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European Journal of Medicinal Chemistry Jan 2021Carbonic anhydrase (CA, EC 4.2.1.1) is an enzyme and a very omnipresent zinc metalloenzyme which catalyzed the reversible hydration and dehydration of carbon dioxide and... (Review)
Review
Carbonic anhydrase (CA, EC 4.2.1.1) is an enzyme and a very omnipresent zinc metalloenzyme which catalyzed the reversible hydration and dehydration of carbon dioxide and bicarbonate; a reaction which plays a crucial role in many physiological and pathological processes. Carbonic anhydrase is present in human (h) with sixteen different isoforms ranging from hCA I-hCA XV. All these isoforms are widely distributed in different tissues/organs and are associated with a range of pivotal physiological activities. Due to their involvement in various physiological roles, inhibitors of different human isoforms of carbonic anhydrase have found clinical applications for the treatment of various diseases including glaucoma, retinopathy, hemolytic anemia, epilepsy, obesity, and cancer. However, clinically used inhibitors of CA (acetazolamide, brinzolamide, dorzolamide, etc.) are not selective causing the undesirable side effects. One of the major hurdles in the design and development of carbonic anhydrase inhibitors is the lack of balanced isoform selectivity which thrived to new chemotypes. In this review, we have compiled the recent strategies of various researchers related to the development of carbonic anhydrase inhibitors belonging to different structural classes like pyrimidine, pyrazoline, selenourea, isatin, indole, etc. This review also summarizes the structure-activity relationships, analysis of isoform selectivity including mechanistic and in silico studies to afford ideas and to provide focused direction for the design and development of novel isoform-selective carbonic anhydrase inhibitors with therapeutic implications.
Topics: Acetazolamide; Animals; Antineoplastic Agents; Antioxidants; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Humans; Indoles; Isatin; Molecular Docking Simulation; Organoselenium Compounds; Oxadiazoles; Protein Binding; Protein Isoforms; Pyrimidines; Structure-Activity Relationship; Sulfonamides; Thiazines; Thiophenes; Urea; Benzenesulfonamides
PubMed: 33121862
DOI: 10.1016/j.ejmech.2020.112923 -
Molecular Microbiology Dec 2021Trichomoniasis is a common and widespread sexually-transmitted infection, caused by the protozoan parasite Trichomonas vaginalis. T. vaginalis lacks the biosynthetic...
Trichomoniasis is a common and widespread sexually-transmitted infection, caused by the protozoan parasite Trichomonas vaginalis. T. vaginalis lacks the biosynthetic pathways for purines and pyrimidines, making nucleoside metabolism a drug target. Here we report the first comprehensive investigation into purine and pyrimidine uptake by T. vaginalis. Multiple carriers were identified and characterized with regard to substrate selectivity and affinity. For nucleobases, a high-affinity adenine transporter, a possible guanine transporter and a low affinity uracil transporter were found. Nucleoside transporters included two high affinity adenosine/guanosine/uridine/cytidine transporters distinguished by different affinities to inosine, a lower affinity adenosine transporter, and a thymidine transporter. Nine Equilibrative Nucleoside Transporter (ENT) genes were identified in the T. vaginalis genome. All were expressed equally in metronidazole-resistant and -sensitive strains. Only TvagENT2 was significantly upregulated in the presence of extracellular purines; expression was not affected by co-culture with human cervical epithelial cells. All TvagENTs were cloned and separately expressed in Trypanosoma brucei. We identified the main broad specificity nucleoside carrier, with high affinity for uridine and cytidine as well as purine nucleosides including inosine, as TvagENT3. The in-depth characterization of purine and pyrimidine transporters provides a critical foundation for the development of new anti-trichomonal nucleoside analogues.
Topics: Biological Transport; Cloning, Molecular; Humans; Kinetics; Nucleoside Transport Proteins; Protozoan Proteins; Purines; Pyrimidines; Trichomonas Infections; Trichomonas vaginalis
PubMed: 34738285
DOI: 10.1111/mmi.14840 -
Leukemia Apr 2021Mechanisms-of-resistance to decitabine and 5-azacytidine, mainstay treatments for myeloid malignancies, require investigation and countermeasures. Both are nucleoside...
Mechanisms-of-resistance to decitabine and 5-azacytidine, mainstay treatments for myeloid malignancies, require investigation and countermeasures. Both are nucleoside analog pro-drugs processed by pyrimidine metabolism into a deoxynucleotide analog that depletes the key epigenetic regulator DNA methyltranseferase 1 (DNMT1). Here, upon serial analyses of DNMT1 levels in patients' bone marrows on-therapy, we found DNMT1 was not depleted at relapse. Showing why, bone marrows at relapse exhibited shifts in expression of key pyrimidine metabolism enzymes in directions adverse to pro-drug activation. Further investigation revealed the origin of these shifts. Pyrimidine metabolism is a network that senses and regulates deoxynucleotide amounts. Deoxynucleotide amounts were disturbed by single exposures to decitabine or 5-azacytidine, via off-target depletion of thymidylate synthase and ribonucleotide reductase respectively. Compensating pyrimidine metabolism shifts peaked 72-96 h later. Continuous pro-drug exposures stabilized these adaptive metabolic responses to thereby prevent DNMT1-depletion and permit exponential leukemia out-growth as soon as day 40. The consistency of the acute metabolic responses enabled exploitation: simple treatment modifications in xenotransplant models of chemorefractory leukemia extended noncytotoxic DNMT1-depletion and leukemia control by several months. In sum, resistance to decitabine and 5-azacytidine originates from adaptive responses of the pyrimidine metabolism network; these responses can be anticipated and thus exploited.
Topics: Animals; Antimetabolites, Antineoplastic; Azacitidine; Cell Line, Tumor; DNA (Cytosine-5-)-Methyltransferase 1; DNA Methylation; Decitabine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Humans; Metabolic Networks and Pathways; Mice; Pyrimidines; Uridine Kinase
PubMed: 32770088
DOI: 10.1038/s41375-020-1003-x -
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 -
Journal of Virology Apr 2020Human enteroviruses (EVs), including coxsackieviruses, the numbered enteroviruses, and echoviruses, cause a wide range of diseases, such as hand, foot, and mouth disease...
Human enteroviruses (EVs), including coxsackieviruses, the numbered enteroviruses, and echoviruses, cause a wide range of diseases, such as hand, foot, and mouth disease (HFMD), encephalitis, myocarditis, acute flaccid myelitis (AFM), pneumonia, and bronchiolitis. Therefore, broad-spectrum anti-EV drugs are urgently needed to treat EV infection. Here, we demonstrate that FNC (2'-deoxy-2'-β-fluoro-4'-azidocytidine), a small nucleoside analog inhibitor that has been demonstrated to be a potent inhibitor of HIV and entered into a clinical phase II trial in China, potently inhibits the viral replication of a multitude of EVs, including enterovirus 71 (EV71), coxsackievirus A16 (CA16), CA6, EVD68, and coxsackievirus B3 (CVB3), at the nanomolar level. The antiviral mechanism of FNC involves mainly positive- and negative-strand RNA synthesis inhibition by targeting and competitively inhibiting the activity of EV71 viral RNA-dependent RNA polymerase (3D), as demonstrated through quantitative real-time reverse transcription-PCR (RT-qPCR), 3D activity, and isothermal titration calorimetry (ITC) experiments. We further demonstrated that FNC treatment every 2 days with 1 mg/kg of body weight in EV71 and CA16 infection neonatal mouse models successfully protected mice from lethal challenge with EV71 and CA16 viruses and reduced the viral load in various tissues. These findings provide important information for the clinical development of FNC as a broad-spectrum inhibitor of human EV pathogens. Human enterovirus (EV) pathogens cause various contagious diseases such as hand, foot, and mouth disease, encephalitis, myocarditis, acute flaccid myelitis, pneumonia, and bronchiolitis, which have become serious health threats. However, except for the EV71 vaccine on the market, there are no effective strategies to prevent and treat other EV pathogen infections. Therefore, broad-spectrum anti-EV drugs are urgently needed. In this study, we demonstrated that FNC, a small nucleoside analog inhibitor that has been demonstrated to be a potent inhibitor of HIV and entered into a clinical phase II trial in China, potently inhibits the viral replication of a multitude of EVs at the nanomolar level. Further investigation revealed that FNC inhibits positive- and negative-strand RNA synthesis of EVs by interacting and interfering with the activity of EV71 viral RNA-dependent RNA polymerase (3D). Our findings demonstrate for the first time that FNC is an effective broad-spectrum inhibitor for human EV pathogens.
Topics: Animals; Azides; China; Coxsackievirus Infections; Deoxycytidine; Enterovirus; Enterovirus A, Human; Enterovirus B, Human; Enterovirus Infections; Mice; Pyrimidines; Viral Load; Virus Replication
PubMed: 32075935
DOI: 10.1128/JVI.00204-20 -
Plant Science : An International... Aug 2018Thiamin is essential for plant growth but is short-lived in vivo and energetically very costly to produce - a combination that makes thiamin biosynthesis a prime target...
Thiamin is essential for plant growth but is short-lived in vivo and energetically very costly to produce - a combination that makes thiamin biosynthesis a prime target for improvement by redesign. Thiamin consists of thiazole and pyrimidine moieties. Its high biosynthetic cost stems from use of the suicide enzyme THI4 to form the thiazole and the near-suicide enzyme THIC to form the pyrimidine. These energetic costs lower biomass yield potential and are likely compounded by environmental stresses that destroy thiamin and hence increase the rate at which it must be made. The energy costs could be slashed by refactoring the thiamin biosynthesis pathway to eliminate the suicidal THI4 and THIC reactions. To substantiate this design concept, we first document the energetic costs of the THI4 and THIC steps in the pathway and explain how cutting these costs could substantially increase crop biomass and grain yields. We then show that a refactored pathway must produce thiamin itself rather than a stripped-down analog because the thiamin molecule cannot be simplified without losing biological activity. Lastly, we consider possible energy-efficient alternatives to the inefficient natural THI4- and THIC-mediated steps.
Topics: Metabolic Engineering; Metabolic Networks and Pathways; Oxygen; Plants; Pyrimidines; Synthetic Biology; Thiamine; Thiazoles
PubMed: 29907313
DOI: 10.1016/j.plantsci.2018.01.019 -
Nucleosides, Nucleotides & Nucleic Acids 2023In this study, it was reported that twelve nucleoside analogues were synthesized by click reactions. The reactions were carried out between the azide derivatives of...
In this study, it was reported that twelve nucleoside analogues were synthesized by click reactions. The reactions were carried out between the azide derivatives of D-glucopyranose, D-galactopyranose, D-ribofuranose and propargylamino pyrimidine derivatives ( and ) that are synthesized a different route for the first time. In the first step, -propargyl guanidine was obtained with the reaction of 1-pyrazole-1-carboxamidine hydrochloride and propargyl amine, then condensation of -propargyl guanidine and -diketone ( and ) resulted in 2-propargylamino pyrimidines ( and ) for the first time in good yields (85%). Finally, click reactions were performed with azidosugars () and 2-propargylamino pyrimidine derivatives and produced twelve new nucleoside analogues in good yields. (, 65-73% yields). The chemical structures of the new derivatives were elucidated spectroscopic techniques, such as FT-IR, H NMR, F NMR, C NMR and TOF-ESI-MS.
Topics: Pyrimidines; Nucleosides; Spectroscopy, Fourier Transform Infrared; Magnetic Resonance Spectroscopy
PubMed: 36047982
DOI: 10.1080/15257770.2022.2118317 -
Journal of Medicinal Chemistry Nov 2023The breakthrough in drug development of KRAS inhibitors provides inspiration for targeting alternative KRAS mutations, especially the most prevalent KRAS variant. Based...
The breakthrough in drug development of KRAS inhibitors provides inspiration for targeting alternative KRAS mutations, especially the most prevalent KRAS variant. Based on the structural analysis of MRTX1133 in complex with KRAS, a comprehensive structure-activity study was conducted, which led to the discovery of several compounds (, , and ) that showed higher potency in suppressing the clonogenic growth of KRAS-dependent cancer cells. These new compounds markedly and selectively inhibited the binding of RBD peptide to GTP-bound KRAS with IC values between 0.48 and 1.21 nM. These new inhibitors were found to have dose-dependent anti-tumor efficacy in the AsPC-1 xenograft mouse models with a tumor growth inhibition of approximately 70% at a dose of 20 mg/kg twice daily (i.p.). Despite the non-optimal pharmacokinetic properties similar to those of MRTX1133, the high and potency of these new inhibitors call for further profiling.
Topics: Animals; Humans; Mice; Mutation; Proto-Oncogene Proteins p21(ras); Pyrimidines
PubMed: 37921024
DOI: 10.1021/acs.jmedchem.3c01724 -
Nature Jun 2020The nature of the first genetic polymer is the subject of major debate. Although the 'RNA world' theory suggests that RNA was the first replicable information carrier of...
The nature of the first genetic polymer is the subject of major debate. Although the 'RNA world' theory suggests that RNA was the first replicable information carrier of the prebiotic era-that is, prior to the dawn of life-other evidence implies that life may have started with a heterogeneous nucleic acid genetic system that included both RNA and DNA. Such a theory streamlines the eventual 'genetic takeover' of homogeneous DNA from RNA as the principal information-storage molecule, but requires a selective abiotic synthesis of both RNA and DNA building blocks in the same local primordial geochemical scenario. Here we demonstrate a high-yielding, completely stereo-, regio- and furanosyl-selective prebiotic synthesis of the purine deoxyribonucleosides: deoxyadenosine and deoxyinosine. Our synthesis uses key intermediates in the prebiotic synthesis of the canonical pyrimidine ribonucleosides (cytidine and uridine), and we show that, once generated, the pyrimidines persist throughout the synthesis of the purine deoxyribonucleosides, leading to a mixture of deoxyadenosine, deoxyinosine, cytidine and uridine. These results support the notion that purine deoxyribonucleosides and pyrimidine ribonucleosides may have coexisted before the emergence of life.
Topics: Adenosine; Cytidine; DNA; Evolution, Chemical; Origin of Life; Oxidation-Reduction; Purine Nucleosides; Pyrimidine Nucleosides; RNA; Uridine
PubMed: 32494078
DOI: 10.1038/s41586-020-2330-9 -
Antimicrobial Agents and Chemotherapy Mar 2018infection is responsible for a global pandemic. New drugs are needed that do not show cross-resistance with the existing front-line therapeutics. A triazine...
infection is responsible for a global pandemic. New drugs are needed that do not show cross-resistance with the existing front-line therapeutics. A triazine antitubercular hit led to the design of a related pyrimidine family. The synthesis of a focused series of these analogs facilitated exploration of their activity, cytotoxicity, and physiochemical and absorption-distribution-metabolism-excretion properties. Select pyrimidines were then evaluated for their pharmacokinetic profiles in mice. The findings suggest a rationale for the further evolution of this promising series of antitubercular small molecules, which appear to share some similarities with the clinical compound PA-824 in terms of activation, while highlighting more general guidelines for the optimization of small-molecule antitubercular agents.
Topics: Animals; Antitubercular Agents; Disease Models, Animal; Drug Design; Drug Stability; Female; Humans; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitroimidazoles; Pyrimidines; Solubility; Structure-Activity Relationship; Tuberculosis
PubMed: 29311070
DOI: 10.1128/AAC.02063-17