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1.
Toxicology ; 472: 153160, 2022 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-35367320

RESUMO

Flumioxazin, is a herbicide that has inhibitory activity on protoporphyrinogen oxidase (PPO), a key enzyme in the biosynthetic pathway for heme. Flumioxazin induces anemia and developmental toxicity in rats, including ventricular septal defect and embryofetal death. Studies to elucidate the mode of action (MOA) of flumioxazin as a developmental toxicant and to evaluate its relevance to humans have been undertaken. The MOA in the rat has now been elucidated. The first key event is PPO inhibition, which results in reduced heme synthesis in embryonic erythroblasts. The critical window for this effect is gestational day 12 when almost all erythroblasts are at the polychromatophilic stage, synthesizing heme very actively. Embryonic anemia/hypoxemia is induced and the heart pumps more strongly as a compensatory action during organogenesis, leading to thinning of the ventricular walls and failure of the interventricular septum to build completely and close. Investigations showed that this MOA is specific to rats and has no relevancy to humans. Flumioxazin inhibited PPO in rat hepatocyte mitochondria more strongly than in human. A 3-dimensional molecular simulation revealed that species differences in binding affinity of flumioxazin to PPO, observed previously in vitro, were due to differences in binding free energy. In vitro studies using several types of rat and human cells (erythroblasts derived from erythroleukemia cell lines, cord blood, or pluripotent stem cells), showed that flumioxazin decreased heme synthesis in rat cells but not in human cells, demonstrating a clear, qualitative species difference. Considering all available information, including data from PBPK modelling in rat and human, as well as the fact that anemia is not a symptom in patients with variegate porphyria, a congenital hereditary PPO defect, shows that the sequence of events leading to adverse effects in the rat embryo and fetus are very unlikely to occur in humans.


Assuntos
Anemia , Ftalimidas , Animais , Benzoxazinas , Heme , Humanos , Ftalimidas/química , Ftalimidas/metabolismo , Ftalimidas/farmacologia , Protoporfirinogênio Oxidase/metabolismo , Ratos
2.
N Engl J Med ; 386(11): 1034-1045, 2022 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-35294813

RESUMO

BACKGROUND: Iberdomide, a cereblon modulator promoting degradation of the transcription factors Ikaros and Aiolos, which affect leukocyte development and autoimmunity, is being evaluated for the treatment of systemic lupus erythematosus (SLE). METHODS: In this phase 2 trial, we randomly assigned patients in a 2:2:1:2 ratio to receive oral iberdomide (at a dose of 0.45, 0.30, or 0.15 mg) or placebo once daily for 24 weeks, in addition to standard medications. The primary end point at week 24 was a response on the SLE Responder Index (SRI-4), which was defined as a reduction of at least 4 points in the Systemic Lupus Erythematosus Disease Activity Index 2000 score (a 24-item weighted score of lupus activity that ranges from 0 to 105, with higher scores indicating greater disease activity), no new disease activity as measured on the British Isles Lupus Assessment Group 2004 index, and no increase of 0.3 points or more in the Physician's Global Assessment score (on a visual-analogue scale ranging from 0 [no disease activity] to 3 [maximal disease]). RESULTS: A total of 288 patients received the assigned intervention: 81 received iberdomide at a dose of 0.45 mg, 82 received iberdomide at a dose of 0.30 mg, 42 received iberdomide at a dose of 0.15 mg, and 83 received placebo. At week 24, the percentages of patients with an SRI-4 response were 54% in the iberdomide 0.45-mg group, 40% in the iberdomide 0.30-mg group, 48% in the iberdomide 0.15-mg group, and 35% in the placebo group (adjusted difference between the iberdomide 0.45-mg group and the placebo group, 19.4 percentage points; 95% confidence interval, 4.1 to 33.4; P = 0.01), with no significant differences between the groups that received the lower doses of iberdomide and the group that received placebo. Iberdomide-associated adverse events included urinary tract and upper respiratory tract infections and neutropenia. CONCLUSIONS: In this 24-week, phase 2 trial involving patients with SLE, iberdomide at a dose of 0.45 mg resulted in a higher percentage of patients with an SRI-4 response than did placebo. Data from larger, longer trials are needed to determine the efficacy and safety of iberdomide in SLE. (Funded by Bristol Myers Squibb; ClinicalTrials.gov number, NCT03161483; EudraCT number, 2016-004574-17.).


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/agonistas , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Morfolinas/uso terapêutico , Ftalimidas/uso terapêutico , Piperidonas/uso terapêutico , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Fator de Transcrição Ikaros/metabolismo , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Morfolinas/farmacologia , Ftalimidas/administração & dosagem , Ftalimidas/farmacologia , Piperidonas/administração & dosagem , Piperidonas/farmacologia , Índice de Gravidade de Doença , Ubiquitina-Proteína Ligases/metabolismo
3.
Eur J Med Chem ; 229: 114053, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34974338

RESUMO

Multiple myeloma is currently incurable, and the incidence rate is increasing year by year worldwide. Although in recent years the combined treatment plan based on proteasome inhibitors and immunomodulatory drugs has greatly improved the treatment effect of multiple myeloma, most patients still relapse and become resistant to current treatments. To solve this problem, scientists are committed to developing drugs with higher specificity, such as iberdomide, which is highly specific to ikaros and aiolos. This review aims to focus on the small molecular agents that are being researched/clinically used for the treatment of multiple myeloma, including the target mechanism, structure-activity relationship and application prospects of small molecular agents.


Assuntos
Antineoplásicos/química , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/química , Animais , Antineoplásicos/farmacologia , Biomarcadores Tumorais/química , Terapia Combinada , Enzimas Desubiquitinantes/química , Desenvolvimento de Medicamentos , Resistência a Medicamentos , Histona Desacetilases/química , Humanos , Fator de Transcrição Ikaros/química , Modelos Moleculares , Morfolinas/química , Morfolinas/farmacologia , Ftalimidas/química , Ftalimidas/farmacologia , Piperidonas/química , Piperidonas/farmacologia , Inibidores de Proteassoma/farmacologia , Resultado do Tratamento , Ubiquitina-Proteína Ligases/química
4.
PLoS One ; 16(11): e0260633, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34847172

RESUMO

Chlamydia pneumoniae (Cpn) is a gram-negative intracellular pathogen that causes a variety of pulmonary diseases, and there is growing evidence that it may play a role in Alzheimer's disease (AD) pathogenesis. Cpn can interact functionally with host histones, altering the host's epigenetic regulatory system by introducing bacterial products into the host tissue and inducing a persistent inflammatory response. Because Cpn is difficult to propagate, isolate, and detect, a modified LPS-like neuroinflammation model was established using lyophilized cell free supernatant (CFS) obtained from infected cell cultures, and the effects of CFS were compared to LPS. The neuroprotective effects of Trichostatin A (TSA), givinostat, and RG108, which are effective on epigenetic mechanisms, and the antibiotic rifampin, were studied in this newly introduced model and in the presence of amyloid beta (Aß) 1-42. The neuroprotective effects of the drugs, as well as the effects of CFS and LPS, were evaluated in Aß-induced neurotoxicity using a real-time cell analysis system, total ROS, and apoptotic impact. TSA, RG108, givinostat, and rifampin all demonstrated neuroprotective effects in both this novel model and Aß-induced neurotoxicity. The findings are expected to provide early evidence on neuroprotective actions against Cpn-induced neuroinflammation and Aß-induced neurotoxicity, which could represent a new treatment option for AD, for which there are currently few treatment options.


Assuntos
Carbamatos/farmacologia , Infecções por Chlamydophila , Chlamydophila pneumoniae/metabolismo , Epigênese Genética/efeitos dos fármacos , Ácidos Hidroxâmicos/farmacologia , Fármacos Neuroprotetores/farmacologia , Ftalimidas/farmacologia , Triptofano/análogos & derivados , Doença de Alzheimer/metabolismo , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Infecções por Chlamydophila/metabolismo , Infecções por Chlamydophila/prevenção & controle , Humanos , Inflamação/metabolismo , Fragmentos de Peptídeos/metabolismo , Células THP-1 , Triptofano/farmacologia
5.
Antiviral Res ; 195: 105193, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34687820

RESUMO

Transient receptor potential mucolipin 2 and 3 (TRPML2 and TRPML3), as key channels in the endosomal-lysosomal system, are associated with many different cellular processes, including ion release, membrane trafficking and autophagy. In particular, they can also facilitate viral entry into host cells and enhance viral infection. We previously identified that two selective TRPML agonists, ML-SA1 and SN-2, that showed antiviral activities against dengue virus type 2 (DENV2) and Zika virus (ZIKV) in vitro, but their antiviral mechanisms are still elusive. Here, we reported that ML-SA1 could inhibit DENV2 replication by downregulating the expression of both TRPML2 and TRPML3, while the other TRPML activator, SN-2, suppressed DENV2 infection by reducing only TRPML3 expression. Consistently, the channel activities of both TRPML2 and TRPML3 were also found to be associated with the antiviral activity of ML-SA1 on DENV2 and ZIKV, but SN-2 relied only on TRPML3 channel activity. Further mechanistic experiments revealed that ML-SA1 and SN-2 decreased the expression of the late endosomal marker Rab7, dependent on TRPML2 and TRPML3, indicating that these two compounds likely inhibit viral infection by promoting vesicular trafficking from late endosomes to lysosomes and then accelerating lysosomal degradation of the virus. As expected, neither ML-SA1 nor SN-2 inhibited herpes simplex virus type I (HSV-1), whose entry is independent of the endolysosomal network. Together, our work reveals the antiviral mechanisms of ML-SA1 and SN-2 in targeting TRPML channels, possibly leading to the discovery of new drug candidates to inhibit endocytosed viruses.


Assuntos
Antivirais/farmacologia , Ftalimidas/farmacologia , Quinolinas/farmacologia , Canais de Potencial de Receptor Transitório/agonistas , Zika virus/efeitos dos fármacos , Células A549 , Animais , Autofagia , Chlorocebus aethiops , Endossomos/enzimologia , Endossomos/metabolismo , Humanos , Lisossomos/enzimologia , Lisossomos/metabolismo , Células Vero , Infecção por Zika virus/virologia
6.
Pestic Biochem Physiol ; 178: 104917, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34446193

RESUMO

Fusarium head blight(FHB)caused by Fusarium graminearum species complex (FGSC) is one of the most important diseases around the world. Deoxynivalenol (DON) is a type of mycotoxin produced by FGSC when infecting cereal crops. It is a serious threat to the health of both humans and livestock. Trehalose-6-phosphate phosphatase (TPP), a conserved metabolic enzyme found in many plants and pathogens, catalyzes the formation of trehalose. N-(phenylthio) phthalimide (NPP) has been reported to inhibit the normal growth of nematodes by inhibiting the activity of TPP, but this inhibitor of nematodes has not previously been tested against F. graminearum. In this study, we found that TPP in F. graminearum (FgTPP) had similar secondary structures and conserved cysteine (Cys356) to nematodes by means of bioinformatics. At the same time, the sensitivity of F. graminearum strains to NPP was determined. NPP exhibited a better inhibitory effect on conidia germination than mycelial growth. In addition, the effects of NPP on DON biosynthesis and trehalose biosynthesis pathway in PH-1 were also determined. We found that NPP decreased DON production, trehalose content, glucose content and TPP enzyme activity but increased trehalose-6-phosphate content and trehalose-6-phosphate synthase (TPS) enzyme activity. Moreover, the expression of TRI1, TRI4, TRI5, TRI6, and TPP genes were downregulated, on the contrary, the TPS gene was upregulated. Finally, in order to further determine the control ability of NPP on DON production in the field, we conducted a series of field experiments, and found that NPP could effectively reduce the DON content in wheat grain and had a general control effect on FHB. In conclusion, the research in this study will provide important theoretical basis for controlling FHB caused by F. graminearum and reducing DON production in the field.


Assuntos
Fusarium , Tricotecenos , Monoéster Fosfórico Hidrolases , Ftalimidas/farmacologia , Doenças das Plantas
7.
Int J Mol Sci ; 22(14)2021 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-34299298

RESUMO

Isoindoline-1,3-dione derivatives constitute an important group of medicinal substances. In this study, nine new 1H-isoindole-1,3(2H)-dione derivatives and five potential pharmacophores were obtained in good yield (47.24-92.91%). The structure of the new imides was confirmed by the methods of elemental and spectral analysis: FT-IR, H NMR, and MS. Based on the obtained results of ESI-MS the probable path of the molecules decay and the hypothetical structure of the resulting pseudo-molecular ions have been proposed. The physicochemical properties of the new phthalimides were determined on the basis of Lipinski's rule. The biological properties were determined in terms of their cyclooxygenase (COX) inhibitory activity. Three compounds showed greater inhibition of COX-2, three compounds inhibited COX-1 more strongly than the reference compound meloxicam. From the obtained results, the affinity ratio COX-2/COX-1 was calculated. Two compounds had a value greater than that of meloxicam. All tested compounds showed oxidative or nitrosan stress (ROS and RNS) scavenging activity. The degree of chromatin relaxation outside the cell nucleus was lower than the control after incubation with all test compounds. The newly synthesized phthalimide derivatives showed no cytotoxic activity in the concentration range studied (10-90 µM). A molecular docking study was used to determined interactions inside the active site of cyclooxygenases.


Assuntos
Isoindóis/química , Ftalimidas/química , Prostaglandina-Endoperóxido Sintases/metabolismo , Domínio Catalítico , Inibidores de Ciclo-Oxigenase/química , Isoindóis/metabolismo , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Ftalimidas/farmacologia , Prostaglandina-Endoperóxido Sintases/química , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Relação Estrutura-Atividade
8.
J Mol Histol ; 52(4): 705-715, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34105058

RESUMO

Lipopolysaccharide (LPS)-induced autophagy is involved in sepsis-associated myocardial injury with increased PKCß2 activation. We previously found hyperglycemia-induced PKCß2 activation impaired the expression of caveolin-3 (Cav-3), the dominant isoform to form cardiomyocytes caveolae which modulate eNOS signaling to confer cardioprotection in diabetes. However, little is known about the roles of PKCß2 in autophagy and Cav-3/eNOS signaling in cardiomyocytes during LPS exposure. We hypothesize LPS-induced PKCß2 activation promotes autophagy and impairs Cav-3/eNOS signaling in LPS-treated cardiomyocytes. H9C2 cardiomyocytes were treated with LPS (10 µg/mL) in the presence or absence of PKCß2 inhibitor CGP53353 (CGP, 1 µM) or autophagy inhibitor 3-methyladenine (3-MA, 10 µM). LPS stimulation induced cytotoxicity overtime in H9C2 cardiomyocytes, accompanied with excessive PKCß2 activation. Selective inhibition of PKCß2 with CGP significantly reduced LPS-induced cytotoxicity and autophagy (measured by LC-3II, Beclin-1, p62 and autophagic flux). In addition, CGP significantly attenuated LPS-induced oxidative injury, and improved Cav-3 expression and eNOS activation, similar effects were shown by the treatment of autophagy inhibitor 3-MA. LPS-induced myocardial injury is associated with excessive PKCß2 activation, which contributes to elevated autophagy and impaired Cav-3/eNOS signaling. Selective inhibition of PKCß2 improves Cav-3/eNOS signaling and attenuates LPS-induced injury through inhibiting autophagy in H9C2 cardiomyocytes.


Assuntos
Autofagia/efeitos dos fármacos , Caveolina 3/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Ftalimidas/farmacologia , Proteína Quinase C beta/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Western Blotting , Sobrevivência Celular , L-Lactato Desidrogenase/metabolismo , Lipopolissacarídeos/toxicidade , Malondialdeído/metabolismo , Miócitos Cardíacos/metabolismo , Proteína Quinase C beta/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo
9.
Chem Commun (Camb) ; 57(53): 6558-6561, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34113937

RESUMO

A blue light activated anti-cancer prodrug, NST, was designed based on a photoactive 4-aminonaphthalimide derivative and an anticancer drug, 10-hydroxycamptothecin. NST was hard to be taken up by living cells and showed negligible dark cytotoxicity. The irradiation caused photocleavage of NST and resulted in high cytotoxicity.


Assuntos
Luz , Ftalimidas/química , Ftalimidas/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Antineoplásicos/metabolismo , Camptotecina/análogos & derivados , Camptotecina/metabolismo , Linhagem Celular Tumoral , Humanos , Ftalimidas/metabolismo , Pró-Fármacos/metabolismo
10.
PLoS One ; 16(6): e0252504, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34115770

RESUMO

Chemicals reactivating epigenetically silenced genes target diverse classes of enzymes, including DNMTs, HDACs, HMTs and BET protein family members. They can strongly influence the expression of genes and endogenous retroviral elements with concomitant dsRNA synthesis and massive transcription of LTRs. Chemicals reactivating gene expression may cause both beneficial effects in cancer cells and may be hazardous by promoting carcinogenesis. Among chemicals used in medicine and commerce, only a small fraction has been studied with respect to their influence on epigenetic silencing. Screening of chemicals reactivating silent genes requires adequate systems mimicking whole-genome processes. We used a HeLa TSA-inducible cell population (HeLa TI cells) obtained by retroviral infection of a GFP-containing vector followed by several rounds of cell sorting for screening purposes. Previously, the details of GFP epigenetic silencing in HeLa TI cells were thoroughly described. Herein, we show that the epigenetically repressed gene GFP is reactivated by 15 agents, including HDAC inhibitors-vorinostat, sodium butyrate, valproic acid, depsipeptide, pomiferin, and entinostat; DNMT inhibitors-decitabine, 5-azacytidine, RG108; HMT inhibitors-UNC0638, BIX01294, DZNep; a chromatin remodeler-curaxin CBL0137; and BET inhibitors-JQ-1 and JQ-35. We demonstrate that combinations of epigenetic modulators caused a significant increase in cell number with reactivated GFP compared to the individual effects of each agent. HeLa TI cells are competent to metabolize xenobiotics and possess constitutively expressed and inducible cytochrome P450 mono-oxygenases involved in xenobiotic biotransformation. Thus, HeLa TI cells may be used as an adequate test system for the extensive screening of chemicals, including those that must be metabolically activated. Studying the additional metabolic activation of xenobiotics, we surprisingly found that the rat liver S9 fraction, which has been widely used for xenobiotic activation in genotoxicity tests, reactivated epigenetically silenced genes. Applying the HeLa TI system, we show that N-nitrosodiphenylamine and N-nitrosodimethylamine reactivate epigenetically silenced genes, probably by affecting DNA methylation.


Assuntos
Epigênese Genética/fisiologia , Azacitidina/farmacologia , Azepinas/farmacologia , Metilação de DNA/genética , Metilação de DNA/fisiologia , Epigênese Genética/genética , Células HeLa , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ftalimidas/farmacologia , Quinazolinas/farmacologia , Triptofano/análogos & derivados , Triptofano/farmacologia
11.
Angew Chem Int Ed Engl ; 60(32): 17514-17521, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34018657

RESUMO

Macrophage migration inhibitory factor (MIF) is involved in protein-protein interactions that play key roles in inflammation and cancer. Current strategies to develop small molecule modulators of MIF functions are mainly restricted to the MIF tautomerase active site. Here, we use this site to develop proteolysis targeting chimera (PROTAC) in order to eliminate MIF from its protein-protein interaction network. We report the first potent MIF-directed PROTAC, denoted MD13, which induced almost complete MIF degradation at low micromolar concentrations with a DC50 around 100 nM in A549 cells. MD13 suppresses the proliferation of A549 cells, which can be explained by deactivation of the MAPK pathway and subsequent induction of cell cycle arrest at the G2/M phase. MD13 also exhibits antiproliferative effect in a 3D tumor spheroid model. In conclusion, we describe the first MIF-directed PROTAC (MD13) as a research tool, which also demonstrates the potential of PROTACs in cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Benzoxazinas/farmacologia , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Ftalimidas/farmacologia , Células A549 , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos/síntese química , Benzoxazinas/síntese química , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Oxirredutases Intramoleculares/química , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fatores Inibidores da Migração de Macrófagos/química , Ftalimidas/síntese química , Proteólise/efeitos dos fármacos , Esferoides Celulares/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo
12.
Int J Mol Sci ; 22(8)2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33918086

RESUMO

BACKGROUND: In the latest years, there has been an increased interest in nanomaterials that may provide promising novel approaches to disease diagnostics and therapeutics. Our previous results demonstrated that Carbon-dots prepared from N-hydroxyphthalimide (CD-NHF) exhibited anti-tumoral activity on several cancer cell lines such as MDA-MB-231, A375, A549, and RPMI8226, while U87 glioma tumor cells were unaffected. Gliomas represent one of the most common types of human primary brain tumors and are responsible for the majority of deaths. In the present in vitro study, we expand our previous investigation on CD-NHF in the U87 cell line by adding different drug combinations. METHODS: Cell viability, migration, invasion, and immunofluorescent staining of key molecular pathways have been assessed after various treatments with CD-NHF and/or K252A and AKTVIII inhibitors in the U87 cell line. RESULTS: Association of an inhibitor strongly potentiates the anti-tumoral properties of CD-NHF identified by significant impairment of migration, invasion, and expression levels of phosphorylated Akt, p70S6Kinase, or by decreasing expression levels of Bcl-2, IL-6, STAT3, and Slug. CONCLUSIONS: Using simultaneously reduced doses of both CD-NHF and an inhibitor in order to reduce side effects, the viability and invasiveness of U87 glioma cells were significantly impaired.


Assuntos
Antineoplásicos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Ftalimidas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Ftalimidas/química
13.
Bioorg Med Chem Lett ; 42: 128046, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33865969

RESUMO

PI3K-δ mediates key immune cell signaling pathways and is a target of interest for treatment of oncological and immunological disorders. Here we describe the discovery and optimization of a novel series of PI3K-δ selective inhibitors. We first identified hits containing an isoindolinone scaffold using a combined ligand- and receptor-based virtual screening workflow, and then improved potency and selectivity guided by structural data and modeling. Careful optimization of molecular properties led to compounds with improved permeability and pharmacokinetic profile, and high potency in a whole blood assay.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Ftalimidas/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Fosfoinositídeo-3 Quinase/química , Ftalimidas/síntese química , Ftalimidas/química , Relação Estrutura-Atividade
14.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803750

RESUMO

The mode of action of 1-naphthylphthalamic acid (NPA) to induce conspicuous local stem swelling in the area of its application to the growing internode in intact Bryophyllum calycinum was studied based on the aspects of histological observation and comprehensive analyses of plant hormones. Histological analyses revealed that NPA induced an increase in cell size and numerous cell divisions in the cortex and pith, respectively, compared to untreated stem. In the area of NPA application, vascular tissues had significantly wider cambial zones consisting of 5-6 cell layers, whereas phloem and xylem seemed not to be affected. This indicates that stem swelling in the area of NPA application is caused by stimulation of cell division and cell enlargement mainly in the cambial zone, cortex, and pith. Comprehensive analyses of plant hormones revealed that NPA substantially increased endogenous levels of indole-3-acetic acid (IAA) in the swelling area. NPA also increased endogenous levels of cytokinins, jasmonic acid, and its precursor, 12-oxo-phytodienoic acid, but did not increase abscisic acid and gibberellin levels. It was shown, using radiolabeled 14C-IAA, that NPA applied to the middle of internode segments had little effect on polar auxin transport, while 2,3,5-triiodobenzoic acid substantially inhibited it. These results strongly suggest that NPA induces changes in endogenous levels of plant hormones, such as IAA, cytokinins, and jasmonic acid, and their hormonal crosstalk results in a conspicuous local stem swelling. The possible different mode of action of NPA from other polar auxin transport inhibitors in succulent plants is extensively discussed.


Assuntos
Kalanchoe/citologia , Ftalimidas/farmacologia , Reguladores de Crescimento de Plantas/farmacologia , Caules de Planta/fisiologia , Transporte Biológico/efeitos dos fármacos , Ácidos Indolacéticos/farmacologia , Kalanchoe/anatomia & histologia , Caules de Planta/efeitos dos fármacos
15.
Bioorg Chem ; 111: 104835, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33798850

RESUMO

This study reports an efficient and convenient click chemistry synthesis of a novel series of phthalimide scaffold linked to 1,2,3 triazole ring and terminal lipophilic fragments. Structures of newly synthesized compounds were well characterized by different spectroscopic tools. In vitro MTT cytotoxicity assay was performed comparing the cytotoxic effects of newly synthesized compounds to staurosporine using three different types: human liver cancer cell line (HepG2), Michigan cancer foundation-7 (MCF-7) and human colorectal carcinoma cell line (HCT116). The initial screening showed excellent to moderate anticancer activity for these newly synthesized compounds with high degree of cell line selectivity with micromolar (µM) half maximal inhibitory concentration (IC50) values against tumor cells. The SAR analysis of these derivatives confirmed the role of molecular fragments including phthalimide, linker, triazole, and terminal tails in correlation to activity. In addition, enzymatic inhibitory assay against wild type EGFR was performed for the most active compounds to get more details about their mechanism of action. In order to further explore their binding affinities, molecular docking simulation was studied against EGFR site. The results obtained from molecular docking study and those obtained from cytotoxic screening were correlated. One of the most prominent analogs is (6f) with terminal disubstituted ring and amide linker showed selective MCF-7 cytotoxicity profile with IC50 0.22 µM and 79 nM to EGFR target. Extensive structure activity relationship (SAR) analyses were also carried out. The pharmacokinetic profile of (6f) was studied showing good metabolic stability and long duration behavior. This design offered a potent selective anticancer phthalimide-triazole leads for further optimization in cancer drug discovery.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Ftalimidas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Triazóis/farmacologia , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Células Hep G2 , Humanos , Células MCF-7 , Estrutura Molecular , Ftalimidas/química , Ftalimidas/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Relação Estrutura-Atividade , Triazóis/química , Triazóis/metabolismo
16.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800748

RESUMO

The plant hormone indole-3-acetic acid (IAA) is one of the main signals playing a role in the communication between host and endophytes. Endophytes can synthesize IAA de novo to influence the IAA homeostasis in plants. Although much is known about IAA biosynthesis in microorganisms, there is still less known about the pathway by which IAA is synthesized in fungal endophytes. The aim of this study is to examine a possible IAA biosynthesis pathway in Cyanodermella asteris. In vitro cultures of C. asteris were incubated with the IAA precursors tryptophan (Trp) and indole, as well as possible intermediates, and they were additionally treated with IAA biosynthesis inhibitors (2-mercaptobenzimidazole and yucasin DF) to elucidate possible IAA biosynthesis pathways. It was shown that (a) C. asteris synthesized IAA without adding precursors; (b) indole-3-acetonitrile (IAN), indole-3-acetamide (IAM), and indole-3-acetaldehyde (IAD) increased IAA biosynthesis; and (c) C. asteris synthesized IAA also by a Trp-independent pathway. Together with the genome information of C. asteris, the possible IAA biosynthesis pathways found can improve the understanding of IAA biosynthesis in fungal endophytes. The uptake of fungal IAA into Arabidopsis thaliana is necessary for the induction of lateral roots and other fungus-related growth phenotypes, since the application of the influx inhibitor 2-naphthoxyacetic acid (NOA) but not the efflux inhibitor N-1-naphtylphthalamic acid (NPA) were altering these parameters. In addition, the root phenotype of the mutation in an influx carrier, aux1, was partially rescued by C. asteris.


Assuntos
Arabidopsis/microbiologia , Ascomicetos/metabolismo , Endófitos/metabolismo , Adaptação ao Hospedeiro , Ácidos Indolacéticos/metabolismo , Indóis/farmacologia , Raízes de Plantas/microbiologia , Triptofano/farmacologia , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Ascomicetos/efeitos dos fármacos , Ascomicetos/genética , Benzimidazóis/farmacologia , Meios de Cultivo Condicionados , Genoma Fúngico , Glicolatos/farmacologia , Especificidade de Hospedeiro , Ácidos Indolacéticos/farmacologia , Indóis/metabolismo , Redes e Vias Metabólicas/genética , Ftalimidas/farmacologia , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/genética , Triazóis/farmacologia , Triptofano/metabolismo
17.
Bioorg Chem ; 110: 104819, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33752144

RESUMO

Phthalimide derivatives are a promising group of anticancer drugs, while aminothiazoles have great potential as elastase inhibitors. In these context fourteen phthalimido-thiazoles containing a dichloro-substituted phenyl ring with high antiproliferative activity against various cancer cell lines were designed and synthesized. Among the screened derivatives, compounds 5a-5e and 6a-6f showed high activity against human leukemia (MV4-11) cells with IC50 values in the range of 5.56-16.10 µM. The phthalimide-thiazoles 5a, 5b and 5d showed the highest selectivity index (SI) relative to MV4-11 with 11.92, 10.80 and 8.21 values, respectively. The antiproliferative activity of compounds 5e, 5f and 6e, 6f against human lung carcinoma (A549) cells is also very high, with IC50 values in the range of 6.69-10.41 µM. Lead compounds 6e and 6f showed elastase inhibition effect, with IC50 values about 32 µM with mixed mechanism of action. The molecular modeling studies showed that the binding energies calculated for all set of compounds are strongly correlated with the experimentally determined values of IC50. The lead compound 6e also increases almost 16 times caspase 3/7 activity in A549 cells compared to control. We have also demonstrated that compound 6f reduced EGFR tyrosine kinase levels in A549 cells by approximately 31%. These results clearly suggest that 3,4-dichloro-derivative 6e and 3,5-dichloro-derivative 6f could constitute lead dual-targeted anticancer drug candidates.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Ftalimidas/farmacologia , Tiazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Caspases/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Elastase Pancreática/antagonistas & inibidores , Elastase Pancreática/metabolismo , Ftalimidas/química , Relação Estrutura-Atividade , Tiazóis/química , Células Tumorais Cultivadas
18.
DNA Cell Biol ; 40(5): 662-674, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33751901

RESUMO

Periodontal ligament cells (PDLCs) have well documented osteogenic potential; however, this commitment can be highly heterogenous, limiting their applications in tissue regeneration. In this study, we use PDLC populations characterized by high and low osteogenic potential (h-PDLCs and l-PDLCs, respectively) to identify possible sources of such heterogeneity and to investigate whether the osteogenic differentiation can be enhanced by epigenetic modulation. In h-PDLCs, low basal expression levels of pluripotency markers (NANOG, OCT4), DNA methyltransferases (DNMT1, DNMT3B), and enzymes involved in active DNA demethylation (TET1, TET3) were prerequisite to high osteogenic potential. Furthermore, these genes were downregulated upon early osteogenesis, possibly allowing for the increase in expression of the key osteogenic transcription factors, Runt-related transcription factor 2 (RUNX2) and SP7, and ultimately, mineral nodule formation. l-PDLCs appeared locked in the multipotent state and this was further enhanced upon early osteogenic stimulation, correlating with low RUNX2 expression and impaired mineralization. Further upregulation of DNMTs was also evident, while pretreatment with RG108, the DNMTs' inhibitor, enhanced the osteogenic program in l-PDLCs through downregulation of DNMTs, increased RUNX2 expression and nuclear localization, accelerated expression of osteogenic markers, and increased mineralization. These findings point toward the role of DNMTs and Ten Eleven Translocations (TETs) in osteogenic commitment and support application of epigenetic approaches to modulate biomineralization in PDLCs.


Assuntos
Calcificação Fisiológica , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Ligamento Periodontal/citologia , Calcificação Fisiológica/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Regulação para Baixo/efeitos dos fármacos , Humanos , Osteogênese/genética , Ftalimidas/farmacologia , Triptofano/análogos & derivados , Triptofano/farmacologia , Regulação para Cima/efeitos dos fármacos , Adulto Jovem
19.
SLAS Discov ; 26(4): 547-559, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33780296

RESUMO

Recent advances in targeted protein degradation have enabled chemical hijacking of the ubiquitin-proteasome system to treat disease. The catalytic rate of cereblon (CRBN)-dependent bifunctional degradation activating compounds (BiDAC), which recruit CRBN to a chosen target protein, resulting in its ubiquitination and proteasomal degradation, is an important parameter to consider during the drug discovery process. In this work, an in vitro system was developed to measure the kinetics of BRD4 bromodomain 1 (BD1) ubiquitination by fitting an essential activator kinetic model to these data. The affinities between BiDACs, BD1, and CRBN in the binary complex, ternary complex, and full ubiquitination complex were characterized. Together, this work provides a new tool for understanding and optimizing the catalytic and thermodynamic properties of BiDACs.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Bioensaio , Proteínas de Ciclo Celular/metabolismo , Oxindóis/farmacologia , Ftalimidas/farmacologia , Processamento de Proteína Pós-Traducional , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/genética , Sistema Livre de Células/química , Sistema Livre de Células/metabolismo , Células HeLa , Humanos , Cinética , Oxindóis/síntese química , Ftalimidas/síntese química , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Ligação Proteica , Domínios Proteicos , Proteólise/efeitos dos fármacos , Termodinâmica , Fatores de Transcrição/química , Fatores de Transcrição/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/efeitos dos fármacos
20.
J Med Chem ; 64(5): 2829-2848, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33606537

RESUMO

EZH2 mediates both PRC2-dependent gene silencing via catalyzing H3K27me3 and PRC2-independent transcriptional activation in various cancers. Given its oncogenic role in cancers, EZH2 has constituted a compelling target for anticancer therapy. However, current EZH2 inhibitors only target its methyltransferase activity to downregulate H3K27me3 levels and show limited efficacy because of inadequate suppression of the EZH2 oncogenic activity. Therefore, therapeutic strategies to completely block the oncogenic activity of EZH2 are urgently needed. Herein, we report a series of EZH2-targeted proteolysis targeting chimeras (PROTACs) that induce proteasomal degradation of PRC2 components, including EZH2, EED, SUZ12, and RbAp48. Preliminary assessment identified E7 as the most active PROTAC molecule, which decreased PRC2 subunits and H3K27me2/3 levels in various cancer cells. Furthermore, E7 strongly inhibited transcriptional silencing mediated by EZH2 dependent on PRC2 and transcriptional activation mediated by EZH2 independent of PRC2, showing significant antiproliferative activities against cancer cell lines dependent on the enzymatic and nonenzymatic activities of EZH2.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Ftalimidas/farmacologia , Proteólise/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos/síntese química , Benzamidas/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Humanos , Ftalimidas/síntese química , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/efeitos dos fármacos
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