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1.
J Enzyme Inhib Med Chem ; 36(1): 1622-1631, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34284695

RESUMO

Some methoxy-, hydroxyl-, pyridyl-, or fluoro-substituted 3,5-bis(arylidene)-4-piperidones (BAPs) could reduce inflammation and promote hepatoma cell apoptosis by inhibiting activation of NF-κB, especially after introduction of trifluoromethyl. Herein, a series of trifluoromethyl-substituted BAPs (4-30) were synthesised and the biological activities were evaluated. We successfully found the most potential 16, which contains three trifluoromethyl substituents and exhibits the best anti-tumour and anti-inflammatory activities. Preliminary mechanism research revealed that 16 could promote HepG2 cell apoptosis in a dose-dependent manner by down-regulating the expression of Bcl-2 and up-regulating the expression of Bax, C-caspase-3. Meanwhile, 16 inhibited activation of NF-κB by directly inhibiting the phosphorylation of p65 and IκBα induced by LPS, together with indirectly inhibiting MAPK pathway, thereby exhibiting both anti-hepatoma and anti-inflammatory activities. Molecular docking confirmed that 16 could bind to the active sites of Bcl-2, p65, and p38 reasonably. The above results suggested that 16 has enormous potential to be developed as a multifunctional agent for the clinical treatment of liver cancers and inflammatory diseases.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , NF-kappa B/antagonistas & inibidores , Piperidonas/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Simulação de Acoplamento Molecular , Estrutura Molecular , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Piperidonas/síntese química , Piperidonas/química , Relação Estrutura-Atividade
2.
Appl Microbiol Biotechnol ; 105(14-15): 6087-6102, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34291315

RESUMO

During the last few decades, whole-cell biosensors have attracted increasing attention for their enormous potential in monitoring bioavailable heavy metal contaminations in the ecosystem. Visual and measurable output signals by employing natural pigments have been demonstrated to offer another potential choice to indicate the existence of bioavailable heavy metals in recent years. The biosynthesis of the blue pigment indigoidine has been achieved in E. coli following heterologous expression of both BpsA (a single-module non-ribosomal peptide synthetase) and PcpS (a PPTase to activate apo-BpsA). Moreover, we demonstrated herein the development of the indigoidine-based whole-cell biosensors to detect bioavailable Hg(II) and Pb(II) in water samples by employing metal-responsive transcriptional regulator MerR and PbrR as the sensory elements, and the indigoidine biosynthesis gene cluster as a reporter element. The resulting indigoidine-based biosensors presented a good selectivity and high sensitivity to target metal ions. High concentration of target metal exposure could be clearly recognized by the naked eye due to the color change by the secretion of indigoidine, and quantified by measuring the absorbance of the culture supernatants at 600 nm. Dose-response relationships existed between the exposure concentrations of target heavy metals and the production of indigoidine. Although fairly good linear relationships were obtained in a relatively limited concentration range of the concentrations of heavy metal ions, these findings suggest that genetically controlled indigoidine biosynthesis triggered by the MerR family transcriptional regulator can enable a sensitive, visual, and qualitative whole-cell biosensor for bioindicating the presence of bioaccessible heavy metal in environmental water samples. KEY POINTS: • Biosynthesis pathway of indigoidine reconstructed in a high copy number plasmid in E. coli. • Visual and colorimetric detection of Hg(II) and Pb(II) by manipulation of indigoidine biosynthesis through MerR family metalloregulator. •Enhanced detection sensitivity toward Hg(II) and Pb(II) achieved using novel pigment-based whole-cell biosensors.


Assuntos
Técnicas Biossensoriais , Metais Pesados , Ecossistema , Escherichia coli/genética , Piperidonas
3.
J Org Chem ; 86(15): 10455-10466, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34275281

RESUMO

The development of efficient methods for facilitating N-C(O) bond activation in amides is an important objective in organic synthesis that permits the manipulation of the traditionally unreactive amide bonds. Herein, we report a comparative evaluation of a series of cyclic amides as activating groups in amide N-C(O) bond cross-coupling. Evaluation of N-acyl-imides, N-acyl-lactams, and N-acyl-oxazolidinones bearing five- and six-membered rings using Pd(II)-NHC and Pd-phosphine systems reveals the relative reactivity order of N-activating groups in Suzuki-Miyaura cross-coupling. The reactivity of activated phenolic esters and thioesters is evaluated for comparison in O-C(O) and S-C(O) cross-coupling under the same reaction conditions. Most notably, the study reveals N-acyl-δ-valerolactams as a highly effective class of mono-N-acyl-activated amide precursors in cross-coupling. The X-ray structure of the model N-acyl-δ-valerolactam is characterized by an additive Winkler-Dunitz distortion parameter Σ(τ+χN) of 54.0°, placing this amide in a medium distortion range of twisted amides. Computational studies provide insight into the structural and energetic parameters of the amide bond, including amidic resonance, N/O-protonation aptitude, and the rotational barrier around the N-C(O) axis. This class of N-acyl-lactams will be a valuable addition to the growing portfolio of amide electrophiles for cross-coupling reactions by acyl-metal intermediates.


Assuntos
Amidas , Lactamas , Reações Cruzadas , Imidas , Piperidonas
4.
J Med Chem ; 64(15): 10606-10620, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34319094

RESUMO

Targeted protein degradation is a promising area in the discovery and development of innovative therapeutics. Molecular glues mediate proximity-induced protein degradation and have intrinsic advantages over heterobifunctional proteolysis-targeting chimeras, including unprecedented mechanisms, distinct biological activities, and favorable physicochemical properties. Classical molecular glue degraders have been identified serendipitously, but rational discovery and design strategies are emerging rapidly. In this review, we aim to highlight the recent advances in molecular glues for targeted protein degradation and discuss the challenges in developing molecular glues into therapeutic agents. In particular, discovery strategies, action mechanisms, and representative case studies will be addressed.


Assuntos
Acetamidas/farmacologia , Descoberta de Drogas , Isoindóis/farmacologia , Piperidonas/farmacologia , Proteínas/antagonistas & inibidores , Acetamidas/química , Humanos , Isoindóis/química , Estrutura Molecular , Piperidonas/química , Proteínas/metabolismo , Proteólise/efeitos dos fármacos
5.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 50(1): 106-112, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-34117854

RESUMO

:To investigate the effect of transient receptor potential melastatin 2 (TRPM2) inhibitor A10 on oxygen glucose deprivation/reperfusion (OGD/R) injury in SH-SY5Y cells.:Human neuroblastoma SH-SY5Y cells were subject to OGD/R injury,and then were divided into blank control group,model control group and A10 group randomly. The cell survival rate was detected by cell counting kit 8 (CCK-8); the level of cellular reactive oxygen species (ROS) was detected by reactive oxygen detection kit; the mitochondrial membrane potential was detected by tetramethylrhodamine (TMRM) method; the number of apoptotic cells was detected by TUNEL apoptosis assay kit; the protein expression level of cleaved caspase 3 was detected by Western blot.:Compared with 3,20,30,50, has lower cytotoxicity and better inhibition effect on channel activity. Compared with the model control group,ROS level was reduced,the mitochondrial membrane potential was improved,the number of apoptosis cells was reduced ,and the expression of cleaved caspase 3 was significantly reduced in the A10 group(all <0.05). : A10 can alleviate cell damage after OGD/R by inhibiting TRPM2 channel function,reducing extracellular calcium influx,reducing cell ROS levels,stabilizing mitochondrial membrane potential levels,and reducing apoptosis.


Assuntos
Glucose , Canais de Cátion TRPM , Apoptose , Benzenoacetamidas , Sobrevivência Celular , Humanos , Oxigênio/metabolismo , Piperidonas , Espécies Reativas de Oxigênio/metabolismo , Reperfusão
6.
Parasitol Res ; 120(6): 2199-2218, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33963899

RESUMO

Leishmaniasis is considered a neglected disease, which makes it an unattractive market for the pharmaceutical industry; hence, efforts in the search for biologically active substances are hampered by this lack of financial motivation. Thus, in the present study, we report the leishmanicidal activity and the possible mechanisms of action of compounds with promising activity against the species Leishmania (V.) braziliensis, the causative agent of the skin disease leishmaniasis. The natural compound 1a (piplartine) and the analog 2a were the most potent against promastigote forms with growth inhibition values for 50% of the parasite population (IC50) = 8.58 and 11.25 µM, respectively. For amastigote forms, the ICa50 values were 1.46 and 16.7 µM, respectively. In the molecular docking study, piplartine showed favorable binding energy (-7.13 kcal/mol) and with 50% inhibition of trypanothione reductase (IC50) = 91.1 µM. Preliminary investigations of the mechanism of action indicate that piplartine increased ROS levels, induced loss of cell membrane integrity, and caused accumulation of lipid bodies after 24 h of incubation at its lowest effective concentration (IC50), which was not observed for the synthetic analog 2a. The mode of action for the leishmanicidal activity of piplartine (1a) was assigned to involve affinity for the trypanothione reductase of Leishmania (V.) braziliensis TR.


Assuntos
Amidas/farmacologia , Leishmania braziliensis/efeitos dos fármacos , Piperidonas/farmacologia , Tripanossomicidas/farmacologia , Amidas/química , Animais , Linhagem Celular Tumoral , Chlorocebus aethiops , Simulação por Computador , Humanos , Simulação de Acoplamento Molecular , NADH NADPH Oxirredutases/antagonistas & inibidores , Piperidonas/química , Células Vero
7.
Methods Mol Biol ; 2296: 91-141, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33977444

RESUMO

Bacteria of the genus Streptomyces are one of the most important producers of biologically active natural products. Recent robust genomic sequencing of Streptomyces strains has shown enormous genetic potential for new natural products. However, many biosynthetic gene clusters are silent. Therefore, efficient and stable genome modification methods are needed to induce their production or to manipulate them for the production of new compounds or biotechnologically improved strains. We have recently developed a simple and efficient markerless genome modification system for these bacteria based on the positive selection of double crossovers using the blue pigment indigoidine bpsA gene. This chapter is an attempt to provide methodological details of this strategy for stable markerless genomic engineering (deletions/insertions) to improve their biotechnological properties and to produce biologically active compounds.


Assuntos
Engenharia Genética/métodos , Genômica/métodos , Streptomyces/genética , Proteínas de Bactérias/genética , Produtos Biológicos , Família Multigênica/genética , Piperidonas/metabolismo
8.
Molecules ; 26(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807791

RESUMO

In the present work, the thermochemistry of solution, solvation, and hydrogen bonding of cyclic amides in proton acceptor (B) and proton donor (RXH) solvents were studied. The infinite dilution solution enthalpies of δ-valerolactam, N-methylvalerolactam, ε-caprolactam, and N-methylcaprolactam were measured at 298.15 K. The solvation enthalpies of cyclic amides were calculated based on the measured solution enthalpies and sublimation/vaporization enthalpies from literature. The enthalpies of hydrogen bonding between cyclic amides and proton acceptor and donor solvents were then calculated as a difference between the total solvation enthalpy and the non-specific contribution. The latter was estimated via two different approaches in proton donor and proton accepting solvents. The effect of the cycle size on the strength of hydrogen bonding of the cyclic amides in solution is discussed.


Assuntos
Amidas/química , Lactamas/química , Solventes/química , Calorimetria , Caprolactama/química , Ligação de Hidrogênio , Piperidonas/química , Prótons
9.
Blood Adv ; 5(7): 2027-2039, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33847741

RESUMO

CC-122 is a next-generation cereblon E3 ligase-modulating agent that has demonstrated promising clinical efficacy in patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL). Mechanistically, CC-122 induces the degradation of IKZF1/3, leading to T-cell activation and robust cell-autonomous killing in DLBCL. We report a genome-wide CRISPR/Cas9 screening for CC-122 in a DLBCL cell line SU-DHL-4 with follow-up mechanistic characterization in 6 DLBCL cell lines to identify genes regulating the response to CC-122. Top-ranked CC-122 resistance genes encode, not only well-defined members or regulators of the CUL4/DDB1/RBX1/CRBN E3 ubiquitin ligase complex, but also key components of signaling and transcriptional networks that have not been shown to modulate the response to cereblon modulators. Ablation of CYLD, NFKBIA, TRAF2, or TRAF3 induces hyperactivation of the canonical and/or noncanonical NF-κB pathways and subsequently diminishes CC-122-induced apoptosis in 5 of 6 DLBCL cell lines. Depletion of KCTD5, the substrate adaptor of the CUL3/RBX1/KCTD5 ubiquitin ligase complex, promotes the stabilization of its cognate substrate, GNG5, resulting in CC-122 resistance in HT, SU-DHL-4, and WSU-DLCL2. Furthermore, knockout of AMBRA1 renders resistance to CC-122 in SU-DHL-4 and U-2932, whereas knockout of RFX7 leads to resistance specifically in SU-DHL-4. The ubiquitous and cell line-specific mechanisms of CC-122 resistance in DLBCL cell lines revealed in this work pinpoint genetic alternations that are potentially associated with clinical resistance in patients and facilitate the development of biomarker strategies for patient stratification, which may improve clinical outcomes of patients with R/R DLBCL.


Assuntos
Linfoma Difuso de Grandes Células B , Piperidonas , Proteínas Adaptadoras de Transdução de Sinal , Linhagem Celular Tumoral , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Canais de Potássio , Quinazolinonas , Ubiquitina-Proteína Ligases
10.
Nat Commun ; 12(1): 1422, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658492

RESUMO

Trans-acyltransferase polyketide synthases (trans-AT PKSs) are bacterial multimodular enzymes that biosynthesize diverse pharmaceutically and ecologically important polyketides. A notable feature of this natural product class is the existence of chemical hybrids that combine core moieties from different polyketide structures. To understand the prevalence, biosynthetic basis, and evolutionary patterns of this phenomenon, we developed transPACT, a phylogenomic algorithm to automate global classification of trans-AT PKS modules across bacteria and applied it to 1782 trans-AT PKS gene clusters. These analyses reveal widespread exchange patterns suggesting recombination of extended PKS module series as an important mechanism for metabolic diversification in this natural product class. For three plant-associated bacteria, i.e., the root colonizer Gynuella sunshinyii and the pathogens Xanthomonas cannabis and Pseudomonas syringae, we demonstrate the utility of this computational approach for uncovering cryptic relationships between polyketides, accelerating polyketide mining from fragmented genome sequences, and discovering polyketide variants with conserved moieties of interest. As natural combinatorial hybrids are rare among the more commonly studied cis-AT PKSs, this study paves the way towards evolutionarily informed, rational PKS engineering to produce chimeric trans-AT PKS-derived polyketides.


Assuntos
Aciltransferases/genética , Proteínas de Bactérias/genética , Filogenia , Policetídeo Sintases/genética , Policetídeos/metabolismo , Aciltransferases/metabolismo , Algoritmos , Arabidopsis/microbiologia , Proteínas de Bactérias/metabolismo , Evolução Molecular , Genoma Bacteriano , Células HeLa , Humanos , Lactonas/metabolismo , Macrolídeos/metabolismo , Família Multigênica , Piperidonas/química , Plantas/microbiologia , Policetídeo Sintases/metabolismo , Policetídeos/química , Pseudomonas syringae/metabolismo , Xanthomonas/metabolismo , Xanthomonas/patogenicidade
11.
Bioorg Med Chem Lett ; 40: 127928, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33705899

RESUMO

Four new aminothiazole-oximepiperidone cephalosporins (10a-10d) were synthesized, with their in vitro antibacterial activities against hospital isolated Gram-negative bacteria assessed. The results showed that compounds 10a-10d effectively inhibit a variety of Gram-negative bacteria. Compound 10a was the most potent compound, with comparable activity as ceftazidime. The combination of compound 10a and Avibactam was very active against almost all bacteria tested, which including multidrug resistant K. pneumoniae and A. baumannii. Compared to Avycaz, this combination is more potent against ESBL producing K. pneumoniae. Thus, the combination of 10a and Avibactam is of interest for further studies.


Assuntos
Antibacterianos/farmacologia , Cefalosporinas/farmacologia , Oximas/farmacologia , Piperidonas/farmacologia , Tiazóis/farmacologia , Antibacterianos/síntese química , Compostos Azabicíclicos/farmacologia , Cefalosporinas/síntese química , Combinação de Medicamentos , Bactérias Gram-Negativas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Oximas/síntese química , Piperidonas/síntese química , Tiazóis/síntese química
12.
J Med Chem ; 64(4): 1835-1843, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33591756

RESUMO

Acute myeloid leukemia (AML) is marked by significant unmet clinical need due to both poor survival and high relapse rates where long-term disease control for most patients with relapsed or refractory AML remain dismal. Inspired to bring novel therapeutic options to these patients, we envisioned protein degradation as a potential therapeutic approach for the treatment of AML. Following this course, we discovered and pioneered a novel mechanism of action which culminated in the discovery of CC-90009. CC-90009 represents a novel protein degrader and the first cereblon E3 ligase modulating drug to enter clinical development that specifically targets GSPT1 (G1 to S phase transition 1) for proteasomal degradation. This manuscript briefly summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and efficacy data for CC-90009, which is currently in phase 1 clinical development.


Assuntos
Acetamidas/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos/uso terapêutico , Isoindóis/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Fatores de Terminação de Peptídeos/antagonistas & inibidores , Piperidonas/uso terapêutico , Ubiquitina-Proteína Ligases/metabolismo , Acetamidas/química , Acetamidas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Isoindóis/química , Isoindóis/farmacologia , Macaca fascicularis , Masculino , Camundongos , Estrutura Molecular , Fatores de Terminação de Peptídeos/química , Fatores de Terminação de Peptídeos/metabolismo , Piperidonas/química , Piperidonas/farmacologia , Proteólise/efeitos dos fármacos , Relação Estrutura-Atividade
13.
Drug Des Devel Ther ; 15: 651-658, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33628012

RESUMO

Purpose: A fixed-dose combination (FDC) of gemigliptin/rosuvastatin 50/20 mg as a monolayer tablet has been used to treat patients with both type 2 diabetes mellitus and dyslipidemia. To improve the stability of the FDC, a new FDC formulation as a bilayer tablet was developed. This study aimed to compare the pharmacokinetics (PKs) and pharmacodynamics (PDs) of the FDC of gemigliptin/rosuvastatin 50/20 mg between the newly developed bilayer tablet and the approved monolayer tablet in healthy subjects. Materials and Methods: A randomized, open-label, single-dose, two-treatment, two-way crossover study was conducted. Subjects received a single dose of the FDC of gemigliptin/rosuvastatin 50/20 mg as the bilayer tablet or the monolayer tablet in each period with a 7-day washout. For PK and PD analyses, serial blood samples were collected up to 72 hours after dosing to determine plasma concentrations of gemigliptin, its active metabolite LC15-0636 and rosuvastatin, and plasma dipeptidyl peptidase-4 (DPP-4) activity. PK and PD parameters were calculated using non-compartmental methods and compared between the two formulations. Results: A total of 48 healthy subjects were randomized, and 45 subjects completed the study. The concentration-time profiles of gemigliptin, LC15-0636 and rosuvastatin were comparable between the two formulations. All geometric mean ratios (90% confidence intervals) of the bilayer tablet to the monolayer tablet for maximum plasma concentration and area under concentration-time curve from 0 to last measurable time point of the three compounds fulfilled the bioequivalence criteria of 0.80-1.25. Likewise, area under plasma DPP-4 activity inhibition from baseline-time curve from 0 to last measurable time point and maximum inhibition of plasma DPP-4 activity were similar between the two formulations. Conclusion: The FDC of gemigliptin/rosuvastatin 50/20 mg as the bilayer tablet showed equivalent PK and PD properties with the FDC of gemigliptin/rosuvastatin 50/20 mg as the monolayer tablet in healthy subjects. These results suggest that the newly developed bilayer tablet can become an alternative formulation to the commercially available monolayer tablet.


Assuntos
Piperidonas/farmacocinética , Pirimidinas/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Adulto , Estudos Cross-Over , Composição de Medicamentos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Estrutura Molecular , Piperidonas/administração & dosagem , Pirimidinas/administração & dosagem , Rosuvastatina Cálcica/administração & dosagem , Comprimidos/administração & dosagem
14.
Biomed Pharmacother ; 136: 111202, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33453607

RESUMO

PURPOSE: EF24, a synthetic analogue of curcumin, was developed as an anti-tumor compound to induce apoptosis, inhibit proliferation and metastasis in various cancers. However, whether EF24 induces ferroptosis in osteosarcoma cells or not, and its underlying mechanism remains largely elusive. METHODS: After EF24 combining with or without other compounds treatments, mRNA expression profiles were proceeded by RNA sequencing. Cytotoxicity was measured by cell counting kit-8 assay. Cell death was quantified by flow cytometer. Gene expression was quantified by real-time PCR. Protein level was detected by western blot. Malonydialdehyde (MDA) level was measured by lipid peroxidation MDA assay kit. Reactive oxygen species (ROS) level was measured by ROS Assay Kit. Ferric ion was measured by Iron Assay kit. RESULTS: EF24 significantly induced cell death in osteosarcoma cell lines, and this effect was significantly reversed by ferrostatin-1, but not Z-VAD(Ome)-FMK, MRT68921 or necrosulfonamide. EF24 significantly increased MDA level, ROS level and intracellular ferric ion level, these effects were significantly attenuated by ferrostatin-1. EF24 upregulated HMOX1 expression in a dose dependent manner, overexpression of HMOX1 facilitated EF24 to induce ferroptosis in osteosarcoma cell lines. HMOX1 knockdown attenuated EF24-induced cytotoxicity and attenuated EF24-induced inhibition of Glutathione Peroxidase 4 (GPX4) expression. CONCLUSION: Our results showed that EF24 upregulated HMOX1 to suppress GPX4 expression to induce ferroptosis by increasing MDA level, ROS level and intracellular ferric ion level. Thus, EF24 might serve as a potential agent for the treatment of HMOX1-positive osteosarcoma patients.


Assuntos
Antineoplásicos/farmacologia , Compostos de Benzilideno/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Ferroptose/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Osteossarcoma/tratamento farmacológico , Piperidonas/farmacologia , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Heme Oxigenase-1/genética , Humanos , Ferro/metabolismo , Malondialdeído/metabolismo , Osteossarcoma/enzimologia , Osteossarcoma/genética , Osteossarcoma/patologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
15.
Biomed Pharmacother ; 137: 111297, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33493968

RESUMO

Patients with diabetes commonly experience hyposalivation, which induces discomfort in eating, swallowing, dryness, smell, and speaking, as well as increases the incidence of periodontal disease. Dipeptidyl peptidase-4 (DPP4) inhibitors are frequently used as antidiabetic drugs that lower glucose levels by utilizing similar mechanisms; however, additional protective functions of each gliptin have been discovered. In this study, the protective roles of gemigliptin, a DPP4 inhibitor, against salivary dysfunction under diabetic conditions were investigated. Streptozotocin-induced diabetic rats received gemigliptin 10 mg/kg or 100 mg/kg via oral gavage for 3 weeks. The weights of salivary gland tissues, saliva secretion, and antioxidant capacity in salivary glands were reduced after diabetes induction, but were significantly preserved following gemigliptin treatment. In salivary gland analysis, expression of apoptotic proteins, as well as amylase and aquaporin-5 (AQP5) protein expression, were increased following gemigliptin treatment. Furthermore, the number of TUNEL-positive cells decreased after gemigliptin treatment. Therefore, gemigliptin has protective roles against salivary dysfunction observed in diabetes, mediated via antioxidant, anti-apoptotic, and salivary secretion mechanisms. These results may help in selecting a suitable drug for patients with diabetes experiencing salivary dysfunction.


Assuntos
Antioxidantes/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Piperidonas/farmacologia , Pirimidinas/farmacologia , Doenças das Glândulas Salivares/prevenção & controle , Glândulas Salivares/efeitos dos fármacos , Salivação/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/fisiopatologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Doenças das Glândulas Salivares/etiologia , Doenças das Glândulas Salivares/fisiopatologia , Glândulas Salivares/metabolismo , Glândulas Salivares/fisiopatologia , Estreptozocina
16.
Blood ; 137(2): 216-231, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33024998

RESUMO

Cancer treatment has been transformed by checkpoint blockade therapies, with the highest anti-tumor activity of anti-programmed death 1 (PD-1) antibody therapy seen in Hodgkin lymphoma. Disappointingly, response rates have been low in the non-Hodgkin lymphomas, with no activity seen in relapsed/refractory chronic lymphocytic leukemia (CLL) with PD-1 blockade. Thus, identifying more powerful combination therapy is required for these patients. Here, we preclinically demonstrate enhanced anti-CLL activity following combinational therapy with anti-PD-1 or anti-PD-1 ligand (PD-L1) and avadomide, a cereblon E3 ligase modulator (CELMoD). Avadomide induced type I and II interferon (IFN) signaling in patient T cells, triggering a feedforward cascade of reinvigorated T-cell responses. Immune modeling assays demonstrated that avadomide stimulated T-cell activation, chemokine expression, motility and lytic synapses with CLL cells, as well as IFN-inducible feedback inhibition through upregulation of PD-L1. Patient-derived xenograft tumors treated with avadomide were converted to CD8+ T cell-inflamed tumor microenvironments that responded to anti-PD-L1/PD-1-based combination therapy. Notably, clinical analyses showed increased PD-L1 expression on T cells, as well as intratumoral expression of chemokine signaling genes in B-cell malignancy patients receiving avadomide-based therapy. These data illustrate the importance of overcoming a low inflammatory T-cell state to successfully sensitize CLL to checkpoint blockade-based combination therapy.


Assuntos
Inibidores de Checkpoint Imunológico/farmacologia , Leucemia Linfocítica Crônica de Células B/imunologia , Ativação Linfocitária/efeitos dos fármacos , Piperidonas/farmacologia , Quinazolinonas/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Humanos , Imunoterapia/métodos , Interferons/imunologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/imunologia , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Curr Med Chem ; 28(13): 2453-2464, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32744955

RESUMO

This review outlines the discovery and development of a novel series of 1-[4-2- aminoethoxy)phenylcarbonyl]-3,5-bis-(benzylidene)-4-piperidones (5-8) as potential drug candidates over the last 15 years in our laboratory. Many of these compounds demonstrate excellent cytotoxic properties and are often more potent than contemporary anticancer drugs. Two highly important features of many of these molecules are first, the greater tumour-selective toxicity and second, the ability of these molecules to act as modulators of multi-drug resistance. The modes of action of some of the potent compounds are by apoptosis induction, generation of reactive oxygen species, activation of certain caspases and affecting mitochondrial functions. These molecules also display promising antimalarial and antimycobacterial properties. In a short term toxicity study, these molecules are well tolerated in mice. Structure-activity relationships and a drug delivery system along with pharmacokinetic studies and metabolic stability of these compounds, have been presented. The positive characteristics associated with the series (5-8) warrant their further evaluations as candidate antineoplastic drug candidates.


Assuntos
Antineoplásicos , Piperidonas , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos , Camundongos , Piperidonas/farmacologia , Relação Estrutura-Atividade
18.
Cancer Sci ; 112(1): 331-338, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33075165

RESUMO

Non-Hodgkin lymphoma (NHL) treated with chemoimmunotherapy has limited efficacy in some patients, resulting in relapsed or refractory disease. Avadomide (CC-122) is a novel cereblon-binding agent that exhibits antilymphoma and immune-modulation activities with a biological profile distinct from similar agents, such as lenalidomide. This phase I multicenter study evaluated avadomide in Japanese patients with advanced solid tumors or NHL. Fourteen patients with NHL and one with a solid tumor (esophageal carcinoma), were enrolled in four dose-escalation cohorts using a 3 + 3 design. Primary endpoints included safety, dose-limiting toxicities (DLT), maximum-tolerated dose and/or recommended phase II dose (RP2D), and pharmacokinetics. Secondary endpoints included overall response rate (ORR) and duration of response. One patient with NHL experienced DLT, which included face edema, pharyngeal edema, and tumor flare (all grade 1) that led to a dose reduction. Eleven patients had grade ≥3 treatment-emergent adverse events, most frequently decreased neutrophil count (33%) and decreased lymphocyte count (20%). The ORR in patients with NHL (n = 13) was 54%, including four complete and three partial responses. The best response for the solid tumor patient was progressive disease. Avadomide dose intensity was consistent across cohorts, and the 3-mg dose given five consecutive days/week was established as the RP2D. This phase I study identified a tolerable dose of avadomide, with an acceptable toxicity profile and clinically meaningful efficacy in Japanese patients with previously treated NHL.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Piperidonas/administração & dosagem , Quinazolinonas/administração & dosagem , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Japão , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Piperidonas/efeitos adversos , Piperidonas/farmacocinética , Quinazolinonas/efeitos adversos , Quinazolinonas/farmacocinética
19.
Aten Primaria ; 53(1): 3-11, 2021 01.
Artigo em Espanhol | MEDLINE | ID: mdl-32035754

RESUMO

OBJECTIVE: To evaluate the measurement characteristics of the Spanish and Catalan versions of the 10-Item Primary Care Assessment Tool for adults (PCAT-A10), shortened from the original Primary Care Assessment Tool (PCAT), with a new mental health item. DESIGN: Cross-sectional observational study. LOCATION: The city of Barcelona. PARTICIPANTS: Of the 3,496 people over 14 years of age from the representative random sample of the Barcelona population, from the 2016-17 Barcelona Health Survey, those who declared they had a family doctor, and had visited a specialist at some time in their lives, and had answered more than 50% of PCAT-A10 items were selected (n=3,107). MAIN MEASUREMENTS: Item descriptive analysis, analysis of internal consistency, corrected item - total correlation, of the PCAT-A10 index and the 10 items that make it up. Three scenarios for non-response to treatment were analysed: substitution by 0, by the intermediate value, and excluding people who did not answer any item. RESULTS: The PCAT-A10 index obtained Cronbach alphas of 0.73, 0.79, and 0.85 in the three mentioned scenarios, correlation item total corrected between 0.41 and 0.66, and 20.8% non-responses to the mental health item. CONCLUSIONS: The new version of PCAT-A10 has a high reliability with a higher response in the mental health item compared to the previous version.


Assuntos
Atenção Primária à Saúde , Adulto , Benzenoacetamidas , Estudos Transversais , Humanos , Piperidonas , Psicometria , Reprodutibilidade dos Testes , Inquéritos e Questionários
20.
Nucleic Acids Res ; 49(2): e9, 2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33264395

RESUMO

There has been a surge of interest towards targeting protein synthesis to treat diseases and extend lifespan. Despite the progress, few options are available to assess translation in live animals, as their complexity limits the repertoire of experimental tools to monitor and manipulate processes within organs and individual cells. It this study, we developed a labeling-free method for measuring organ- and cell-type-specific translation elongation rates in vivo. It is based on time-resolved delivery of translation initiation and elongation inhibitors in live animals followed by ribosome profiling. It also reports translation initiation sites in an organ-specific manner. Using this method, we found that the elongation rates differ more than 50% among mouse organs and determined them to be 6.8, 5.0 and 4.3 amino acids per second for liver, kidney, and skeletal muscle, respectively. We further found that the elongation rate is reduced by 20% between young adulthood and mid-life. Thus, translation, a major metabolic process in cells, is tightly regulated at the level of elongation of nascent polypeptide chains.


Assuntos
Envelhecimento/metabolismo , Rim/metabolismo , Fígado/metabolismo , Músculo Esquelético/metabolismo , Elongação Traducional da Cadeia Peptídica , Envelhecimento/genética , Animais , Análise por Conglomerados , Cavidades Cranianas , Cicloeximida/administração & dosagem , Cicloeximida/farmacologia , Esquema de Medicação , Harringtoninas/administração & dosagem , Harringtoninas/farmacologia , Sequenciamento de Nucleotídeos em Larga Escala , Injeções Intravenosas , Cinética , Longevidade , Macrolídeos/administração & dosagem , Macrolídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Órbita , Especificidade de Órgãos , Elongação Traducional da Cadeia Peptídica/efeitos dos fármacos , Iniciação Traducional da Cadeia Peptídica , Piperidonas/administração & dosagem , Piperidonas/farmacologia , Ribossomos/metabolismo , Cauda , Transcriptoma
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