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1.
Eur J Med Chem ; 189: 112091, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32007665

RESUMO

Mycophenolic acid (MPA) was coupled with amino acids and biologically active peptides including derivatives of tuftsin to modify its immunosuppressive properties. Both amino acid unit in the case of simple MPA amides and modifications within peptide moiety of MPA - tuftsin conjugates influenced the observed activity. Antiproliferative potential of the obtained conjugates was investigated in vitro and MPA amides with threonine methyl ester and conjugate of MPA with retro-tuftisin occurred to be more selective against PBMC in comparison to parent MPA. Both amino acid and peptide derivatives of MPA acted as inosine-5'-monophosphate dehydrogenaze (IMPDH) inhibitors.


Assuntos
Aminoácidos/química , Proliferação de Células , Inibidores Enzimáticos/farmacologia , Imunossupressores/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Ácido Micofenólico/química , Fragmentos de Peptídeos/química , Inibidores Enzimáticos/química , Humanos , IMP Desidrogenase/antagonistas & inibidores , Imunossupressores/química , Células Jurkat , Estrutura Molecular , Relação Estrutura-Atividade
2.
J Dermatolog Treat ; 31(8): 810-814, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31294617

RESUMO

Background: For severe cases of atopic dermatitis, systemic or potent agents may be required for control of disease. There have been some reports of treatment efficacy of off-label use of mycophenolate mofetil (MMF) in patients with refractory atopic dermatitis or have developed adverse effects to initial systemic agents.Methods: Electronic searches were performed using six databases from their inception to April 2019. Data were extracted and analyzed according to predefined clinical endpoints.Results: From 140 cases, the mean age was 38.21 ± 22.8 years. There were 52.9% males and 47.1% females. The average number of failed agents was 3.5 ± 1.2. 77.6% reported partial or full remission. Relapses occurred in 8.2% of cases. The average time for initial effects was 6.8 ± 7 weeks. There was a significant reduction in pre to post SCORAD scores by 18 points (p = .0002). More males had complications compared to females. Prolonged duration of treatment ≥1 year was associated with herpes infections.Conclusions: In summary, the current evidence to date is low-quality in nature but is promising regarding the efficacy and safety of MMF for adult and pediatric atopic dermatitis. There should be ongoing monitoring for infections that may develop on long term therapy.


Assuntos
Dermatite Atópica/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , IMP Desidrogenase/antagonistas & inibidores , Ácido Micofenólico/uso terapêutico , Adolescente , Adulto , Análise de Variância , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Masculino , Ácido Micofenólico/efeitos adversos , Uso Off-Label , Indução de Remissão
3.
Biomed Pharmacother ; 118: 109305, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545264

RESUMO

Foot-and-mouth disease virus (FMDV) is an important pathogen that affects livestock breeding and causes huge economic losses worldwide. Currently, the development of antiviral agents to combat FMDV infection at the early stages is being explored. As viral replication critically depends on the host for nucleoside supply, host enzymes involved in nucleotides biosynthesis may represent potential targets for the development of antiviral agents. In the present study, the effects of IMP dehydrogenase (AVN-944 and mycophenolate mofetil) and dihydroorotate dehydrogenase (teriflunomide) inhibitors were evaluated both in vitro and in vivo. The results revealed that these compounds were effective in suppressing FMDV (O/MY98/BY/2010 and A/GD/MM/2013) infection. With regard to the antiviral mechanism, time-of-addition experiments revealed that these compounds were effective when added at the early stages of viral lifecycle (0-8 h post infection). However, exogenous guanosine/uridine eliminated the antiviral activity of these compounds. Importantly, treatment AVN-944 and teriflunomide significantly improved the survival of mice that were subcutaneously treated with FMDV. Together, the results of the present study indicate the broad-spectrum activities of anti-FMDV agents targeting IMP dehydrogenase or dihydroorotate dehydrogenase, which could be useful in developing strategies to prevent FMD.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Vírus da Febre Aftosa/fisiologia , IMP Desidrogenase/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/uso terapêutico , Morte Celular , Linhagem Celular , Inibidores Enzimáticos/química , Febre Aftosa/tratamento farmacológico , Febre Aftosa/virologia , Vírus da Febre Aftosa/efeitos dos fármacos , Guanosina/farmacologia , IMP Desidrogenase/metabolismo , Camundongos Endogâmicos BALB C , Miocárdio/patologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Uridina/farmacologia
4.
Int J Hematol ; 110(5): 606-617, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31407254

RESUMO

FF-10501 is a novel inhibitor of inosine monophosphate dehydrogenase (IMPDH). Clinical trials of FF-10501 for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are currently being conducted in the United States. Although it has been shown that FF-10501 induces apoptosis in hematological malignant cells, the intracellular mechanisms of this effect have not been characterized. We conducted an in vitro study to elucidate the mechanisms of FF-10501-induced cell death using 12 hematological malignant cell lines derived from myeloid and lymphoid malignancies. FF-10501 suppressed the growth of each cell line in a dose-dependent manner. However, the clinically relevant dose (40 µM) of FF-10501 induced cell death in three cell lines (MOLM-13, OCI-AML3, and MOLT-3). Investigation of the cell death mechanism suggested that FF-10501 induces both apoptotic and necrotic cell death. FF-10501-induced apoptosis was mediated by caspase-8 activation followed by activation of the mitochondrial pathway in MOLM-13 and MOLT-3 cells. FF-10501 induced necrotic cell death via endoplasmic reticulum stress in OCI-AML3 cells. The present study is the first to identify intracellular pathways involved in FF-10501-induced cell death.


Assuntos
Morte Celular/efeitos dos fármacos , Neoplasias Hematológicas/patologia , IMP Desidrogenase/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Caspase 8/metabolismo , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Mitocôndrias/metabolismo , Necrose/induzido quimicamente
5.
J Antibiot (Tokyo) ; 72(12): 934-942, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31296916

RESUMO

We have found cyclophane-type adenosine derivatives having p-quinone amide moieties (1 and 2) as weak inhibitors of Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase (CpIMPDH) from the Hokkaido University Chemical Library via the luciferase-based high-throughput screening. To obtain more potent inhibitors, we synthesized four new derivatives free from cyclophane rings (3-6). The N-H derivatives 3 and 5 showed more potent activities (24.4 and 11.1 µM, respectively) in the presence of dithiothreitol (DTT), whereas the N-methyl derivative 4 indicated more potent activity (2.1 µM) without DTT. Conformational analysis of compounds 3 and 4 suggested that N-H amide 3 binds to IMP-binding site in the DTT mediated manner.


Assuntos
Cryptosporidium parvum/enzimologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Antiparasitários/química , Antiparasitários/farmacologia , Sítios de Ligação , Ditiotreitol/química , Inibidores Enzimáticos/síntese química , Ensaios de Triagem em Larga Escala , Humanos , IMP Desidrogenase/genética , IMP Desidrogenase/metabolismo , Relação Estrutura-Atividade
6.
Eur J Med Chem ; 174: 309-329, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31055147

RESUMO

Tuberculosis (TB) is a major infectious disease associated increasingly with drug resistance. Thus, new anti-tubercular agents with novel mechanisms of action are urgently required for the treatment of drug-resistant TB. In prior work, we identified compound 1 (cyclohexyl(4-(isoquinolin-5-ylsulfonyl)piperazin-1-yl)methanone) and showed that its anti-tubercular activity is attributable to inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH) in Mycobacterium tuberculosis. In the present study, we explored the structure-activity relationship around compound 1 by synthesizing and evaluating the inhibitory activity of analogues against M. tuberculosis IMPDH in biochemical and whole-cell assays. X-ray crystallography was performed to elucidate the mode of binding of selected analogues to IMPDH. We establish the importance of the cyclohexyl, piperazine and isoquinoline rings for activity, and report the identification of an analogue with IMPDH-selective activity against a mutant of M. tuberculosis that is highly resistant to compound 1. We also show that the nitrogen in urea analogues is required for anti-tubercular activity and identify benzylurea derivatives as promising inhibitors that warrant further investigation.


Assuntos
Antituberculosos/farmacologia , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Isoquinolinas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Piperazinas/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Domínio Catalítico , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , IMP Desidrogenase/química , Isoquinolinas/síntese química , Isoquinolinas/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Relação Estrutura-Atividade
7.
Bioorg Chem ; 87: 753-764, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30974298

RESUMO

Inosine 5'-monophosphate dehydrogenase (IMPDH, EC 1.1.1.205) catalyzes a crucial step in guanine nucleotide biosynthesis, thereby governing cell proliferation. In contrast to mammalian IMPDHs, microbial IMPDHs are relatively less explored as potential targets for antimicrobial drug discovery. In continuation with our previous work, here we report the discovery of moderately potent and highly selective Helicobacter pylori IMPDH (HpIMPDH) inhibitors. The present study is mainly focused around our previously identified, modestly potent and relatively nonselective (for HpIMPDH over human IMPDH2) hit molecule IX (16i). In an attempt to optimize the selectivity for the bacterial enzyme, we screened a set of 48 redesigned new chemical entities (NCEs) belonging to 5-aminoisobenzofuran-1(3H)-one series for their in vitro HpIMPDH and human IMPDH2 inhibition. A total of 12 compounds (hits) demonstrated ≥70% HpIMPDH inhibition at 10 µM concentration; none of the hits were active against hIMPDH2. Compound 24 was found to be the most potent and selective molecule (HpIMPDH IC50 = 2.21 µM) in the series. The study reaffirmed the utility of 5-aminoisobenzofuran-1(3H)-one as a promising scaffold with great potential for further development of potent and selective HpIMPDH inhibitors.


Assuntos
Antibacterianos/farmacologia , Benzofuranos/farmacologia , Inibidores Enzimáticos/farmacologia , Helicobacter pylori/efeitos dos fármacos , IMP Desidrogenase/antagonistas & inibidores , Antibacterianos/síntese química , Antibacterianos/química , Benzofuranos/síntese química , Benzofuranos/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Helicobacter pylori/enzimologia , Humanos , IMP Desidrogenase/metabolismo , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Software , Relação Estrutura-Atividade
8.
Curr Top Med Chem ; 19(5): 376-382, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30827248

RESUMO

BACKGROUND & OBJECTIVE: Helicobacter pylori infection is one of the primary causes of peptic ulcer followed by gastric cancer in the world population. Due to increased occurrences of multi-drug resistance to the currently available antibiotics, there is an urgent need for a new class of drugs against H. pylori. Inosine 5'-monophosphate dehydrogenase (IMPDH), a metabolic enzyme plays a significant role in cell proliferation and cell growth. It catalyses guanine nucleotide synthesis. IMPDH enzyme has been exploited as a target for antiviral, anticancer and immunosuppressive drugs. Recently, bacterial IMPDH has been studied as a potential target for treating bacterial infections. Differences in the structural and kinetic parameters of the eukaryotic and prokaryotic IMPDH make it possible to target bacterial enzyme selectively. METHODS: In the current work, we have synthesised and studied the effect of substituted 3-aryldiazenyl indoles on Helicobacter pylori IMPDH (HpIMPDH) activity. The synthesised molecules were examined for their inhibitory potential against recombinant HpIMPDH. RESULTS: In this study, compounds 1 and 2 were found to be the most potent inhibitors amongst the database with IC50 of 0.8 ± 0.02µM and 1 ± 0.03 µM, respectively. CONCLUSION: When compared to the most potent known HpIMPDH inhibitor molecule C91, 1 was only four-fold less potent and can be a good lead for further development of selective and potent inhibitors of HpIMPDH.


Assuntos
Inibidores Enzimáticos/farmacologia , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/enzimologia , IMP Desidrogenase/antagonistas & inibidores , Indóis/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , IMP Desidrogenase/metabolismo , Indóis/síntese química , Indóis/química , Estrutura Molecular , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
9.
Chem Res Toxicol ; 32(3): 456-466, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30746940

RESUMO

Reactive nitrogen species (RNS) are produced during infection and inflammation, and the effects of these agents on proteins, DNA, and lipids are well recognized. In contrast, the effects of RNS damaged metabolites are less appreciated. 5-Amino-3-ß-(d-ribofuranosyl)-3 H-imidazo-[4,5- d][1,3]oxazine-7-one (oxanosine) and its nucleotides are products of guanosine nitrosation. Here we demonstrate that oxanosine monophosphate (OxMP) is a potent reversible competitive inhibitor of IMPDH. The value of Ki varies from 50 to 340 nM among IMPDHs from five different organisms. UV spectroscopy and X-ray crystallography indicate that OxMP forms a ring-opened covalent adduct with the active site Cys (E-OxMP*). Unlike the covalent intermediate of the normal catalytic reaction, E-OxMP* does not hydrolyze, but instead recyclizes to OxMP. IMPDH inhibitors block proliferation and can induce apoptosis, so the inhibition of IMPDH by OxMP presents another potential mechanism for RNS toxicity.


Assuntos
Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Fosfatos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , IMP Desidrogenase/isolamento & purificação , IMP Desidrogenase/metabolismo , Estrutura Molecular , Fosfatos/síntese química , Fosfatos/química , Ribonucleosídeos/síntese química , Ribonucleosídeos/química , Ribonucleosídeos/farmacologia
10.
Sci Rep ; 9(1): 190, 2019 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-30655593

RESUMO

Helicobacter pylori (H. pylori), the major cause of several gastric disorders has been recognied as a type I carcinogen. By virtue of resistance developed by H. pylori strains, currently used antibiotic based treatments rather demonstrate high failure rates. Hence, there is an emerging need for identification of new targets to treat H. pylori infection. Inosine-5'-monophosphate dehydrogenase (IMPDH) has been studied as a potential target to treat H. pylori infection. Here, a detailed enzyme kinetic study of recombinant expressed H. pylori inosine-5'-monophosphate dehydrogenase (HpIMPDH) is presented. A new in-house synthesized indole-based scaffold is identified as an inhibitor for HpIMPDH. These indole-based compounds showed non-competitive inhibition against IMP and NAD+ whereas the benzimidazole compounds were found be uncompetitive inhibitors. The new indole scaffold ensures specificity due to its high selectivity for bacterial IMPDH over human IMPDH II. Our work aims to overcome the drawback of existing inhibitors by introducing new indole scaffold for targeting bacterial IMPDH.


Assuntos
Antibacterianos/farmacologia , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/enzimologia , IMP Desidrogenase/antagonistas & inibidores , Antibacterianos/uso terapêutico , Proteínas de Bactérias , Inibidores Enzimáticos , Humanos , Indóis/química , Indóis/farmacologia , Cinética , Terapia de Alvo Molecular/métodos , Proteínas Recombinantes
11.
J Enzyme Inhib Med Chem ; 34(1): 171-178, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30451014

RESUMO

Inosine 5'-monophosphate dehydrogenase (IMPDH) is an essential enzyme for the production of guanine nucleotides. Disruption of IMPDH activity has been explored as a therapeutic strategy for numerous purposes, such as for anticancer, immunosuppression, antiviral, and antimicrobial therapy. In the present study, we established a luciferase-based high-throughput screening system to identify IMPDH inhibitors from our chemical library of known bioactive small molecules. The screening of 1400 compounds resulted in the discovery of three irreversible inhibitors: disulfiram, bronopol, and ebselen. Each compound has a distinct chemical moiety that differs from other reported IMPDH inhibitors. Further evaluation revealed that these compounds are potent inhibitors of IMPDHs with kon values of 0.7 × 104 to 9.3 × 104 M-1·s-1. Both disulfiram and bronopol exerted similar degree of inhibition to protozoan and mammalian IMPDHs. Ebselen showed an intriguing difference in mode of inhibition for different IMPDHs, with reversible and irreversible inhibition to each Cryptosporidium parvum IMPDH and human IMPDH type II, respectively. In the preliminary efficacy experiment against cryptosporidiosis in severe combined immunodeficiency (SCID) mouse, a decrease in the number of oocyst shed was observed upon the oral administration of disulfiram and bronopol, providing an early clinical proof-of-concept for further utilization of these compounds as IMPDH inhibitors.


Assuntos
Descoberta de Drogas , Reposicionamento de Medicamentos , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala/métodos , IMP Desidrogenase/antagonistas & inibidores , Animais , Azóis/química , Azóis/isolamento & purificação , Azóis/farmacologia , Cryptosporidium parvum/enzimologia , Dissulfiram/química , Dissulfiram/isolamento & purificação , Dissulfiram/farmacologia , Inibidores Enzimáticos/química , Humanos , IMP Desidrogenase/metabolismo , Cinética , Camundongos , Camundongos SCID , Compostos Organosselênicos/química , Compostos Organosselênicos/isolamento & purificação , Compostos Organosselênicos/farmacologia , Estudo de Prova de Conceito , Propilenoglicóis/química , Propilenoglicóis/isolamento & purificação , Propilenoglicóis/farmacologia , Bibliotecas de Moléculas Pequenas
12.
Drug Dev Res ; 80(1): 125-132, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30381846

RESUMO

Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes a crucial step in the biosynthesis of guanine nucleotides. Being a validated target for immunosuppressive, antiviral, and anticancer drug development, lately it has been exploited as a promising target for antimicrobial therapy. Extending our previous work on Mycobacterium tuberculosis IMPDH, GuaB2, inhibitor development, we screened a set of 23 new chemical entities (NCEs) with substituted flavone (Series 1) and 1,2,3-triazole (Series 2) core structures for their in vitro Helicobacter pylori IMPDH (HpIMPDH) and human IMPDH2 (hIMPDH2) inhibitory activities. All the NCEs possessed acceptable molecular, physicochemical, and toxicity property profiles. The ranges for HpIMPDH and hIMPDH2 inhibition were 9-99.9% and 16-57%, respectively, at 10 µM concentration. The most potent HpIMPDH inhibitor, 25c, exhibited IC50 value of 1.27 µM with no hIMPDH2 inhibitory activity. The moderately potent, structurally novel hit molecule, 25c, may serve as a lead for further design and development of highly potent HpIMPDH inhibitors.


Assuntos
Antibacterianos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/enzimologia , IMP Desidrogenase/antagonistas & inibidores , Antibacterianos/síntese química , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/síntese química , Humanos , IMP Desidrogenase/metabolismo , Simulação de Acoplamento Molecular/métodos , Relação Estrutura-Atividade
13.
FEBS J ; 285(20): 3724-3728, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30285320

RESUMO

CTP synthase (CTPS) and IMP dehydrogenase (IMPDH) catalyse the rate-limiting steps of de novo CTP and guanosine nucleotide biosynthesis, respectively, and form filament assemblies in response to inhibitors. A recent study explores the morphology and dynamics of these assemblies using fluorescence and super-resolution confocal microscopy with cell lines expressing CTPS1 and IMPDH2 fusion proteins. The formation and dismantling of mixed assemblies depends on nucleotide levels, suggesting a co-regulation function.


Assuntos
Carbono-Nitrogênio Ligases , IMP Desidrogenase/antagonistas & inibidores , Linhagem Celular , Nucleotídeos
14.
Bioorg Med Chem ; 26(20): 5408-5419, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30322754

RESUMO

Fungi cause serious life-threatening infections in immunocompromised individuals and current treatments are now complicated by toxicity issues and the emergence of drug resistant strains. Consequently, there is a need for development of new antifungal drugs. Inosine monophosphate dehydrogenase (IMPDH), a key component of the de novo purine biosynthetic pathway, is essential for growth and virulence of fungi and is a potential drug target. In this study, a high-throughput screen of 114,000 drug-like compounds against Cryptococcus neoformans IMPDH was performed. We identified three 3-((5-substituted)-1,3,4-oxadiazol-2-yl)thio benzo[b]thiophene 1,1-dioxides that inhibited Cryptococcus IMPDH and also possessed whole cell antifungal activity. Analogs were synthesized to explore the SAR of these hits. Modification of the fifth substituent on the 1,3,4-oxadiazole ring yielded compounds with nanomolar in vitro activity, but with associated cytotoxicity. In contrast, two analogs generated by substituting the 1,3,4-oxadiazole ring with imidazole and 1,2,4-triazole gave reduced IMPDH inhibition in vitro, but were not cytotoxic. During enzyme kinetic studies in the presence of DTT, nucleophilic attack of a free thiol occurred with the benzo[b]thiophene 1,1-dioxide. Two representative compounds with substitution at the 5 position of the 1,3,4-oxadiazole ring, showed mixed inhibition in the absence of DTT. Incubation of these compounds with Cryptococcus IMPDH followed by mass spectrometry analysis showed non-specific and covalent binding with IMPDH at multiple cysteine residues. These results support recent reports that the benzo[b]thiophene 1,1-dioxides moiety as PAINS (pan-assay interference compounds) contributor.


Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Cryptococcus neoformans/efeitos dos fármacos , Proteínas Fúngicas/antagonistas & inibidores , IMP Desidrogenase/antagonistas & inibidores , Tiofenos/química , Tiofenos/farmacologia , Criptococose/tratamento farmacológico , Criptococose/metabolismo , Criptococose/microbiologia , Cryptococcus neoformans/enzimologia , Proteínas Fúngicas/metabolismo , Células HEK293 , Células Hep G2 , Humanos , IMP Desidrogenase/metabolismo , Modelos Moleculares , Oxidiazóis/química , Oxidiazóis/farmacologia
15.
Eur J Med Chem ; 158: 286-301, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30223117

RESUMO

The enzyme inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes an essential step in the de novo biosynthesis of guanine nucleotides, and thus regulates the guanine nucleotide pool required for cell proliferation. Of the two isoforms, human IMPDH type 2 (hIMPDH2) is a validated molecular target for potential immunosuppressive, antiviral and anticancer chemotherapy. In search of newer hIMPDH2 inhibitors as potential anticancer agents, three novel series (A: 5-aminoisobenzofuran-1(3H)-one, B: 3,4-dimethoxyaniline and C: benzo[d]-[1,3]dioxol-5-ylmethanamine) were synthesized and evaluated for in vitro and cell-based activities. A total of 37 molecules (29-65) were screened for their in vitro hIMPDH2 inhibition, with particular emphasis on establishing their structure-activity relationship (SAR) trends. Eight compounds (hits, 30, 31, 33-35, 37, 41 and 43) demonstrated significant enzyme inhibition (>70% @ 10 µM); especially the A series molecules were more potent than B series (<70% inhibition @ 10 µM), while C series members were found to be inactive. The hIMPDH2 IC50 values for the hits ranged from 0.36 to 7.38 µM. The hits displaying >80% hIMPDH2 inhibition (30, 33, 35, 41 and 43) were further assessed for their cytotoxic activity against cancer cell lines such as MDA-MB-231 (breast adenocarcinoma), DU145 (prostate carcinoma), U87 MG (glioblastoma astrocytoma) and a normal cell line, NIH-3T3 (mouse embryonic fibroblast) using MTT assay. Most of the compounds exhibited higher cellular potency against cancer cell lines and notably lower toxicity towards NIH-3T3 cells compared to mycophenolic acid (MPA), a prototypical hIMPDH2 inhibitor. Two of the series A hits (30 and 35) were evaluated in human peripheral blood mononuclear cells (hPBMC) assay and found to be better tolerated than MPA. The calculated/predicted molecular and physicochemical properties were satisfactory with reference to drug-likeness. The molecular docking studies clearly demonstrated crucial interactions of the hits with the cofactor-binding site of hIMPDH2, further providing critical information for refining the design strategy. The present study reports the design and discovery of structurally novel hIMPDH2 inhibitors as potential anticancer agents and provides a guide for further research on the development of safe and effective anticancer agents, especially against glioblastoma.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas , Humanos , IMP Desidrogenase/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Células NIH 3T3 , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade
16.
Antiviral Res ; 157: 140-150, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30031760

RESUMO

Infection with Junín virus (JUNV) is currently being effectively managed in the endemic region using a combination of targeted vaccination and plasma therapy. However, the long-term sustainability of plasma therapy is unclear and similar resources are not available for other New World arenaviruses. As a result, there has been renewed interest regarding the potential of drug-based therapies. To facilitate work on this issue, we present the establishment and subsequent optimization of a JUNV minigenome system to a degree suitable for high-throughput miniaturization, thereby providing a screening platform focused solely on factors affecting RNA synthesis. Using this tool, we conducted a limited drug library screen and identified AVN-944, a non-competitive inosine monophosphate dehydrogenase (IMPDH) inhibitor, as an inhibitor of arenavirus RNA synthesis. We further developed a transcription and replication competent virus-like particle (trVLP) system based on these minigenomes and used it to screen siRNAs against IMPDH, verifying its role in supporting arenavirus RNA synthesis. The antiviral effect of AVN-944, as well as siRNA inhibition, on JUNV RNA synthesis supports that, despite playing only a minor role in the activity of ribavirin, exclusive IMPDH inhibitors may indeed have significant therapeutic potential for use against New World arenaviruses. Finally, we confirmed that AVN-944 is also active against arenavirus infection in cell culture, supporting the suitability of arenavirus lifecycle modelling systems as tools for the screening and identification, as well as the mechanistic characterization, of novel antiviral compounds.


Assuntos
Antivirais/isolamento & purificação , Carbamatos/isolamento & purificação , Inibidores Enzimáticos/isolamento & purificação , IMP Desidrogenase/metabolismo , Vírus Junin/efeitos dos fármacos , Vírus Junin/crescimento & desenvolvimento , Compostos de Fenilureia/isolamento & purificação , Animais , Antivirais/farmacologia , Carbamatos/farmacologia , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Humanos , IMP Desidrogenase/antagonistas & inibidores , Vírus Junin/genética , Compostos de Fenilureia/farmacologia , Genética Reversa/métodos , Transcrição Genética/efeitos dos fármacos , Cultura de Vírus , Replicação Viral/efeitos dos fármacos
17.
Br J Clin Pharmacol ; 84(10): 2433-2442, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29974488

RESUMO

AIMS: Although therapeutic drug monitoring of plasma mycophenolic acid (MPA) concentrations has been recommended to individualize dosage in transplant recipients, little is known regarding lymphocyte concentrations of MPA, where MPA inhibits inosine monophosphate dehydrogenase (IMPDH). This study investigated the utility of measuring predose MPA concentrations in peripheral blood mononuclear cells (C0C ) and predose IMPDH activity, as predictors of graft rejection in renal transplant recipients. METHODS: Forty-eight patients commencing mycophenolate mofetil (1 g twice daily) in combination with tacrolimus and prednisolone were recruited. Blood was collected for determination of trough total (C0P ) and unbound (C0u ) plasma MPA concentrations. Peripheral blood mononuclear cells were isolated for determination of C0C and IMPDH activity. The incidence of rejection within 2 days of sample collection was determined histologically and classified according to the Banff 2007 criteria. RESULTS: There was no association between MPA C0C and C0P (rs  = 0.28, P = 0.06), however, MPA C0C were weakly correlated with MPA C0u (rs  = 0.42, P = 0.013). Multivariate analysis indicated that MPA C0C was the only covariate independently associated with rejection (FDR-adjusted P = 0.033). The receiver operating characteristic area under the curve (AUC) for the prediction of severe rejection using MPA C0C was 0.75 (P = 0.013), with 73% sensitivity and specificity at a C0C threshold of 0.5 ng 10-7 cells. However, predose IMPDH activity was not a predictor of rejection (P > 0.15). CONCLUSIONS: MPA C0C measurement within the early post-transplant period may be useful to facilitate early titration of MPA dosing to significantly reduce rejection.


Assuntos
Monitoramento de Medicamentos/métodos , Rejeição de Enxerto/diagnóstico , Imunossupressores/farmacocinética , Transplante de Rim/efeitos adversos , Leucócitos Mononucleares/química , Ácido Micofenólico/farmacocinética , Adulto , Idoso , Área Sob a Curva , Quimioterapia Combinada/métodos , Ensaios Enzimáticos , Feminino , Rejeição de Enxerto/sangue , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/prevenção & controle , Humanos , IMP Desidrogenase/antagonistas & inibidores , IMP Desidrogenase/imunologia , Imunossupressores/administração & dosagem , Imunossupressores/análise , Incidência , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/análise , Prednisolona/administração & dosagem , Prognóstico , Estudos Prospectivos , Sensibilidade e Especificidade , Tacrolimo/administração & dosagem , Transplantados , Adulto Jovem
18.
Mar Drugs ; 16(7)2018 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-29986508

RESUMO

Mycophenolic acid (MPA) is a potent inosine-5′-monophosphate dehydrogenase (IMPDH) inhibitor for immunosuppressive chemotherapy. Most importantly, as the 2-morpholinoethyl ester prodrug of MPA, mycophenolate mofetil (MMF) is a well-known immunosuppressant used to prevent rejection in organ transplantations. Nevertheless, due to its frequently occurred side effects, searching for new therapeutic agents is ongoing. In our current work, by virtue of efficient bioassay-guided fractionation and purification, eleven mycophenolic acid derivatives, including five previously unreported metabolites (3⁻7) and six known compounds (1, 2, and 8⁻11), were obtained from the coral-derived fungus Penicillium bialowiezense. Their structures were elucidated by means of extensive spectroscopic analyses (including 1D and 2D NMR and HRESIMS data) and comparison of the NMR and other physical data with those reported in the literature in the case of the known compounds. All the isolates 1⁻11 were evaluated for the immunosuppressive activity, and 1⁻3 showed potent IMPDH2 inhibitory potency with IC50 values of 0.84⁻0.95 μM, which were comparable to that of MPA (the positive control), while 4⁻10 showed significant inhibitory potency with IC50 values of 3.27⁻24.68 μM. All the MPA derivatives showed promising immunosuppressive activity, endowing them as potential drug leads for organ transplantations and autoimmune related diseases.


Assuntos
Antozoários/microbiologia , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Imunossupressores/farmacologia , Ácido Micofenólico/farmacologia , Penicillium/química , Animais , Ensaios Enzimáticos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Humanos , Imunossupressores/química , Imunossupressores/isolamento & purificação , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/química , Ácido Micofenólico/isolamento & purificação , Cultura Primária de Células , Baço/citologia , Linfócitos T/efeitos dos fármacos
19.
Cell Metab ; 28(3): 369-382.e5, 2018 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-30043754

RESUMO

Small cell lung cancer (SCLC) is a rapidly lethal disease with few therapeutic options. We studied metabolic heterogeneity in SCLC to identify subtype-selective vulnerabilities. Metabolomics in SCLC cell lines identified two groups correlating with high or low expression of the Achaete-scute homolog-1 (ASCL1) transcription factor (ASCL1High and ASCL1Low), a lineage oncogene. Guanosine nucleotides were elevated in ASCL1Low cells and tumors from genetically engineered mice. ASCL1Low tumors abundantly express the guanosine biosynthetic enzymes inosine monophosphate dehydrogenase-1 and -2 (IMPDH1 and IMPDH2). These enzymes are transcriptional targets of MYC, which is selectively overexpressed in ASCL1Low SCLC. IMPDH inhibition reduced RNA polymerase I-dependent expression of pre-ribosomal RNA and potently suppressed ASCL1Low cell growth in culture, selectively reduced growth of ASCL1Low xenografts, and combined with chemotherapy to improve survival in genetic mouse models of ASCL1Low/MYCHigh SCLC. The data define an SCLC subtype-selective vulnerability related to dependence on de novo guanosine nucleotide synthesis.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Guanosina/metabolismo , IMP Desidrogenase/fisiologia , Neoplasias Pulmonares/enzimologia , Carcinoma de Pequenas Células do Pulmão/enzimologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem Celular Tumoral , Xenoenxertos , Humanos , IMP Desidrogenase/antagonistas & inibidores , Camundongos , Camundongos Knockout
20.
J Enzyme Inhib Med Chem ; 33(1): 972-977, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29792360

RESUMO

Human inosine 5'-monophosphate dehydrogenase 2 (hIMPDH2), being an age-old target, has attracted attention recently for anticancer drug development. Mycophenolic acid (MPA), a well-known immunosuppressant drug, was used a lead structure to design and develop modestly potent and selective analogues. The steep structure-activity relationship (SAR) requirements of the lead molecule left little scope to synthesise newer analogues. Here, newer MPA amides were designed, synthesised and evaluated for hIMPDH2 inhibition and cellular efficacy in breast, prostate and glioblastoma cell lines. Few title compounds exhibited cellular activity profile better than MPA itself. The observed differences in the overall biological profile could be attributed to improved structural and physicochemical properties of the analogues over MPA. This is the first report of the activity of MPA derivatives in glioblastoma, the most aggressive brain cancer.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Ácido Micofenólico/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , IMP Desidrogenase/metabolismo , Estrutura Molecular , Ácido Micofenólico/síntese química , Ácido Micofenólico/química , Relação Estrutura-Atividade
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