-Quinolincarboxylates Selected from Virtual Screening as Enhanced Lactate Dehydrogenase (LDH) Inhibitors.

The inhibition of the hLDHA (human lactate dehydrogenase A) enzyme has been demonstrated to be of great importance in the treatment of cancer and other diseases, such as primary hyperoxalurias. In that regard, we have designed, using virtual docking screening, a novel family of ethyl pyrimidine-quinolinecarboxylate derivatives (13-18)(a-d) as enhanced hLDHA inhibitors. These inhibitors were synthesised through a convergent pathway by coupling the key ethyl 2-aminophenylquinoline-4-carboxylate scaffolds (7-12), which were prepared by Pfitzinger synthesis followed by a further esterification, to the different 4-aryl-2-chloropyrimidines (VIII(a-d)) under microwave irradiation at 150-170 °C in a green solvent. The values obtained from the hLDHA inhibition were in line with the preliminary of the preliminary docking results, the most potent ones being those with U-shaped disposition. Thirteen of them showed IC50 values lower than 5 µM, and for four of them (16a, 18b, 18c and 18d), IC50 ≈ 1 µM. Additionally, all compounds with IC50 < 10 µM were also tested against the hLDHB isoenzyme, resulting in three of them (15c, 15d and 16d) being selective to the A isoform, with their hLDHB IC50 > 100 µM, and the other thirteen behaving as double inhibitors.