-
Synthetic Strategies of Pyrimidine-Based Scaffolds as Aurora Kinase and Polo-like Kinase Inhibitors.Molecules (Basel, Switzerland) Aug 2021The past few decades have witnessed significant progress in anticancer drug discovery. Small molecules containing heterocyclic moieties have attracted considerable... (Review)
Review
The past few decades have witnessed significant progress in anticancer drug discovery. Small molecules containing heterocyclic moieties have attracted considerable interest for designing new antitumor agents. Of these, the pyrimidine ring system is found in multitude of drug structures, and being the building unit of DNA and RNA makes it an attractive scaffold for the design and development of anticancer drugs. Currently, 22 pyrimidine-containing entities are approved for clinical use as anticancer drugs by the FDA. An exhaustive literature search indicates several publications and more than 59 patents from the year 2009 onwards on pyrimidine derivatives exhibiting potent antiproliferative activity. These pyrimidine derivatives exert their activity via diverse mechanisms, one of them being inhibition of protein kinases. Aurora kinase (AURK) and polo-like kinase (PLK) are protein kinases involved in the regulation of the cell cycle. Within the numerous pyrimidine-based small molecules developed as anticancer agents, this review focuses on the pyrimidine fused heterocyclic compounds modulating the AURK and PLK proteins in different phases of clinical trials as anticancer agents. This article aims to provide a comprehensive overview of synthetic strategies for the preparation of pyrimidine derivatives and their associated biological activity on AURK/PLK. It will also present an overview of the synthesis of the heterocyclic-2-aminopyrimidine, 4-aminopyrimidine and 2,4-diaminopyrimidine scaffolds, and one of the pharmacophores in AURK/PLK inhibitors is described systematically.
Topics: Animals; Antineoplastic Agents; Aurora Kinases; Cell Cycle; Cell Cycle Proteins; Drug Discovery; Humans; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pyrimidines; Polo-Like Kinase 1
PubMed: 34500603
DOI: 10.3390/molecules26175170 -
Chemistry (Weinheim An Der Bergstrasse,... Oct 2022Catch and release DNA decoys (CRDDs) utilize photochemically responsive nucleoside analogues that generate abasic sites upon exposure to light. Herein, we describe the...
Catch and release DNA decoys (CRDDs) utilize photochemically responsive nucleoside analogues that generate abasic sites upon exposure to light. Herein, we describe the synthesis and evaluation of four candidate CRDD monomers containing nucleobases that mimic endogenous pyrimidines: 2-nitroimidazole (2-NI), 2-nitrobenzene (2-NB), 2-nitropyrrole (2-NP) and 3-nitropyrrole (3-NP). Our studies reveal that 2-NI and 2-NP can function as CRDDs, whereas 3-NP and 2-NB undergo decomposition and transformation to a higher-ordered structure upon photolysis, respectively. When incorporated into DNA, 2-NP undergoes rapid photochemical cleavage of the anomeric bond (1.8 min half-life) to yield an abasic site. Finally, we find that all four pyrimidine mimics show significantly greater stability when base-paired against the previously reported 7-nitroindole CRDD monomer. Our work marks the expansion of CRDD technology to both purine and pyrimidine scaffolds.
Topics: Nucleosides; DNA; Pyrimidines; Purines; Technology; Nitrobenzenes; Nitroimidazoles
PubMed: 35849314
DOI: 10.1002/chem.202201355 -
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 -
Molecules (Basel, Switzerland) Sep 2022To search for Zika virus (ZIKV) antivirals, we have further explored previously reported 7-pyrrolo[2,3-]pyrimidines by examining an alternative substitution pattern of...
To search for Zika virus (ZIKV) antivirals, we have further explored previously reported 7-pyrrolo[2,3-]pyrimidines by examining an alternative substitution pattern of their central scaffold, leading to compound with low micromolar antiviral activity. To circumvent the synthetic difficulties associated with compound , we have exploited a 1-pyrazolo[3,4-]pyrimidine scaffold and performed structure-activity relationship studies on its peripheral rings A and B. While ring B is less sensitive to structural modifications, an electron-withdrawing group at the para position of ring A is preferred for enhanced antiviral activity. Overall, we have not only discovered an alternative substitution pattern centered on a 1-pyrazolo[3,4-]pyrimidine scaffold but also generated anti-ZIKV compounds including and , which possess low micromolar antiviral activity and relatively low cytotoxicity. These compounds represent new chemotypes that will be further optimized in our continued efforts to discover anti-ZIKV agents.
Topics: Amines; Antiviral Agents; Humans; Pyrimidines; Zika Virus; Zika Virus Infection
PubMed: 36144841
DOI: 10.3390/molecules27186109 -
International Journal of Molecular... Sep 2021To explore a new set of anticancer agents, a novel series of pyrazolo[4,3-]pyrido[1,2-]pyrimidine derivativeshave been designed and synthesized viacyclocondensation...
To explore a new set of anticancer agents, a novel series of pyrazolo[4,3-]pyrido[1,2-]pyrimidine derivativeshave been designed and synthesized viacyclocondensation reactions of pyrazolo-enaminone with a series of arylidenemalononitriles; compound was obtained from 5-amino-4-cyanopyrazole. The structures of the target compounds were investigated by spectral techniques and elemental analysis (IR, UV-Vis, H NMR, C NMR and ESI-MS). All compounds were evaluated for their in vitro cytotoxicity employing a panel of different human tumor cell lines, A375, HT29, MCF7, A2780, FaDu as well as non-malignant NIH 3T3 and HEK293 cells. It has been found that the pyrazolo-pyrido-pyrimidine analog bearing a 4-Br-phenyl moiety was the most active toward many cell lines with EC values ranging between 9.1 and 13.5 µM. Moreover, in silico docking studies of the latter with six anticancer drug targets, i.e., DHFR, VEGFR2, HER-2/neu, hCA-IX, CDK6 and LOX5, were also performed, in order to gain some insights into their putative mode of binding interaction and to estimate the free binding energy of this bioactive molecule.
Topics: Animals; Antineoplastic Agents; Cell Line; Cell Line, Tumor; Computer Simulation; Cytotoxins; Drug Screening Assays, Antitumor; HEK293 Cells; HT29 Cells; Humans; MCF-7 Cells; Mice; Molecular Docking Simulation; NIH 3T3 Cells; Pyrazoles; Pyrimidines
PubMed: 34638600
DOI: 10.3390/ijms221910258 -
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 -
Scientific Reports Dec 2022A mild and efficient method was developed for the synthesis of new derivatives of thiazolo[3,2-a] pyrimidin-3(2H)-ones from available starting materials based on the...
A mild and efficient method was developed for the synthesis of new derivatives of thiazolo[3,2-a] pyrimidin-3(2H)-ones from available starting materials based on the oxidation of catechols to ortho-quinone by Myceliophthora thermophila laccase (Novozym 51,003) and 1,4-addition of active methylene carbon to these in situ generated intermediates in moderate to good yields (35-93%). The structure of the products was confirmed through H NMR, C NMR, HMBC, HSQC, DEPT-135, and mass spectroscopy techniques. These novel compounds were evaluated as active antitumor agents against human colorectal adenocarcinoma and liver adenocarcinoma cell lines. All compounds displayed potent inhibition activities against the HT-29 cell line with IC values of 9.8-35.9 µM, superior to the positive control doxorubicin, and most showed potent anticancer activities against the HepG2 cell line.
Topics: Humans; Antineoplastic Agents; Cell Proliferation; Drug Screening Assays, Antitumor; Hep G2 Cells; HT29 Cells; Laccase; Molecular Structure; Structure-Activity Relationship; Thiazoles; Pyrimidines
PubMed: 36567332
DOI: 10.1038/s41598-022-26820-9 -
PloS One 2013Rapid response to chemotherapy in metastatic colorectal cancer (mCRC) patients (response within 12 weeks of chemotherapy) may increase the chance of complete resection... (Clinical Trial)
Clinical Trial
BACKGROUND
Rapid response to chemotherapy in metastatic colorectal cancer (mCRC) patients (response within 12 weeks of chemotherapy) may increase the chance of complete resection and improved survival. Few molecular markers predict irinotecan-induced rapid response and survival. Single-nucleotide polymorphisms (SNPs) in solute carrier genes are reported to correlate with the variable pharmacokinetics of irinotecan and folate in cancer patients. This study aims to evaluate the predictive role of 3 SNPs in mCRC patients treated with irinotecan and fluoropyrimidine-containing regimens.
MATERIALS AND METHODS
Three SNPs were selected and genotyped in 137 mCRC patients from a Chinese prospective multicenter trial (NCT01282658). The chi-squared test, univariate and multivariable logistic regression model, and receiver operating characteristic analysis were used to evaluate correlations between the genotypes and rapid response. Kaplan-Meier survival analysis and Cox proportional hazard models were used to evaluate the associations between genotypes and survival outcomes. Benjamini and Hochberg False Discovery Rate correction was used in multiple testing.
RESULTS
Genotype GA/AA of SNP rs2306283 of the gene SLCO1B1 and genotype GG of SNP rs1051266 of the gene SLC19A1 were associated with a higher rapid response rate (odds ratio [OR] =3.583 and 3.521, 95%CI =1.301-9.871 and 1.271-9.804, p=0.011 and p=0.013, respectively). The response rate was 70% in patients with both genotypes, compared with only 19.7% in the remaining patients (OR = 9.489, 95%CI = 2.191-41.093, Fisher's exact test p=0.002). Their significances were all maintained even after multiple testing (all p c < 0.05). The rs2306283 GA/AA genotype was also an independent prognostic factor of longer progression-free survival (PFS) (hazard ratio = 0.402, 95%CI = 0.171-0.945, p=0.037). None of the SNPs predicted overall survival.
CONCLUSIONS
Polymorphisms of solute carriers' may be useful to predict rapid response to irinotecan plus fluoropyrimidine and PFS in mCRC patients.
Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Haplotypes; Humans; Irinotecan; Linkage Disequilibrium; Liver-Specific Organic Anion Transporter 1; Male; Middle Aged; Neoplasm Metastasis; Organic Anion Transporters; Pharmacogenetics; Polymorphism, Single Nucleotide; Prospective Studies; Pyrimidines; Reduced Folate Carrier Protein; Survival Analysis; Time Factors; Treatment Outcome; Young Adult
PubMed: 24143213
DOI: 10.1371/journal.pone.0077223 -
Molecules (Basel, Switzerland) Nov 2022A series of novel 4-(aryl)-benzo[4,5]imidazo[1,2-]pyrimidine-3-carbonitriles were obtained through the Povarov (aza-Diels-Alder) and oxidation reactions, starting from...
A series of novel 4-(aryl)-benzo[4,5]imidazo[1,2-]pyrimidine-3-carbonitriles were obtained through the Povarov (aza-Diels-Alder) and oxidation reactions, starting from benzimidazole-2-arylimines. Based on the literature data and X-ray diffraction analysis, it was discovered that during the Povarov reaction, [1,3] sigmatropic rearrangement leading to dihydrobenzimidazo[1,2-]pyrimidines took place. The structures of all the obtained compounds were confirmed based on the data from H- and C-NMR spectroscopy, IR spectroscopy, and elemental analysis. For all the obtained compounds, their photophysical properties were studied. In all the cases, a positive emission solvatochromism with Stokes shifts from 120 to 180 nm was recorded. Aggregation-Induced Emission (AIE) has been illustrated for compound using different water fractions (fw) in THF. The compounds and demonstrated changes in emission maxima or/and intensities after mechanical stimulation.
Topics: Density Functional Theory; Pyrimidines; Fluorescent Dyes; Ionophores; Magnetic Resonance Spectroscopy
PubMed: 36432130
DOI: 10.3390/molecules27228029 -
Molecules (Basel, Switzerland) Jan 2022In an attempt to increase the biological activity of the 1,2,4-triazolo[1,5-]pyrimidine scaffold through complexation with essential metal ions, the complexes...
In an attempt to increase the biological activity of the 1,2,4-triazolo[1,5-]pyrimidine scaffold through complexation with essential metal ions, the complexes -[Cu(mptp)Cl] (), [Zn(mptp)Cl(DMSO)] () (mptp: 5-methyl-7-phenyl-1,2,4-triazolo[1,5-]pyrimidine), [Cu(dmtp)Cl]·2HO () and [Zn(dmtp)Cl] () (dmtp: 5,7-dimethyl-1,2,4-triazolo[1,5-]pyrimidine), were synthesized and characterized as new antiproliferative and antimicrobial species. Both complexes () and () crystallize in the 2/n monoclinic space group, with the tetrahedral surroundings generating a square-planar stereochemistry in the Cu(II) complex and a tetrahedral stereochemistry in the Zn(II) species. The mononuclear units are interconnected in a supramolecular network through π-π interactions between the pyrimidine moiety and the phenyl ring in () while supramolecular chains resulting from C-H∙∙∙π interactions were observed in (). All complexes exhibit an antiproliferative effect against B16 tumor cells and improved antibacterial and antifungal activities compared to the free ligands. Complex () displays the best antimicrobial activity against all four tested strains, both in the planktonic and biofilm-embedded states, which can be correlated to its stronger DNA-binding and nuclease-activity traits.
Topics: Anti-Bacterial Agents; Antifungal Agents; Coordination Complexes; Copper; Crystallography, X-Ray; Humans; Ligands; Microbial Sensitivity Tests; Molecular Structure; Pyrimidines; Spectroscopy, Fourier Transform Infrared; Structure-Activity Relationship; Zinc
PubMed: 35164029
DOI: 10.3390/molecules27030765