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Scientific Reports Sep 2023Quinazoline derivatives, as an important category of heterocyclic compounds, have received much attention for the design and development of new drugs due to their...
Quinazoline derivatives, as an important category of heterocyclic compounds, have received much attention for the design and development of new drugs due to their various pharmacological properties. Besides, there is a great deal of evidence showing pyrimidine analogs as anticancer agents. Thus, in the present study, for the design of new target compounds with cytotoxic activity, we focused on various quinazolinone and pyrimidine hybrids. A new series of quinazoline-pyrimidine hybrid derivatives (6a-6n) have been designed and synthesized as novel antiproliferative agents. All the synthesized compounds characterized based on their IR, NMR and Mass spectroscopic data. Antiproliferative activities of the new compounds were evaluated against three human cancer cell lines (MCF-7, A549, SW-480). The compounds were found to have appropriate potential with IC values ranging from 2.3 ± 5.91 to 176.5 ± 0.7 μM against the tested cell lines. Compound 6n exerted the highest antiproliferative activity with IC values of 5.9 ± 1.69 μM, 2.3 ± 5.91 μM and 5.65 ± 2.33 μM against A549, SW-480 and MCF-7 respectively. The results indicated that 6n could induce apoptosis in A549 cell line in a dose dependent manner and arrest in the S phase of cell cycle. Docking studies were also done to investigate the detailed binding pattern of the synthesized compounds against EGFR. Furthermore, molecular dynamic simulation and binding free energy calculation have been done to rescore initial docking pose of the synthesized compounds using ensemble-based MMGB/PBSA free energy method. According to the results, free energy calculation confirmed biological activity of compounds and also, Arg 817 and Lys 721 residues had the pivotal role in the high potency of 6n. Finally, the drug likeness and in silico ADME study were also predicted.
Topics: Humans; Quinazolines; Pyrimidines; Antineoplastic Agents; Antimetabolites; Quinazolinones; Antihypertensive Agents
PubMed: 37660139
DOI: 10.1038/s41598-023-41530-6 -
Current Topics in Medicinal Chemistry 2016Adenosine was defined as a neuromodulator which exerts its action by interaction with specific G-protein coupled receptor termed adenosine receptors. Adenosine receptors... (Review)
Review
Adenosine was defined as a neuromodulator which exerts its action by interaction with specific G-protein coupled receptor termed adenosine receptors. Adenosine receptors are expressed in several tissues and cells of our body and exist as four different subtypes of these receptors: A1, A2, A2B and A3. In the last years significant efforts were made to obtain highly potent and selective ligands for the four adenosine receptors subtypes. Both agonists and antagonists were used as pharmacological tools to study therapeutic implications of enhancing or blocking the adenosine receptors activity, and some of these compounds have reached clinical phases. The pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines (PTPs) represent one of the several templates designed as adenosine receptor antagonists. A lot of synthetic work was made on this scaffold in order to obtain potent A2 and A3 antagonists. Here were reviewed the synthetic approaches followed by both academia and industry to introduce different substituents at different positions of the PTP nucleus, in particular at the 2, 5, 7, 8 and 9 positions. Nevertheless PTP derivatives are tricyclic compounds with a high molecular weight which exhibit limitations such as poor aqueous solubility and difficult synthetic preparation. With the aim to obtain derivatives with the same potency and selectivity of PTP but with better drug-like properties, researchers made structural simplification of this scaffold. Replacement of the pyrazole or triazole rings of PTP led to the [1,2,4]triazolo[1,5-c]pyrimidine and pyrazolo[3,4- d]pyrimidine derivatives, respectively. Synthetic strategies for these compounds were reported, combined with the SAR profile on the adenosine receptors.
Topics: Humans; Purinergic P1 Receptor Antagonists; Pyrimidines; Structure-Activity Relationship
PubMed: 27150365
DOI: 10.2174/1568026616666160506145831 -
The Journal of Biological Chemistry Feb 2002D-Nucleoside analogs, which are in the natural configuration, as well as the L-nucleoside analogs, are clinically relevant antiviral and anticancer agents. Metabolism of...
D-Nucleoside analogs, which are in the natural configuration, as well as the L-nucleoside analogs, are clinically relevant antiviral and anticancer agents. Metabolism of L-nucleoside analog diphosphates to the triphosphates, however, remains unexplored. Studies with recombinant nm23-H1 and -H2 isoforms indicated that L-nucleoside analog diphosphates were not phosphorylated by their nucleoside diphosphate kinase (NDPK) activity. Therefore, roles of creatine kinase, 3-phosphoglycerate kinase, and pyruvate kinase were evaluated using preparations from commercial sources and human HepG2 cells. Phosphorylation of L-OddC, L-SddC, L-Fd4C, L-FMAU, and L-ddC were compared with D-deoxynucleoside analogs, AraC, dFdC, and D-FMAU, and D-dideoxynucleoside analogs, ddC and d4T. Results based on preparations from HepG2 cells showed that L-nucleoside analog diphosphates were selectively phosphorylated by 3-phosphoglycerate kinase, whereas, D-deoxynucleoside analog diphosphates were phosphorylated by NDPK. Interestingly, ddCDP and d4TDP were substrates for creatine kinase, but were not phosphorylated by NDPK. In conclusion, it is proposed that specificity of the phosphorylating enzymes toward the nucleoside analog diphosphates is dependent on the configuration of the analog (L or D) and the presence or absence of 3'-hydroxyl group in the sugar moiety. The enzymatic process of phosphorylation of L- and D-nucleoside analog diphosphates is different in cells.
Topics: Adenosine Diphosphate; Adenosine Triphosphate; Blotting, Western; Cell Line; Cloning, Molecular; Creatine Kinase; Diphosphates; Humans; Models, Biological; Models, Chemical; Nucleosides; Phosphates; Phosphoglycerate Kinase; Phosphorylation; Protein Isoforms; Protein Structure, Tertiary; Pyrimidines; Pyruvate Kinase; Thermodynamics
PubMed: 11741981
DOI: 10.1074/jbc.M109025200 -
Nature Communications Apr 2022The lack of pyrimidine diversity in meteorites remains a mystery since prebiotic chemical models and laboratory experiments have predicted that these compounds can also...
The lack of pyrimidine diversity in meteorites remains a mystery since prebiotic chemical models and laboratory experiments have predicted that these compounds can also be produced from chemical precursors found in meteorites. Here we report the detection of nucleobases in three carbonaceous meteorites using state-of-the-art analytical techniques optimized for small-scale quantification of nucleobases down to the range of parts per trillion (ppt). In addition to previously detected purine nucleobases in meteorites such as guanine and adenine, we identify various pyrimidine nucleobases such as cytosine, uracil, and thymine, and their structural isomers such as isocytosine, imidazole-4-carboxylic acid, and 6-methyluracil, respectively. Given the similarity in the molecular distribution of pyrimidines in meteorites and those in photon-processed interstellar ice analogues, some of these derivatives could have been generated by photochemical reactions prevailing in the interstellar medium and later incorporated into asteroids during solar system formation. This study demonstrates that a diversity of meteoritic nucleobases could serve as building blocks of DNA and RNA on the early Earth.
Topics: Meteoroids; Purines; Pyrimidines; Thymine
PubMed: 35473908
DOI: 10.1038/s41467-022-29612-x -
Bioorganic & Medicinal Chemistry Letters Jan 2019Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase II (TOP2) mediated DNA damages and causes cellular resistance to clinically used TOP2 poisons. Inhibiting...
Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase II (TOP2) mediated DNA damages and causes cellular resistance to clinically used TOP2 poisons. Inhibiting TDP2 can potentially sensitize cancer cells toward TOP2 poisons. Commercial compound P10A10, to which the structure was assigned as 7-phenyl triazolopyrimidine analogue 6a, was previously identified as a TDP2 inhibitor hit in our virtual and fluorescence-based biochemical screening campaign. We report herein that the hit validation through resynthesis and structure elucidation revealed the correct structure of P10A10 (Chembridge ID 7236827) to be the 5-phenyl triazolopyrimidine regioisomer 7a. Subsequent structure-activity relationship (SAR) via the synthesis of a total of 47 analogues of both the 5-phenyl triazolopyrimidine scaffold (7) and its bioisosteric triazolopyridine scaffold (17) identified four derivatives (7a, 17a, 17e, and 17z) with significant TDP2 inhibition (IC < 50 µM), with 17z showing excellent cell permeability and no cytotoxicity.
Topics: DNA-Binding Proteins; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Molecular Structure; Nuclear Proteins; Phosphoric Diester Hydrolases; Pyridines; Pyrimidines; Structure-Activity Relationship; Transcription Factors; Triazoles
PubMed: 30522956
DOI: 10.1016/j.bmcl.2018.11.044 -
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 -
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 -
Nature Communications Feb 2021Aspartate transcarbamoylase (ATC), an essential enzyme for de novo pyrimidine biosynthesis, is uniquely regulated in plants by feedback inhibition of uridine...
Aspartate transcarbamoylase (ATC), an essential enzyme for de novo pyrimidine biosynthesis, is uniquely regulated in plants by feedback inhibition of uridine 5-monophosphate (UMP). Despite its importance in plant growth, the structure of this UMP-controlled ATC and the regulatory mechanism remain unknown. Here, we report the crystal structures of Arabidopsis ATC trimer free and bound to UMP, complexed to a transition-state analog or bearing a mutation that turns the enzyme insensitive to UMP. We found that UMP binds and blocks the ATC active site, directly competing with the binding of the substrates. We also prove that UMP recognition relies on a loop exclusively conserved in plants that is also responsible for the sequential firing of the active sites. In this work, we describe unique regulatory and catalytic properties of plant ATCs that could be exploited to modulate de novo pyrimidine synthesis and plant growth.
Topics: Arabidopsis; Aspartate Carbamoyltransferase; Aspartic Acid; Binding Sites; Catalytic Domain; Feedback; Models, Molecular; Protein Conformation; Pyrimidines; Uridine Monophosphate
PubMed: 33574254
DOI: 10.1038/s41467-021-21165-9 -
Molecular Pharmacology Feb 2013African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host. However, uptake of pyrimidines in bloodstream form...
African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host. However, uptake of pyrimidines in bloodstream form trypanosomes has not been investigated, making it difficult to judge the relative importance of salvage and synthesis or to design a pyrimidine-based chemotherapy. Detailed characterization of pyrimidine transport activities in bloodstream form Trypanosoma brucei brucei found that these cells express a high-affinity uracil transporter (designated TbU3) that is clearly distinct from the procyclic pyrimidine transporters. This transporter had low affinity for uridine and 2'deoxyuridine and was the sole pyrimidine transporter expressed in these cells. In addition, thymidine was taken up inefficiently through a P1-type nucleoside transporter. Of importance, the anticancer drug 5-fluorouracil was an excellent substrate for TbU3, and several 5-fluoropyrimidine analogs were investigated for uptake and trypanocidal activity; 5F-orotic acid, 5F-2'deoxyuridine displayed activity in the low micromolar range. The metabolism and mode of action of these analogs was determined using metabolomic assessments of T. brucei clonal lines adapted to high levels of these pyrimidine analogs, and of the sensitive parental strains. The analysis showed that 5-fluorouracil is incorporated into a large number of metabolites but likely exerts toxicity through incorporation into RNA. 5F-2'dUrd and 5F-2'dCtd are not incorporated into nucleic acids but act as prodrugs by inhibiting thymidylate synthase as 5F-dUMP. We present the most complete model of pyrimidine salvage in T. brucei to date, supported by genome-wide profiling of the predicted pyrimidine biosynthesis and conversion enzymes.
Topics: Biological Transport; Fluorouracil; Genome-Wide Association Study; Glycosylation; Nucleoside Transport Proteins; Pyrimidines; Trypanosoma brucei brucei; Uracil; Uridine
PubMed: 23188714
DOI: 10.1124/mol.112.082321 -
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