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Journal of Cancer Research and Clinical... Jul 2023Arylamine N-acetyltransferase 1 (NAT1), a phase II metabolic enzyme, is frequently upregulated in breast cancer. Inhibition or depletion of NAT1 leads to growth...
PURPOSE
Arylamine N-acetyltransferase 1 (NAT1), a phase II metabolic enzyme, is frequently upregulated in breast cancer. Inhibition or depletion of NAT1 leads to growth retardation in breast cancer cells in vitro and in vivo. A previous metabolomics study of MDA-MB-231 breast cancer cells suggests that NAT1 deletion leads to a defect in de novo pyrimidine biosynthesis. In the present study, we observed that NAT1 deletion results in upregulation of cytidine deaminase (CDA), which is involved in the pyrimidine salvage pathway, in multiple breast cancer cell lines (MDA-MB-231, MCF-7 and ZR-75-1). We hypothesized that NAT1 KO MDA-MB-231 cells show differential sensitivity to drugs that either inhibit cellular pyrimidine homeostasis or are metabolized by CDA.
METHODS
The cells were treated with (1) inhibitors of dihydroorotate dehydrogenase or CDA (e.g., teriflunomide and tetrahydrouridine); (2) pyrimidine/nucleoside analogs (e.g., gemcitabine and 5-azacytidine); and (3) naturally occurring, modified cytidines (e.g., 5-formyl-2'-deoxycytidine; 5fdC).
RESULTS
Although NAT1 KO cells failed to show differential sensitivity to nucleoside analogs that are metabolized by CDA, they were markedly more sensitive to 5fdC which induces DNA damage in the presence of high CDA activity. Co-treatment with 5fdC and a CDA inhibitor, tetrahydrouridine, abrogated the increase in 5fdC cytotoxicity in NAT1 KO cells, suggesting that the increased sensitivity of NAT1 KO cells to 5fdC is dependent on their increased CDA activity.
CONCLUSIONS
The present findings suggest a novel therapeutic strategy to treat breast cancer with elevated NAT1 expression. For instance, NAT1 inhibition may be combined with cytotoxic nucleosides (e.g., 5fdC) for breast cancer treatment.
Topics: Humans; Female; Cytidine Deaminase; Breast Neoplasms; Tetrahydrouridine; Up-Regulation; Pyrimidines; Arylamine N-Acetyltransferase
PubMed: 36329350
DOI: 10.1007/s00432-022-04436-w -
Cell Death & Disease May 2020Formate is a precursor for the de novo synthesis of purine and deoxythymidine nucleotides. Formate also interacts with energy metabolism by promoting the synthesis of...
Formate is a precursor for the de novo synthesis of purine and deoxythymidine nucleotides. Formate also interacts with energy metabolism by promoting the synthesis of adenine nucleotides. Here we use theoretical modelling together with metabolomics analysis to investigate the link between formate, nucleotide and energy metabolism. We uncover that endogenous or exogenous formate induces a metabolic switch from low to high adenine nucleotide levels, increasing the rate of glycolysis and repressing the AMPK activity. Formate also induces an increase in the pyrimidine precursor orotate and the urea cycle intermediate argininosuccinate, in agreement with the ATP-dependent activities of carbamoyl-phosphate and argininosuccinate synthetase. In vivo data for mouse and human cancers confirms the association between increased formate production, nucleotide and energy metabolism. Finally, the in vitro observations are recapitulated in mice following and intraperitoneal injection of formate. We conclude that formate is a potent regulator of purine, pyrimidine and energy metabolism.
Topics: Adenosine Triphosphate; Adenylate Kinase; Aminoimidazole Carboxamide; Animals; Cell Line, Tumor; Colorectal Neoplasms; Disease Models, Animal; Energy Metabolism; Female; Formates; Humans; Mice, Inbred C57BL; Models, Biological; Models, Genetic; Nucleotides; Orotic Acid; Pyrimidines; Ribonucleotides
PubMed: 32366892
DOI: 10.1038/s41419-020-2523-z -
Anti-cancer Agents in Medicinal... 2017One of the promising scaffolds in drug discovery is the fused pyrimidine derivatives.
BACKGROUND
One of the promising scaffolds in drug discovery is the fused pyrimidine derivatives.
OBJECTIVE AND METHOD
Efficient synthesis of a novel series of 18 new 1,8-naphthyridine-3-carbonitrile, 2-amino pyrido[2,3-d]pyrimidine derivatives via multi-component reactions of aromatic aldehydes, active methylene, and an aromatic amine under microwave irradiation and evaluation of their anticancer activity and possible mechanisms.
RESULTS
Only compounds 5 (a-c) had a significant antiproliferative activity in hepatic HepG2 cells at submicromolar concentration (7.5-10 µM). Similarly, only compound 11 (a-c) had a significant activity in breast MCF7 cells at (4-7 µM). Derivatives with one methoxyphenyl substitution (5a and 11a) were not different from derivatives having dimethoxyphenyl substitution (5b and 11b). However, thiophene substitution (5c and 11c) enhanced the anticancer activity in both cells lines examined by 25% in HepG2 and by ~45% in MCF7 cells compared to a and b derivatives. All compounds were safe to both normal human lung cells (WI-38) and RBCs at concentrations up to 40 mM. The antiproliferative activity of compounds 5 (a-c) in HepG2 could be attributed to an induction of intrinsic apoptotic pathway as evidenced from the induction of initiator caspase 9 by ~ 4 folds. While, the activity of compounds 11 (a-c) could be attributed to their potential to inhibit tyrosine kinases (TK) by up to 85%. The IC50 of derivative 11c against TK was at 173 nM.
CONCLUSION
The present study reported that derivatives 5 and 11 have merit for further investigation as anticancer and TK inhibitors.
Topics: Antineoplastic Agents; Apoptosis; Cell Line; Cell Line, Tumor; Cell Proliferation; Erythrocytes; Hemolysis; Humans; Inhibitory Concentration 50; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Spectrum Analysis; Structure-Activity Relationship
PubMed: 28403776
DOI: 10.2174/1871521409666170412130040 -
Nature Communications Aug 2018Bioluminescence resonance energy transfer (BRET) is extensively used to study dynamic systems and has been utilized in sensors for studying protein proximity,...
Bioluminescence resonance energy transfer (BRET) is extensively used to study dynamic systems and has been utilized in sensors for studying protein proximity, metabolites, and drug concentrations. Herein, we demonstrate that BRET can activate a ruthenium-based photocatalyst which performs bioorthogonal reactions. BRET from luciferase to the ruthenium photocatalyst is used to uncage effector molecules with up to 64 turnovers of the catalyst, achieving concentrations >0.6 μM effector with 10 nM luciferase construct. Using a BRET sensor, we further demonstrate that the catalysis can be modulated in response to an analyte, analogous to allosterically controlled enzymes. The BRET-induced reaction is used to uncage small-molecule drugs (ibrutinib and duocarmycin) at biologically effective concentrations in cellulo.
Topics: Adenine; Bioluminescence Resonance Energy Transfer Techniques; Luciferases; Luminescent Proteins; Photochemistry; Piperidines; Pyrazoles; Pyrimidines; Rhodamines
PubMed: 30166547
DOI: 10.1038/s41467-018-05916-9 -
PloS One 2022Gastric cancer is one of the most common malignancies around the world, and a variety of neoadjuvant chemotherapies with different drug combinations are available for... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Gastric cancer is one of the most common malignancies around the world, and a variety of neoadjuvant chemotherapies with different drug combinations are available for the treatment. R0 resection refers to a microscopically negative margin on resection, where no gross or microscopic tumour remains in the primary tumour. We aimed to find evidence on the relative effectiveness of neoadjuvant therapies for patients with advanced gastroesophageal and gastric cancer on the R0 resection rate.
METHODS
Relevant randomised controlled trials were searched using appropriate keywords in health-related databases. We performed network meta-analysis within a frequentist framework. The endpoint assessed was the R0 resection rate. We assessed consistency and transitivity assumptions that are necessary for network meta-analysis. This study only used data from published studies. The need for consent from participants was waived by the Ethics Review Committee of the International Medical University in Malaysia.
RESULTS
Six randomised controlled trials involving 1700 patients were identified. A network plot was formed with five neoadjuvant regimens [DLX (pyrimidine analogue + platinum compounds + chemoradiotherapy), DELX (pyrimidine analogue + epipodophylllotoxins/etoposide + platinum compounds + chemoradiotherapy), ADL (anthracycline + pyrimidine analogue + platinum compounds), ADM (anthracycline+ pyrimidine analogue + anti-folate compounds) and LTX (platinum compounds + taxane + chemoradiotherapy)] and surgery alone for management of patients with advanced gastroesophageal and gastric cancer. Assumptions required for a network meta-analysis such as consistency ((global test: Chi2 (1): 3.71; p:0.054)), and the transitivity in accord to the characteristics of interventions considered in this review were not violated. In the network comparison, surgery alone has a lower R0 resection rate compared with LTX (OR 0.2, 95%CI:0.01, 0.38) or DLX (OR 0.48, 95%CI: 0.29, 0.79). LTX has higher resection rate compared with DLX (OR 2.47, 95%CI: 1.08 to 5.63), DELX (OR 106.0, 95%CI: 25.29 to 444.21), ADM (OR 5.41, 95%CI: 1.56 to 18.78) or ADL (OR 3.12, 95%CI: 1.27 to 7.67). There were wide or very wide CIs in many of these comparisons. Overall certainty of the evidence was low or very low. Further research in this field is very likely to have an important impact on our confidence in the R0 resection rates between LTX versus other neoadjuvant chemotherapy is likely to change the estimate.
CONCLUSIONS
Findings suggest that overall quality of evidence on the relative effectiveness of neoadjuvant chemotherapies was low to very low level. Therefore, we are very uncertain about the true effect of neoadjuvant therapies in the R0 resection rate in patients with gastroesophageal and gastric cancer. Future well-designed large trials are needed. To recruit large samples in this field, multicountry trials are recommended. Future trials also need to assess treatment-related adverse events, and patients-centered outcomes such as health-related quality of life.
Topics: Anthracyclines; Etoposide; Humans; Neoadjuvant Therapy; Network Meta-Analysis; Platinum Compounds; Pyrimidines; Quality of Life; Randomized Controlled Trials as Topic; Stomach Neoplasms; Taxoids
PubMed: 36156598
DOI: 10.1371/journal.pone.0275186 -
Microbial Drug Resistance (Larchmont,... Oct 2021is the second frequent etiologic agent of mucosal and invasive candidiasis. Based on the recent developments in molecular methods, has been introduced as a complex... (Review)
Review
is the second frequent etiologic agent of mucosal and invasive candidiasis. Based on the recent developments in molecular methods, has been introduced as a complex composed of , , and . The four main classes of antifungal drugs effective against are pyrimidine analogs (flucytosine), azoles, echinocandins, and polyenes. Although the use of antifungal drugs is related to the predictable development of drug resistance, it is not clear why is able to rapidly resist against multiple antifungals in clinics. The enhanced incidence and antifungal resistance of and the high mortality and morbidity need more investigation regarding the resistance mechanisms and virulence associated with ; additional progress concerning the drug resistance of has to be further prevented. The present review highlights the mechanism of resistance to antifungal drugs in .
Topics: Antifungal Agents; Azoles; Candida glabrata; Drug Resistance, Fungal; Echinocandins; Global Health; Polyenes; Pyrimidines
PubMed: 33956513
DOI: 10.1089/mdr.2020.0235 -
Current Medicinal Chemistry 2023Microwave radiation is used as a heating source during the synthesis of heterocyclic compounds. The heating mechanisms involved in microwave-induced synthesis include... (Review)
Review
Microwave radiation is used as a heating source during the synthesis of heterocyclic compounds. The heating mechanisms involved in microwave-induced synthesis include dipolar polarization and ionic conduction. This heating technology follows the green protocol as it involves the use of recyclable organic solvents during synthesis. The microwave heating approach offers a faster rate of reaction, easier work-up procedure, and higher product yield with purity and also reduces environmental pollution. So, microwave heating is applied as a sustainable technology for the efficient production of pyrimidine compounds as one of the heterocyclic moieties. Pyrimidine is a six-membered nitrogenous heterocyclic compound that plays a significant role due to several therapeutic applications. This moiety acts as an essential building block for generating drug candidates with diverse biological activities, including anti-cancer (capecitabine), anti-thyroid (propylthiouracil), antihistaminic (pemirolast), antimalarial (pyrimethamine), antidiabetic (alloxan), antihypertensive (minoxidil), anti-inflammatory (octotiamine), antifungal (cyprodinil), antibacterial (sulfamethazine), etc. This review is focused on the synthesis of pyrimidine analogs under microwave irradiation technique and the study of their therapeutic potentials.
Topics: Humans; Microwaves; Pyrimidines; Heterocyclic Compounds; Technology
PubMed: 35733315
DOI: 10.2174/0929867329666220622150013 -
Journal of Medicinal Chemistry Apr 2021Chagas disease and visceral leishmaniasis are two neglected tropical diseases responsible for numerous deaths around the world. For both, current treatments are largely...
Chagas disease and visceral leishmaniasis are two neglected tropical diseases responsible for numerous deaths around the world. For both, current treatments are largely inadequate, resulting in a continued need for new drug discovery. As both kinetoplastid parasites are incapable of purine synthesis, they depend on purine salvage pathways that allow them to acquire and process purines from the host to meet their demands. Purine nucleoside analogues therefore constitute a logical source of potential antiparasitic agents. Earlier optimization efforts of the natural product tubercidin (7-deazaadenosine) involving modifications to the nucleobase 7-position and the ribofuranose 3'-position led to analogues with potent anti- brucei and anti- activities. In this work, we report the design and synthesis of pyrazolo[3,4-]pyrimidine nucleosides with 3'- and 7-modifications and assess their potential as anti- and antileishmanial agents. One compound was selected for evaluation in an acute Chagas disease mouse model.
Topics: Animals; Chagas Disease; Drug Design; Drug Stability; Humans; Leishmania infantum; Male; Mice; Microsomes, Liver; Molecular Structure; Nucleosides; Pyrazoles; Pyrimidines; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma cruzi
PubMed: 33784107
DOI: 10.1021/acs.jmedchem.1c00135 -
Haematologica Dec 2016
Topics: Adenine; Age Factors; Clinical Studies as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Sweden; United Kingdom
PubMed: 27903711
DOI: 10.3324/haematol.2016.155986 -
Bioorganic Chemistry Sep 2023The synthesis of 24 hybrid molecules, consisting of naturally occurring sclareol (SCL) and synthetic 1,2,4-triazolo[1,5-a]pyrimidines (TPs), is described. New compounds...
The synthesis of 24 hybrid molecules, consisting of naturally occurring sclareol (SCL) and synthetic 1,2,4-triazolo[1,5-a]pyrimidines (TPs), is described. New compounds were designed with the aim of improving the cytotoxic properties, activity, and selectivity of the parent compounds. Six analogs (12a-f) contained 4-benzylpiperazine linkage, while 4-benzyldiamine linkage was present in eighteen derivatives (12g-r and 13a-f). Hybrids 13a-f consist of two TP units. After purification, all hybrids (12a-r and 13a-f), as well as their precursors (9a-e and 11a-c), were tested on human glioblastoma U87 cells. More than half of the tested synthesized molecules, 16 out of 31, caused a significant reduction of U87 cell viability (more than 75% reduction) at 30 µM. The concentration-dependent cytotoxicity of these 16 compounds was also examined on U87 cells, corresponding multidrug-resistant (MDR) U87-TxR cells with increased P-glycoprotein (P-gp) expression and activity, and normal lung fibroblasts MRC-5. Importantly, 12l and 12r were active in the nanomolar range, while seven compounds (11b, 11c, 12i, 12l, 12n, 12q, and 12r) were more selective towards glioblastoma cells than SCL. All compounds except 12r evaded MDR, showing even better cytotoxicity in U87-TxR cells. In particular, 11c, 12a, 12g, 12j, 12k, 12m, 12n, and SCL showed collateral sensitivity. Hybrid compounds 12l, 12q, and 12r decreased P-gp activity to the same extent as a well-known P-gp inhibitor - tariquidar (TQ). Hybrid compound 12l and its precursor 11c affected different cellular processes including the cell cycle, cell death, and mitochondrial membrane potential, and changed the levels of reactive oxygen and nitrogen species (ROS/RNS) in glioblastoma cells. Collateral sensitivity towards MDR glioblastoma cells was caused by the modulation of oxidative stress accompanied by inhibition of mitochondria.
Topics: Humans; Antineoplastic Agents; Cell Line, Tumor; Drug Collateral Sensitivity; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Glioblastoma; Pyrimidines
PubMed: 37201322
DOI: 10.1016/j.bioorg.2023.106605