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Future Medicinal Chemistry Jun 2023Molecular hybridization and isostery are proven approaches in medicinal chemistry, and as such we used them to design novel compounds that we investigated as...
Molecular hybridization and isostery are proven approaches in medicinal chemistry, and as such we used them to design novel compounds that we investigated as potential antimycobacterials to combat drug-resistant strains. Prepared -alkyl-2-(pyrimidine-5-carbonyl)hydrazine-1-carboxamides were cyclized to -alkyl-5-(pyrimidin-5-yl)-1,3,4-oxadiazol-2-amines along with their analogues. A total of 48 compounds were tested against HRv, and , with oxadiazoles and C-C alkyls being the most effective from a concentration of 2 μM. Multidrug-resistant strains were inhibited at same concentrations as the susceptible strain. For the most potent -dodecyl-5-(pyrimidin-5-yl)-1,3,4-oxadiazol-2-amine, the mechanism of action related to cell wall biosynthesis was investigated. Pyrimidine-1,3,4-oxadiazole hybrids are unique antimycobacterial agents inhibiting mainly strains without cross-resistance to current drugs and are thus promising drug candidates.
Topics: Anti-Bacterial Agents; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxadiazoles; Pyrimidines; Amines; Antitubercular Agents; Structure-Activity Relationship
PubMed: 37555280
DOI: 10.4155/fmc-2023-0096 -
Optimization of triazolo[4,5-d]pyrimidines towards human CC chemokine receptor 7 (CCR7) antagonists.European Journal of Medicinal Chemistry May 2023CCR7 signaling directs the migration of both immune cells and cancer cells to the lymph nodes, is involved in numerous chronic inflammatory disorders and lymph node...
CCR7 signaling directs the migration of both immune cells and cancer cells to the lymph nodes, is involved in numerous chronic inflammatory disorders and lymph node metastases. Despite the therapeutic promise of CCR7 antagonists, no potent and selective small molecule CCR7 antagonists have been reported to date. Since most human chemokine G protein-coupled receptors (GPCRs) share a conserved intracellular allosteric binding site, new CCR7 antagonist chemotypes may be identified by screening small molecules that are known to target this site in other chemokine GPCRs. In this work, our previously prepared series of 14 scaffold-modified analogues of a known thiazolo[4,5-d]pyrimidine CXCR2 antagonist were screened as potential CCR7 antagonists. This resulted in the discovery of a triazolo[4,5-d]pyrimidine analogue with an IC of 2.43 μM against CCR7 and 0.66 μM against CXCR2. Exploration of the structure-activity relationship (SAR) for the 3-, 5- and 7-position substituents of this triazolo[4,5-d]pyrimidine resulted in improved potency and selectivity, with an IC of 0.43 μM and 11.02 μM against CCR7 and CXCR2, respectively, for the most selective derivative. Molecular docking showed that the binding mode of these triazolo[4,5-d]pyrimidines in CCR7 and CXCR2 corresponds with those of previously co-crystallized ligands.
Topics: Humans; Receptors, CCR7; Molecular Docking Simulation; Structure-Activity Relationship; Signal Transduction; Receptors, G-Protein-Coupled; Pyrimidines
PubMed: 36924670
DOI: 10.1016/j.ejmech.2023.115240 -
Molecules (Basel, Switzerland) Jun 2021A series of 1,2,3-triazolyl nucleoside analogues in which 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via polymethylene linkers to both nitrogen atoms...
A series of 1,2,3-triazolyl nucleoside analogues in which 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via polymethylene linkers to both nitrogen atoms of the heterocycle moiety (uracil, 6-methyluracil, thymine, quinazoline-2,4-dione, alloxazine) or to the C-5 and -3 atoms of the 6-methyluracil moiety was synthesized. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. Antiviral assays revealed three compounds, , , , which showed moderate activity against influenza virus A H1N1 with IC values of 57.5 µM, 24.3 µM, and 29.2 µM, respectively. In the first two nucleoside analogues, 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via butylene linkers to -1 and -3 atoms of the heterocycle moiety (6-methyluracil and alloxazine, respectively). In nucleoside analogue , two 1,2,3-triazol-4-yl-2',3',5'-tri--acetyl-β-d-ribofuranose fragments are attached via propylene linkers to the C-5 and -3 atoms of the 6-methyluracil moiety. Almost all synthesized 1,2,3-triazolyl nucleoside analogues showed no antiviral activity against the coxsackie B3 virus. Two exceptions are 1,2,3-triazolyl nucleoside analogs and , in which 1,2,3-triazol-4-yl-2',3',5'-tri--acetyl-β-d-ribofuranose fragments are attached to the C-5 and -3 atoms of the heterocycle moiety (6-methyluracil and alloxazine respectively). These compounds exhibited high antiviral potency against the coxsackie B3 virus with IC values of 12.4 and 11.3 µM, respectively, although both were inactive against influenza virus A H1N1. According to theoretical calculations, the antiviral activity of the 1,2,3-triazolyl nucleoside analogues , , and against the H1N1 (A/PR/8/34) influenza virus can be explained by their influence on the functioning of the polymerase acidic protein (PA) of RNA-dependent RNA polymerase (RdRp). As to the antiviral activity of nucleoside analogs and against coxsackievirus B3, it can be explained by their interaction with the coat proteins VP1 and VP2.
Topics: Antiviral Agents; Click Chemistry; Humans; Influenza A Virus, H1N1 Subtype; Molecular Docking Simulation; Nucleosides; Pyrimidines; RNA-Dependent RNA Polymerase; Structure-Activity Relationship
PubMed: 34208647
DOI: 10.3390/molecules26123678 -
Science Advances Apr 2024Despite seizure control by early high-dose pyridoxine (vitamin B6) treatment, at least 75% of pyridoxine-dependent epilepsy (PDE) patients with mutation still suffer...
Despite seizure control by early high-dose pyridoxine (vitamin B6) treatment, at least 75% of pyridoxine-dependent epilepsy (PDE) patients with mutation still suffer from intellectual disability. It points to a need for additional therapeutic interventions for PDE beyond pyridoxine treatment, which provokes us to investigate the mechanisms underlying the impairment of brain hemostasis by ALDH7A1 deficiency. In this study, we show that ALDH7A1-deficient mice with seizure control exhibit altered adult hippocampal neurogenesis and impaired cognitive functions. Mechanistically, ALDH7A1 deficiency leads to the accumulation of toxic lysine catabolism intermediates, α-aminoadipic-δ-semialdehyde and its cyclic form, δ-1-piperideine-6-carboxylate, which in turn impair de novo pyrimidine biosynthesis and inhibit NSC proliferation and differentiation. Notably, supplementation of pyrimidines rescues abnormal neurogenesis and cognitive impairment in ALDH7A1-deficient adult mice. Therefore, our findings not only define the important role of ALDH7A1 in the regulation of adult hippocampal neurogenesis but also provide a potential therapeutic intervention to ameliorate the defective mental capacities in PDE patients with seizure control.
Topics: Humans; Animals; Mice; Pyridoxine; Aldehyde Dehydrogenase; Seizures; Pyrimidines; Cognition; Epilepsy; 2-Aminoadipic Acid
PubMed: 38579001
DOI: 10.1126/sciadv.adl2764 -
Drugs Jun 2018Telotristat ethyl (Xermelo), a first-in-class peripheral tryptophan hydroxylase (TPH) inhibitor, is approved to treat carcinoid syndrome diarrhoea in combination with... (Review)
Review
Telotristat ethyl (Xermelo), a first-in-class peripheral tryptophan hydroxylase (TPH) inhibitor, is approved to treat carcinoid syndrome diarrhoea in combination with somatostatin analogue (SSA) therapy in adults inadequately controlled by SSA therapy alone. Some neuroendocrine tumours secrete serotonin (5-HT) into the blood, resulting in frequent bowel movements (BMs) and other symptoms. Telotristat ethyl inhibits TPH, thereby reducing the production of 5-HT and improving carcinoid syndrome diarrhoea. In the 12-week placebo-controlled phase of randomized trials in patients with carcinoid syndrome diarrhoea (most of whom were receiving SSA therapy), the addition of oral telotristat ethyl 250 three times daily provided significant reductions in the frequency of BMs and levels of urinary 5-hydroxyindolacetic acid (u5-HIAA; a metabolite of 5-HT) relative to placebo. Telotristat ethyl 250 mg three times daily was well tolerated, with the proportion of patients reporting at least one treatment-emergent adverse event being similar to that with placebo. With regard to adverse events of special interest, relative to placebo, telotristat ethyl had a comparable incidence of depression-related symptoms, a somewhat higher incidence of gastrointestinal (GI) disorders and a higher incidence of elevated hepatic enzyme levels.
Topics: Diarrhea; Drug Interactions; Drug Therapy, Combination; Humans; Malignant Carcinoid Syndrome; Phenylalanine; Pyrimidines; Randomized Controlled Trials as Topic; Signal Transduction; Somatostatin; Treatment Outcome; Tryptophan Hydroxylase
PubMed: 29931594
DOI: 10.1007/s40265-018-0935-1 -
Nucleosides, Nucleotides & Nucleic Acids 2021Novel class of amino pyrimidine thioglycoside derivatives were designed from sodium 2-cyano-3-(arylamino)prop-1-ene-1,1-bis(thiolate) and guanidine hydrochloride to...
Novel class of amino pyrimidine thioglycoside derivatives were designed from sodium 2-cyano-3-(arylamino)prop-1-ene-1,1-bis(thiolate) and guanidine hydrochloride to afford the corresponding sodium 2,6-diamino-5-aryl-1,2-dihydropyrimidine-4-thiolate , which in coupling with peracylated -D-gluco- and galactopyranosyl bromides in DMF gave the corresponding pyrimidine thioglycosides . Acidification of 2,6-diamino-5-aryl-1,2-dihydropyrimidine-4-thiolate salts with hydrochloric acid formed the corresponding pyrimidine-4-thioles . The latter were stirred with peracetylated halo sugars α-D-gluco- and galacto-pyranosyl bromides in sodium hydride and DMF to yield the pyrimidine thioglycosides . Deacetylation of the pyrimidine thioglycosides gave the corresponding free pyrimidine thioglycosides . The compounds were characterized by C NMR, H NMR, and IR. The pyrimidine thioglycosides and free pyrimidine thioglycosides were tested against H5N1 virus strain and exhibited high to moderate activity.
Topics: Amides; Antiviral Agents; Chemistry Techniques, Synthetic; Influenza A Virus, H5N1 Subtype; Pyrazines; Pyrimidines; Thioglycosides
PubMed: 33478340
DOI: 10.1080/15257770.2021.1872794 -
The Journal of Biological Chemistry Nov 2021Detection of thymidine analogues after their incorporation into replicating DNA represents a powerful tool for the study of cellular DNA synthesis, progression through... (Review)
Review
Detection of thymidine analogues after their incorporation into replicating DNA represents a powerful tool for the study of cellular DNA synthesis, progression through the cell cycle, cell proliferation kinetics, chronology of cell division, and cell fate determination. Recent advances in the concurrent detection of multiple such analogues offer new avenues for the investigation of unknown features of these vital cellular processes. Combined with quantitative analysis, temporal discrimination of multiple labels enables elucidation of various aspects of stem cell life cycle in situ, such as division modes, differentiation, maintenance, and elimination. Data obtained from such experiments are critically important for creating descriptive models of tissue histogenesis and renewal in embryonic development and adult life. Despite the wide use of thymidine analogues in stem cell research, there are a number of caveats to consider for obtaining valid and reliable labeling results when marking replicating DNA with nucleotide analogues. Therefore, in this review, we describe critical points regarding dosage, delivery, and detection of nucleotide analogues in the context of single and multiple labeling, outline labeling schemes based on pulse-chase, cumulative and multilabel marking of replicating DNA for revealing stem cell proliferative behaviors, and determining cell cycle parameters, and discuss preconditions and pitfalls in conducting such experiments. The information presented in our review is important for rational design of experiments on tracking dividing stem cells by marking replicating DNA with thymidine analogues.
Topics: Animals; Cell Cycle; Cell Self Renewal; Cell Tracking; DNA Replication; Humans; Stem Cells; Thymidine
PubMed: 34717955
DOI: 10.1016/j.jbc.2021.101345 -
Chemosphere Jun 2024As important components of soluble microbial products in water, nucleobases have attracted much attention due to the high toxicity of their direct aromatic halogenated...
As important components of soluble microbial products in water, nucleobases have attracted much attention due to the high toxicity of their direct aromatic halogenated disinfection by-products (AH-DBPs) during chlorination. However, multiple halogenation sites of AH-DBPs pose challenges to identify them. In this study, reaction sites of pyrimidine bases and nucleosides during chlorination were investigated by quantum chemical computational method. The results indicate that the anion salt forms play key roles in chlorination of uracil, thymine, and their nucleosides, while neutral forms make predominant contributions to cytosine and cytidine. In view of both kinetics and thermodynamics, C5 is the most reactive site for uracil and thymine, N3/C5 and N3 for respective uridine and thymidine, N1/C5/N and N for respective cytosine and cytidine, whose estimated apparent rate constants k of ∼10, 10/10, 10/10/10, and 10 M s, respectively, in consistent with the known experimental results. C6 in all pyrimidine compounds is hardly attacked by Cl in HOCl ascribed to its positive charge, but readily attacked by OH‾ in hydrolysis and the N1=C6 bond was found to possess the highest reactivity in hydrolysis among all double bonds. In addition, the structure-kinetic reactivity relationship study reveals a relatively strong correlation between lgk and APT charge in all pyrimidine compounds rather than FED (HOMO). The results are helpful to further understand the reactivity of various reaction sites in aromatic compounds during chlorination.
Topics: Halogenation; Pyrimidines; Nucleosides; Kinetics; Thermodynamics; Disinfection; Uracil; Water Pollutants, Chemical
PubMed: 38688350
DOI: 10.1016/j.chemosphere.2024.142189 -
Blood Advances Mar 2024Adult T-cell leukemia/lymphoma (ATL) is triggered by infection with human T-cell lymphotropic virus-1 (HTLV-1). Here, we describe the reprogramming of pyrimidine...
Adult T-cell leukemia/lymphoma (ATL) is triggered by infection with human T-cell lymphotropic virus-1 (HTLV-1). Here, we describe the reprogramming of pyrimidine biosynthesis in both normal T cells and ATL cells through regulation of uridine-cytidine kinase 2 (UCK2), which supports vigorous proliferation. UCK2 catalyzes the monophosphorylation of cytidine/uridine and their analogues during pyrimidine biosynthesis and drug metabolism. We found that UCK2 was overexpressed aberrantly in HTLV-1-infected T cells but not in normal T cells. T-cell activation via T-cell receptor (TCR) signaling induced expression of UCK2 in normal T cells. Somatic alterations and epigenetic modifications in ATL cells activate TCR signaling. Therefore, we believe that expression of UCK2 in HTLV-1-infected cells is induced by dysregulated TCR signaling. Recently, we established azacitidine-resistant (AZA-R) cells showing absent expression of UCK2. AZA-R cells proliferated normally in vitro, whereas UCK2 knockdown inhibited ATL cell growth. Although uridine and cytidine accumulated in AZA-R cells, possibly because of dysfunction of pyrimidine salvage biosynthesis induced by loss of UCK2 expression, the amount of UTP and CTP was almost the same as in parental cells. Furthermore, AZA-R cells were more susceptible to an inhibitor of dihydroorotic acid dehydrogenase, which performs the rate-limiting enzyme of de novo pyrimidine nucleotide biosynthesis, and more resistant to dipyridamole, an inhibitor of pyrimidine salvage biosynthesis, suggesting that AZA-R cells adapt to UCK2 loss by increasing de novo pyrimidine nucleotide biosynthesis. Taken together, the data suggest that fine-tuning pyrimidine biosynthesis supports vigorous cell proliferation of both normal T cells and ATL cells.
Topics: Adult; Humans; Pyrimidines; Uridine; Cell Proliferation; Cytidine; Human T-lymphotropic virus 1; Pyrimidine Nucleotides; Receptors, Antigen, T-Cell; T-Lymphocytes
PubMed: 38190613
DOI: 10.1182/bloodadvances.2023011131 -
Nucleosides, Nucleotides & Nucleic Acids 2022A novel series of pyridine, cytosine, and uracil thioglycoside analogs ( and respectively) and their corresponding phosphoramidates ( and respectively) were...
A novel series of pyridine, cytosine, and uracil thioglycoside analogs ( and respectively) and their corresponding phosphoramidates ( and respectively) were synthesized and assessed for their antiviral inhibitory activities in a dual-pathogen screening protocol against SARS-CoV-2 and influenza A virus (IAV). MTT cytotoxicity (TC50) and plaque reduction assays were used to explore inhibition and cytotoxicity percentage values for H5N1 influenza virus strain and the half-maximal cytotoxic concentration (CC) and inhibitory concentration (IC) for SARS-CoV-2 virus. Most of the tested compounds demonstrated dose-dependent inhibition behavior. Both cytosine thioglycoside phosphoramidates and exhibited the most potent profiles with 83% and 86% inhibition at 0.25 µM concentration against H5N1 and IC values of 12.16 µM, 14.9 µM against SARS-CoV-2, respectively. Moreover, compounds and have been shown to have the highest selectivity index (SI) among all the tested compounds against SARS-CoV-2 with 28.2 and 26.9 values, respectively.
Topics: Amides; Antiviral Agents; Cytosine; Humans; Influenza A Virus, H5N1 Subtype; Influenza A virus; Phosphoric Acids; Pyridines; Pyrimidines; SARS-CoV-2; Thioglycosides; COVID-19 Drug Treatment
PubMed: 35737369
DOI: 10.1080/15257770.2022.2085293