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1.
Molecules ; 28(2)2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36677558

RESUMO

The present work describes the design and development of seventeen pyrimidine-clubbed benzimidazole derivatives as potential dihydrofolate reductase (DHFR) inhibitors. These compounds were filtered by using ADMET, drug-likeness characteristics calculations, and molecular docking experiments. Compounds 27, 29, 30, 33, 37, 38, and 41 were chosen for the synthesis based on the results of the in silico screening. Each of the synthesized compounds was tested for its in vitro antibacterial and antifungal activities using a variety of strains. All the compounds showed antibacterial properties against Gram-positive bacteria (Staphylococcus aureus and Staphylococcus pyogenes) as well as Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa). Most of the compounds either had a higher potency than chloramphenicol or an equivalent potency to ciprofloxacin. Compounds 29 and 33 were effective against all the bacterial and fungal strains. Finally, the 1,2,3,4-tetrahydropyrimidine-2-thiol derivatives with a 6-chloro-2-(chloromethyl)-1H-benzo[d]imidazole moiety are potent enough to be considered a promising lead for the discovery of an effective antibacterial agent.


Assuntos
Antagonistas do Ácido Fólico , Antagonistas do Ácido Fólico/farmacologia , Simulação de Acoplamento Molecular , Antibacterianos/farmacologia , Benzimidazóis/farmacologia , Resistência Microbiana a Medicamentos , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Testes de Sensibilidade Microbiana , Estrutura Molecular
2.
Molecules ; 28(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36615619

RESUMO

The overexpression of p21-activated kinase 4 (PAK4) is associated with a variety of cancers. In this paper, the binding modes and inhibitory mechanisms of four 7H-pyrrolo[2,3-d]pyrimidine competitive inhibitors of PAK4 were investigated at the molecular level, mainly using molecular dynamics simulations and binding free energy calculations. The results show that the inhibitors had strong interactions with the hinge region, the ß-sheets, and the residues with charged side chains around the 4-substituent. The terminal amino group of the inhibitor 5n was different from the other three, which could cause the enhancement of hydrogen bonds or electrostatic interactions formed with the surrounding residues. Thus, inhibitor 5n had the strongest inhibition capacity. The different halogen atoms on the 2-substituents of the inhibitors 5h, 5g, and 5e caused differences in the positions of the 2-benzene rings and affected the interactions of the hinge region. It also affected to some extent the orientations of the 4-imino groups and consequently their affinities for the surrounding charged residues. The combined results lead to the weakest inhibitory capacity of inhibitor 5e.


Assuntos
Simulação de Dinâmica Molecular , Quinases Ativadas por p21 , Pirimidinas/farmacologia , Pirimidinas/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
3.
Molecules ; 28(2)2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36677798

RESUMO

A novel series of pyrido[2,3-d]pyrimidines; pyrido[3,2-e][1,3,4]triazolo; and tetrazolo[1,5-c]pyrimidines were synthesized via different chemical transformations starting from pyrazolo[3,4-b]pyridin-6-yl)-N,N-dimethylcarbamimidic chloride 3b (prepared from the reaction of o-aminonitrile 1b and phosogen iminiumchloride). The structures of the newly synthesized compounds were elucidated based on spectroscopic data and elemental analyses. Designated compounds are subjected for molecular docking by using Auto Dock Vina software in order to evaluate the antiviral potency for the synthesized compounds against SARS-CoV-2 (2019-nCoV) main protease M pro. The antiviral activity against SARS-CoV-2 showed that tested compounds 7c, 7d, and 7e had the most promising antiviral activity with lower IC50 values compared to Lopinavir, "the commonly used protease inhibitor". Both in silico and in vitro results are in agreement.


Assuntos
Antivirais , Pirimidinas , SARS-CoV-2 , Antivirais/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/farmacologia , Pirimidinas/farmacologia , Pirimidinas/química , SARS-CoV-2/efeitos dos fármacos
4.
J Enzyme Inhib Med Chem ; 38(1): 2169282, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36656085

RESUMO

To explore the potential use of CDK inhibitors in pancreatic ductal adenocarcinoma (PDAC) therapy, a series of novel 2-((4-sulfamoylphenyl)amino)-pyrrolo[2,3-d]pyrimidine derivatives was designed, synthesised, and investigated for inhibition on both CDK kinase activity and cellular proliferation of pancreatic cancer. Most of new sulphonamide-containing derivatives demonstrated strong inhibitory activity on CDK9 and obvious anti-proliferative activity in cell culture. Moreover, two new compounds suppressed cell proliferation of multiple human pancreatic cancer cell lines. The most potent compound 2g inhibited cancer cell proliferation by blocking Rb phosphorylation and induced apoptosis via downregulation of CDK9 downstream proteins Mcl-1 and c-Myc in MIA PaCa-2 cells. CDK9 knockdown experiment suggests its anti-proliferative activity is mainly mediated by CDK9. Additionally, 2g displayed moderate tumour inhibition effect in AsPC-1 derived xenograft mice model. Altogether, this study provided a new start for further optimisation to develop potential CDK inhibitor candidates for PDAC treatment by alone or combination use.


Assuntos
Antineoplásicos , Neoplasias Pancreáticas , Humanos , Camundongos , Animais , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proliferação de Células , Apoptose , Pirimidinas/farmacologia
5.
J Med Chem ; 66(2): 1157-1171, 2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36624931

RESUMO

PDE10A is an important regulator of striatal signaling that, when inhibited, can normalize dysfunctional activity. Given the involvement of dysfunctional striatal activity with schizophrenia, PDE10A inhibition represents a potentially novel means for its treatment. With the goal of developing PDE10A inhibitors, early optimization of a fragment hit through rational design led to a series of potent pyrimidine PDE10A inhibitors that required further improvements in physicochemical properties, off-target activities, and pharmacokinetics. Herein we describe the discovery of an isomeric pyrimidine series that addresses the liabilities seen with earlier compounds and resulted in the invention of compound 18 (MK-8189), which is currently in Phase 2b clinical development for the treatment of schizophrenia.


Assuntos
Inibidores de Fosfodiesterase , Esquizofrenia , Humanos , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/metabolismo , Relação Estrutura-Atividade , Esquizofrenia/tratamento farmacológico , Cristalografia por Raios X , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/química
6.
Eur J Med Chem ; 248: 115085, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36621138

RESUMO

Novel 4,6-pyrimidine analogues were designed and synthesized as colchicine binding site inhibitors (CBSIs) with potent antiproliferative activities. Among them, compound 17j has the most potent activities against 6 human cancer cell lines with IC50 values from 1.1 nM to 4.4 nM, which was 76 times higher than the lead compound 3 in A549 cells. The co-crystal structure of 17j in complex with tubulin confirms the key binding mode at the colchicine binding site. Moreover, 17j inhibited the tubulin polymerization in biochemical assays, depolymerized cellular microtubules, induced the G2/M arrest, inhibited the cell migration, and promoted the initiation of apoptosis. In vivo, 17j effectively inhibits primary tumor growth with tumor growth inhibition rates of 42.51% (5 mg/kg) and 65.42% (10 mg/kg) in A549 xenograft model. Taken together, 17j represents a promising new generation of CBSIs.


Assuntos
Antineoplásicos , Compostos Heterocíclicos , Humanos , Colchicina/farmacologia , Colchicina/metabolismo , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/química , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Pontos de Checagem da Fase G2 do Ciclo Celular , Antineoplásicos/farmacologia , Antineoplásicos/química , Sítios de Ligação , Compostos Heterocíclicos/farmacologia , Pirimidinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-Atividade
7.
Proc Natl Acad Sci U S A ; 120(4): e2217543120, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36669104

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, in which prognosis is determined by liver fibrosis. A common variant in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13, rs72613567-A) is associated with a reduced risk of fibrosis in NAFLD, but the underlying mechanism(s) remains unclear. We investigated the effects of this variant in the human liver and in Hsd17b13 knockdown in mice by using a state-of-the-art metabolomics approach. We demonstrate that protection against liver fibrosis conferred by the HSD17B13 rs72613567-A variant in humans and by the Hsd17b13 knockdown in mice is associated with decreased pyrimidine catabolism at the level of dihydropyrimidine dehydrogenase. Furthermore, we show that hepatic pyrimidines are depleted in two distinct mouse models of NAFLD and that inhibition of pyrimidine catabolism by gimeracil phenocopies the HSD17B13-induced protection against liver fibrosis. Our data suggest pyrimidine catabolism as a therapeutic target against the development of liver fibrosis in NAFLD.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Camundongos , Fígado/metabolismo , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Pirimidinas/farmacologia , Pirimidinas/metabolismo
8.
Eur J Med Chem ; 247: 115034, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36603506

RESUMO

The deep conditional transformer neural network SyntaLinker was applied to identify compounds with pyrrolo[2,3-d]pyrimidine scaffold as potent selective TBK1 inhibitor. Further medicinal chemistry optimization campaign led to the discovery of the most potent compound 7l, which exhibited strong enzymatic inhibitory activity against TBK1 with an IC50 value of 22.4 nM 7l had a superior inhibitory activity in human monocytic THP1-Blue cells reporter gene assay than MRT67307. Furthermore, 7l significantly inhibited TBK1 downstream target genes cxcl10 and ifnß expression in THP1 and RAW264.7 cells induced by poly (I:C) and lipopolysaccharide, respectively. This study suggested that combination of deep conditional transformer neural network SyntaLinker and transfer learning could be a powerful tool for scaffold hopping in drug discovery.


Assuntos
Descoberta de Drogas , Pirimidinas , Humanos , Relação Estrutura-Atividade , Pirimidinas/farmacologia , Pirimidinas/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases
9.
Eur J Med Chem ; 247: 115042, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36577220

RESUMO

Following on our initial discovery of S-CN-DABOs as non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel S-N3-DABO derivatives F1-F31 were developed by substituting the cyano group of S-CN-DABOs with azide group. Some of these compounds were conferred significantly increased potency against wild-type HIV-1 and clinically observed mutant strains. Remarkably, the best compound F10 exerted a 7-fold improvement in potency (EC50 = 0.053 µM) and 12.5-fold higher selectivity (SI = 6818) in MT-4 cells infected with wild-type HIV-1, compared to that of the parent compound B1 (EC50 = 370 nM, SI = 547). The anti-HIV-1 activity of F10 against the tested mutant strains was prominently enhanced. For wild-type reverse transcriptase, it was approximately 19-fold more potent (IC50 = 0.080 µM) than B1 (IC50 = 1.51 µM). It was not found that this analog had significant inhibition of hERG, CYP, and acute toxicity after a single dose of F10 (1.0 g/kg).


Assuntos
Fármacos Anti-HIV , HIV-1 , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade , Transcriptase Reversa do HIV , Pirimidinas/farmacologia , Pirimidinonas/farmacologia , Compostos Heterocíclicos com 1 Anel , HIV-1/metabolismo , Fármacos Anti-HIV/farmacologia , Desenho de Fármacos
10.
Eur J Med Chem ; 245(Pt 1): 114887, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36370549

RESUMO

Monopolar spindle kinase 1 (Mps1), a core component of the spindle assembly checkpoint (SAC), plays a crucial role in the transition of cells from mid-to late mitosis. As an attractive therapeutic target, inhibition of Mps1 induces cell cycle arrest and apoptosis in a variety of tumors, including breast cancer. However, early clinical development of Mps1 inhibitors remains unsatisfactory. Here, we designed and synthesized a new class of Mps1 inhibitors with 7H-pyrrolo[2,3-d]pyrimidine structure using a scaffold hopping approach. Structure-activity relationship (SAR) revealed that 12 is a potent Mps1 inhibitor (IC50 = 29 nM), which inhibited phosphorylation of Mps1 in vitro and in vivo. Treatment with 12 not only impeded proliferation of breast cancer cell lines, but also induced cell cycle arrest and apoptosis of MCF-7 and 4T1 cells. 12 suppressed tumor growth in vivo, and no obvious toxicities were observed. These results demonstrated the potential of Mps1 inhibitor 12 for the treatment of breast cancer.


Assuntos
Antineoplásicos , Neoplasias da Mama , Inibidores de Proteínas Quinases , Proteínas Serina-Treonina Quinases , Pirimidinas , Feminino , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Proteínas de Ciclo Celular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Linhagem Celular Tumoral , Desenho de Fármacos
11.
Bioorg Chem ; 130: 106264, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36395603

RESUMO

Although the effective drugs or vaccines have been developed to prevent the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), their efficacy may be limited for the viral evolution and immune escape. Thus, it is urgently needed to develop the novel broad-spectrum antiviral agents to control the coronavirus disease 2019 (COVID-19) global pandemic. The 3C-like protease (3CLpro) is a highly conserved cysteine proteinase that plays a pivotal role in processing the viral polyprotein to create non-structural proteins (nsps) for replication and transcription of SARS-CoV-2, making it an attractive antiviral target for developing broad-spectrum antiviral agents against SARS-CoV-2. In this study, we identified Thonzonium bromide as an inhibitor of SARS-CoV-2 3CLpro with an IC50 value of 2.04 ± 0.25 µM by fluorescence resonance energy transfer (FRET)-based enzymatic inhibition assay from the FDA-approved drug library. Next, we determined the inhibitory activity of Thonzonium bromide analogues against SARS-CoV-2 3CLpro and analyzed their structure-activity relationship (SAR). Interestingly, Thonzonium bromide showed better inhibitory activity than other analogues. Further fluorescence quenching assay, enzyme kinetics analysis, circular dichroism (CD) analysis and molecular docking studies showed that Thonzonium bromide inhibited SARS-CoV-2 3CLpro activity by firmly occupying the catalytic site and inducing conformational changes of the protease. In addition, Thonzonium bromide didn't exhibit inhibitory activity on human chymotrypsin C (CTRC) and Dipeptidyl peptidase IV (DPP-IV), indicating that it had a certain selectivity. Finally, we measured the inhibitory activities of Thonzonium bromide against 3CLpro of SARS-CoV, MERS-CoV and HCoV-229E and found that it had the broad-spectrum inhibitory activity against the proteases of human coronaviruses. These results provide the possible mechanism of action of Thonzonium bromide, highlighting its potential efficacy against multiple human coronaviruses.


Assuntos
Pirimidinas , Compostos de Amônio Quaternário , SARS-CoV-2 , Inibidores de Protease Viral , Humanos , Antivirais/farmacologia , Endopeptidases , Simulação de Acoplamento Molecular , Peptídeo Hidrolases/metabolismo , SARS-CoV-2/enzimologia , SARS-CoV-2/metabolismo , Compostos de Amônio Quaternário/farmacologia , Pirimidinas/farmacologia , Inibidores de Protease Viral/farmacologia
12.
J Med Chem ; 66(1): 837-854, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36516476

RESUMO

The highly conserved catalytic sites in protein kinases make it difficult to identify ATP competitive inhibitors with kinome-wide selectivity. Serendipitously, during a dedicated fragment campaign for the focal adhesion kinase (FAK), a scaffold that had lost its initial FAK affinity showed remarkable potency and selectivity for serine-arginine-protein kinases 1-3 (SRPK1-3). Non-conserved interactions with the uniquely structured hinge region of the SRPK family were the key drivers of the exclusive selectivity of the discovered fragment hit. Structure-guided medicinal chemistry efforts led to the SRPK inhibitor MSC-1186, which fulfills all hallmarks of a reversible chemical probe, including nanomolar cellular potency and excellent kinome-wide selectivity. The combination of MSC-1186 with CDC2-like kinase (CLK) inhibitors showed additive attenuation of SR-protein phosphorylation compared to the single agents. MSC-1186 and negative control (MSC-5360) are chemical probes available via the Structural Genomics Consortium chemical probe program (https://www.sgc-ffm.uni-frankfurt.de/).


Assuntos
Proteínas Serina-Treonina Quinases , Pirimidinas , Fosforilação , Pirimidinas/farmacologia , Benzimidazóis/farmacologia
13.
Chem Pharm Bull (Tokyo) ; 71(2): 140-147, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36517026

RESUMO

Epidermal growth factor receptor (EGFR) C797S mutation leads to Osimertinib drug resistance by disturbing the covalent biding of Michael acceptor group to the Cys797 residue in the ATP biding cleft. In this manuscript, a class of 2-amine-4-oxyphosaniline pyrimidine derivatives were designed, synthesized and evaluated as new noncovalent reversible EGFR inhibitors against L858R/T790M/C797S (CTL) triple mutant. The kinases inhibitiory activity evaluation showed that four compounds exhibited significant inhibitory activities against CTL (IC50 < 30 nM). In particularly, the most promising compound 7a showed excellent enzymatic inhibitory activity against CTL with IC50 value of 9.9 nM, which was more potent than control compound Osimertinib. Moreover, cell proliferation assays indicated that 7a effectively inhibited H1975-EGFR L858R/T790M/C797S with IC50 value of 0.33 µM. Furthermore, compound 7a displayed good metabolic stabilities in human, rat and mouse liver microsomes, and the putative biding mode of compound 7a with ATP was revealed by molecular docking study. These findings strongly indicated that compound 7a was a promising L858R/T790M/C797S mutant EGFR inhibitor.


Assuntos
Receptores ErbB , Neoplasias Pulmonares , Camundongos , Ratos , Humanos , Animais , Simulação de Acoplamento Molecular , Mutação , Aminas/farmacologia , Inibidores de Proteínas Quinases/química , Pirimidinas/farmacologia , Pirimidinas/química , Trifosfato de Adenosina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células
14.
Antiviral Res ; 209: 105498, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36563943

RESUMO

Enterovirus 71 (EV71), a small, single-stranded, positive-sense RNA virus belonging to the enterovirus genus in the family Picornaviridae, causes hand, foot, and mouth disease. Although EV71 seriously threatens to public health, no effective antiviral drugs are available for treating this disease. In this study, we found that ML390, a dihydroorotate dehydrogenase inhibitor, has potential anti-EV71 activity. ML390 dose-dependently inhibited EV71 replication with IC50 and selectivity index values of 0.06601 µM and 156.5, respectively. Supplementation with the downstream product orotate significantly suppressed the ability of ML390 to inhibit EV71 replication. Moreover, an adequate supply of exogenous uridine and cytosine suppressed the anti-EV71 activity of ML390. Thus, the antiviral activity of ML390 is mediated by the inhibition of the pyrimidine synthesis pathway. In an EV71-infected mouse model, ML390 reduced the load of EV71 in the brain, liver, heart, spleen, front legs, and hind legs, and significantly increased the survival rate of the mice infected by EV71. ML390 shows potential for the treatment of hand, foot, and mouth disease caused by EV71 infection.


Assuntos
Enterovirus Humano A , Infecções por Enterovirus , Enterovirus , Doença de Mão, Pé e Boca , Chlorocebus aethiops , Animais , Camundongos , Doença de Mão, Pé e Boca/tratamento farmacológico , Células Vero , Replicação Viral , Infecções por Enterovirus/tratamento farmacológico , Pirimidinas/farmacologia , Antivirais/uso terapêutico
15.
J Med Chem ; 66(1): 413-434, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36573286

RESUMO

Dry eye disease (DED) is one of the most prevalent ocular diseases but has limited treatment options. Cystic fibrosis transmembrane conductance regulator (CFTR), a major chloride channel that stimulates fluid secretion in the ocular surface, may pave the way for new therapeutic strategies for DED. Herein, we report the optimization of Cact-3, a potent CFTR activator with poor solubility, to 16d, a potent CFTR activator with suitable solubility for eye drop formulation. Notably, 16d was well distributed in target tissues including cornea and conjunctiva with minimal systemic exposure in rabbit. Topical ocular instillation of 16d significantly enhanced tear secretion and improved corneal erosion in a mouse model of DED. In addition, 16d significantly reduced mRNA expression of pro-inflammatory cytokines including IL-1ß, IL-17, and TNF-α and MMP2 in cornea and conjunctiva of DED mice.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Síndromes do Olho Seco , Camundongos , Animais , Coelhos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Solubilidade , Lágrimas/metabolismo , Síndromes do Olho Seco/tratamento farmacológico , Síndromes do Olho Seco/genética , Síndromes do Olho Seco/metabolismo , Túnica Conjuntiva/metabolismo , Córnea , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/metabolismo
16.
Sci Rep ; 12(1): 22326, 2022 12 25.
Artigo em Inglês | MEDLINE | ID: mdl-36567332

RESUMO

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 1H NMR, 13C 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 IC50 values of 9.8-35.9 µM, superior to the positive control doxorubicin, and most showed potent anticancer activities against the HepG2 cell line.


Assuntos
Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Lacase , Pirimidinas , Tiazóis , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Hep G2 , Células HT29 , Lacase/química , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia
17.
Biomolecules ; 12(12)2022 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-36551206

RESUMO

Previously, we reported that MTH1 inhibitors TH588 and TH1579 selectively induce oxidative damage and kill Ras-expressing or -transforming cancer cells, as compared to non-transforming immortalized or primary cells. While this explains the impressive anti-cancer properties of the compounds, the molecular mechanism remains elusive. Several oncogenes induce replication stress, resulting in under replicated DNA and replication continuing into mitosis, where TH588 and TH1579 treatment causes toxicity and incorporation of oxidative damage. Hence, we hypothesized that oncogene-induced replication stress explains the cancer selectivity. To test this, we overexpressed c-Myc in human epithelial kidney cells (HA1EB), resulting in increased proliferation, polyploidy and replication stress. TH588 and TH1579 selectively kill c-Myc overexpressing clones, enforcing the cancer cell selective killing of these compounds. Moreover, the toxicity of TH588 and TH1579 in c-Myc overexpressing cells is rescued by transcription, proteasome or CDK1 inhibitors, but not by nucleoside supplementation. We conclude that the molecular toxicological mechanisms of how TH588 and TH1579 kill c-Myc overexpressing cells have several components and involve MTH1-independent proteasomal degradation of c-Myc itself, c-Myc-driven transcription and CDK activation.


Assuntos
Enzimas Reparadoras do DNA , Estresse Oxidativo , Humanos , Enzimas Reparadoras do DNA/metabolismo , Linhagem Celular Tumoral , Pirimidinas/farmacologia , Dano ao DNA
18.
Molecules ; 27(24)2022 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-36557833

RESUMO

In this work, we describe the design, synthesis, and structure-activity relationship of 6-(tetrazol-5-yl)-7-aminoazolo[1,5-a]pyrimidines as inhibitors of Casein kinase 2 (CK2). At first, we optimized the reaction conditions for the azide-nitrile cycloaddition in the series of 6-cyano-7-aminoazolopyridimines and sodium azide. The regioselectivity of this process has been shown, as the cyano group of the pyrimidine cycle was converted to tetrazole while the nitrile of the azole fragment did not react. The desired tetrazolyl-azolopyrimidines were obtained in a moderate to excellent yields (42-95%) and converted further to water soluble sodium salts by the action of sodium bicarbonate. The obtained 6-(tetrazol-5-yl)-7-aminopyrazolo[1,5-a]pyrimidines 2a-k and their sodium salts 3a-c, 3g-k showed nano to low micromolar range of CK2 inhibition while corresponding [1,2,4]triazolopyrimidines 10a-k were less active (IC50 > 10 µM). The leader compound 3-phenyl-6-(tetrazol-5-yl)-7-aminopyrazolo[1,5-a]pyrimidine 2i as CK2 inhibitor showed IC50 45 nM.


Assuntos
Caseína Quinase II , Sais , Desenho de Fármacos , Relação Estrutura-Atividade , Tetrazóis/farmacologia , Pirimidinas/farmacologia , Nitrilas , Sódio , Estrutura Molecular
19.
Molecules ; 27(23)2022 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-36500341

RESUMO

Positive allosteric modulators (PAMs) of AMPA receptors represent attractive candidates for the development of drugs for the treatment of cognitive and neurodegenerative disorders. Dimeric molecules have been reported to have an especially potent modulating effect, due to the U-shaped form of the AMPA receptor's allosteric binding site. In the present work, novel bis(pyrimidines) were studied as AMPA receptor modulators. A convenient and flexible preparative approach to bis(pyrimidines) containing a hydroquinone linker was elaborated, and a series of derivatives with varied substituents was obtained. The compounds were examined in the patch clamp experiments for their influence on the kainate-induced currents, and 10 of them were found to have potentiating properties. The best potency was found for 2-methyl-4-(4-((2-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)oxy)phenoxy)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidine, which potentiated the kainate-induced currents by up to 77% in all tested concentrations (10-12-10-6 M). The results were rationalized via the modeling of modulator complexes with the dimeric ligand binding domain of the GluA2 AMPA receptor, using molecular docking and molecular dynamics simulation. The prediction of ADMET, physicochemical, and PAINS properties of the studied bis(pyrimidines) confirmed that PAMs of this type may act as the potential lead compounds for the development of neuroprotective drugs.


Assuntos
Pirimidinas , Receptores de AMPA , Receptores de AMPA/química , Receptores de AMPA/metabolismo , Regulação Alostérica , Simulação de Acoplamento Molecular , Pirimidinas/farmacologia
20.
Chem Pharm Bull (Tokyo) ; 70(11): 823-826, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36328525

RESUMO

Here, we synthesized three acetogenin analogs containing pyrimidine moieties linked by amine bonds, which represent the skeleton structure of pyrimidifen, a mitochondrial complex I-inhibiting insecticide. Replacing the pyrimidine moiety linked by the amine bond remarkably enhanced growth-inhibitory activity of the analogs against several human cancer cell lines. Moreover, these analogs selectively and potently inhibited the growth of these human cancer cell lines regardless of the pyrimidine substituents. Furthermore, COMPARE analyses suggested that these analogs inhibited cancer growth by inhibiting mitochondrial complex I. Our study provides insights into the design of acetogenin analogs as novel antitumor agents.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Acetogeninas , Aminas/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Pirimidinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-Atividade , Proliferação de Células , Estrutura Molecular
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