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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.
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
3.
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
4.
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
5.
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
6.
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
7.
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
8.
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
9.
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
10.
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
11.
Blood ; 137(5): 661-677, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33197925

RESUMO

A number of clinically validated drugs have been developed by repurposing the CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 ubiquitin ligase complex with molecular glue degraders to eliminate disease-driving proteins. Here, we present the identification of a first-in-class GSPT1-selective cereblon E3 ligase modulator, CC-90009. Biochemical, structural, and molecular characterization demonstrates that CC-90009 coopts the CRL4CRBN to selectively target GSPT1 for ubiquitination and proteasomal degradation. Depletion of GSPT1 by CC-90009 rapidly induces acute myeloid leukemia (AML) apoptosis, reducing leukemia engraftment and leukemia stem cells (LSCs) in large-scale primary patient xenografting of 35 independent AML samples, including those with adverse risk features. Using a genome-wide CRISPR-Cas9 screen for effectors of CC-90009 response, we uncovered the ILF2 and ILF3 heterodimeric complex as a novel regulator of cereblon expression. Knockout of ILF2/ILF3 decreases the production of full-length cereblon protein via modulating CRBN messenger RNA alternative splicing, leading to diminished response to CC-90009. The screen also revealed that the mTOR signaling and the integrated stress response specifically regulate the response to CC-90009 in contrast to other cereblon modulators. Hyperactivation of the mTOR pathway by inactivation of TSC1 and TSC2 protected against the growth inhibitory effect of CC-90009 by reducing CC-90009-induced binding of GSPT1 to cereblon and subsequent GSPT1 degradation. On the other hand, GSPT1 degradation promoted the activation of the GCN1/GCN2/ATF4 pathway and subsequent apoptosis in AML cells. Collectively, CC-90009 activity is mediated by multiple layers of signaling networks and pathways within AML blasts and LSCs, whose elucidation gives insight into further assessment of CC-90009s clinical utility. These trials were registered at www.clinicaltrials.gov as #NCT02848001 and #NCT04336982).


Assuntos
Acetamidas/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Isoindóis/farmacologia , Leucemia Mieloide Aguda/patologia , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Células-Tronco Neoplásicas/efeitos dos fármacos , Piperidonas/farmacologia , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Acetamidas/uso terapêutico , Animais , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Humanos , Isoindóis/uso terapêutico , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos Moleculares , Células-Tronco Neoplásicas/enzimologia , Proteína do Fator Nuclear 45/fisiologia , Proteínas do Fator Nuclear 90/fisiologia , Fatores de Terminação de Peptídeos/metabolismo , Piperidonas/uso terapêutico , Complexo de Endopeptidases do Proteassoma/metabolismo , Conformação Proteica , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteólise , Bibliotecas de Moléculas Pequenas , Estresse Fisiológico , Serina-Treonina Quinases TOR/fisiologia , Células U937 , Ubiquitinação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Sci Rep ; 10(1): 22283, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33335138

RESUMO

Chronic inflammation provides a favorable microenvironment for tumorigenesis, which opens opportunities for targeting cancer development and progression. Piplartine (PL) is a biologically active alkaloid from long peppers that exhibits anti-inflammatory and antitumor activity. In the present study, we investigated the physical and chemical interactions of PL with anti-inflammatory compounds and their effects on cell proliferation and migration and on the gene expression of inflammatory mediators. Molecular docking data and physicochemical analysis suggested that PL shows potential interactions with a peptide of annexin A1 (ANXA1), an endogenous anti-inflammatory mediator with therapeutic potential in cancer. Treatment of neoplastic cells with PL alone or with annexin A1 mimic peptide reduced cell proliferation and viability and modulated the expression of MCP-1 chemokine, IL-8 cytokine and genes involved in inflammatory processes. The results also suggested an inhibitory effect of PL on tubulin expression. In addition, PL apparently had no influence on cell migration and invasion at the concentration tested. Considering the role of inflammation in the context of promoting tumor initiation, the present study shows the potential of piplartine as a therapeutic immunomodulator for cancer prevention and progression.


Assuntos
Anexina A1/genética , Inflamação/tratamento farmacológico , Neoplasias/tratamento farmacológico , Piper/química , Piperidonas/farmacologia , Alcaloides/química , Alcaloides/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocina CCL2/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/patologia , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neoplasias/patologia , Piperidonas/química , Microambiente Tumoral/efeitos dos fármacos
13.
Angew Chem Int Ed Engl ; 59(51): 23145-23153, 2020 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-32918852

RESUMO

A gene cluster encoding a cryptic trans-acyl transferase polyketide synthase (PKS) was identified in the genomes of Burkholderia gladioli BCC0238 and BCC1622, both isolated from the lungs of cystic fibrosis patients. Bioinfomatics analyses indicated the PKS assembles a novel member of the glutarimide class of antibiotics, hitherto only isolated from Streptomyces species. Screening of a range of growth parameters led to the identification of gladiostatin, the metabolic product of the PKS. NMR spectroscopic analysis revealed that gladiostatin, which has promising activity against several human cancer cell lines and inhibits tumor cell migration, contains an unusual 2-acyl-4-hydroxy-3-methylbutenolide in addition to the glutarimide pharmacophore. An AfsA-like domain at the C-terminus of the PKS was shown to catalyze condensation of 3-ketothioesters with dihydroxyacetone phosphate, thus indicating it plays a key role in polyketide chain release and butenolide formation.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Burkholderia gladioli/química , Piperidonas/farmacologia , Policetídeo Sintases/química , Antibacterianos/química , Antibacterianos/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Burkholderia gladioli/genética , Burkholderia gladioli/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Família Multigênica , Piperidonas/química , Piperidonas/metabolismo , Policetídeo Sintases/genética , Policetídeo Sintases/metabolismo
14.
Int J Biol Macromol ; 165(Pt A): 1055-1065, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32987080

RESUMO

Due to the limited options for topical management of skin cancer, this study aimed at developing and evaluating nanoemulsions (NE) for topical delivery of the cytotoxic agent piplartine (piperlongumine). NEs were modified with chitosan or sodium alginate, and the effects on the physicochemical properties, piplartine delivery and formulation efficacy were evaluated. The nanoemulsion droplets displayed similar size (96-112 nm), but opposite charge; the polysaccharides improved piplartine penetration into and across the skin (1.3-1.9-fold) in a similar manner, increasing the ratio "drug in the skin/receptor phase" by 1.4-1.5-fold compared to the plain NE and highlighting their relevance for cutaneous localization. Oleic acid addition to the chitosan-containing NE further increased drug penetration (~1.9-2.0-fold), as did increases in drug content from 0.5 to 1%. The cytotoxicity of piplartine was ~2.8-fold higher when the drug was incorporated in the chitosan-containing NE compared to its solution (IC50 = 14.6 µM) against melanoma cells. The effects of this nanocarrier on 3D melanoma tissues were concentration-related; at 1%, piplartine elicited marked epidermis destruction. These results support the potential applicability of the chitosan-modified nanoemulsion containing piplartine as a new strategy for local management of skin cancer.


Assuntos
Emulsões/química , Melanoma/tratamento farmacológico , Nanopartículas/química , Neoplasias Cutâneas/tratamento farmacológico , Alginatos/química , Proliferação de Células/efeitos dos fármacos , Quitosana/química , Citotoxinas/química , Emulsões/farmacologia , Humanos , Melanócitos/efeitos dos fármacos , Melanócitos/patologia , Piperidonas/química , Piperidonas/farmacologia , Neoplasias Cutâneas/patologia
15.
Endocrinol Metab (Seoul) ; 35(2): 384-395, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32615723

RESUMO

BACKGROUND: Endothelial-to-mesenchymal transition (EndMT) contributes to inflammatory conditions inducing conversion of endothelial cells (ECs) into activated fibroblasts, promoting fibrotic diseases. Pro-inflammatory cytokine is the most potent inducer of EndMT. We investigated inhibition of interleukin-1ß (IL-1ß)-induced EndMT by gemigliptin, a dipeptidyl peptidase-IV inhibitor. METHODS: We exposed human umbilical vein endothelial cells (HUVECs) to 10 ng/mL IL-1ß/20 µM gemigliptin and analyzed the expression of endothelial, smooth muscle, mesenchymal, and osteoblastic markers, bone morphogenetic protein (BMP), Smad, and non-Smad signaling pathway proteins. RESULTS: Morphological changes showed gemigliptin blocked IL-1ß-induced EndMT, upregulated EC markers, and downregulated smooth muscle and mesenchymal markers. IL-1ß activation of HUVECs is initiated by the BMP/Smad and non-smad BMP signaling pathways. Gemigliptin inhibited IL-1ß induction of BMP2 and 7, activin receptor type IA, BMP receptor type IA, and BMP receptor type II. Reversal of IL-1ß-mediated inhibition of BMP-induced Smad1/5/8, Smad2, and Smad3 phosphorylation by gemigliptin suggests involvement of the Smad pathway in gemigliptin action. In the non-Smad BMP pathway, gemigliptin treatment significantly increased the deactivation of extracellular regulated protein kinase (ERK), p38, and JNK by IL-1ß. Gemigliptin treatment suppressed BMP-2-induced expression of key osteoblastic markers including osterix, runt-related transcription factor 2, and hepcidin during IL-1ß-induced EndMT. CONCLUSION: We demonstrated a novel protective mechanism of gemigliptin against fibrosis by suppressing IL-1ß-induced EndMT.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Transição Epitelial-Mesenquimal , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Interleucina-1beta/farmacologia , Mesoderma/efeitos dos fármacos , Piperidonas/farmacologia , Pirimidinas/farmacologia , Proteínas Morfogenéticas Ósseas/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Mesoderma/metabolismo , Mesoderma/patologia , Transdução de Sinais
16.
Eur J Pharmacol ; 882: 173243, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32535099

RESUMO

This study investigated the vasodilatory effects and acting mechanism of gemigliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor. Tests were conducted in aortic rings pre-contracted with phenylephrine. Gemigliptin induced dose-dependent vasodilation of the aortic smooth muscle. Several pre-treatment groups were used to investigate the mechanism of action. While pre-treatment with paxilline, a large-conductance Ca2+-activated K+ channel inhibitor, glibenclamide, an ATP-sensitive K+ channel inhibitor, and Ba2+, an inwardly rectifying K+ channel inhibitor, had no impact on the vasodilatory effect of gemigliptin, pre-treatment with 4-aminopyridine, a voltage-dependent K+ (Kv) channel inhibitor, effectively attenuated the vasodilatory action of gemigliptin. In addition, pre-treatment with sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors thapsigargin and cyclopiazonic acid significantly reduced the vasodilatory effect of gemigliptin. cAMP/PKA-related or cGMP/PKG-related signaling pathway inhibitors, including adenylyl cyclase inhibitor SQ 22536, PKA inhibitor KT 5720, guanylyl cyclase inhibitor ODQ, and PKG inhibitor KT 5823 did not alter the vasodilatory effect of gemigliptin. Similarly, elimination of the endothelium and pre-treatment with a nitric oxide (NO) synthase inhibitor (L-NAME) or small- and intermediate-conductance Ca2+-activated K+ channels (apamin and TRAM-34, respectively) did not change the gemigliptin effect. These findings suggested that gemigliptin induces vasodilation through the activation of Kv channels and SERCA pumps independent of cAMP/PKA-related or cGMP/PKG-related signaling pathways and the endothelium. Therefore, caution is required when prescribing gemigliptin to the patients with hypotension and diabetes.


Assuntos
Aorta Torácica/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Piperidonas/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/fisiologia , Pirimidinas/farmacologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/fisiologia , Vasodilatadores/farmacologia , Animais , Aorta Torácica/fisiologia , Masculino , Músculo Liso Vascular/fisiologia , Coelhos
17.
Parasitol Res ; 119(7): 2159-2176, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32424554

RESUMO

The proteasome is the key player in the cellular protein degradation machinery and is pivotal for protein homeostasis and Schistosoma mansoni (S. mansoni) survival. Our group study provides insights into proteasome inhibitors and reveals that selective schistosomiasis agents represent an interesting branch of proteasome research linked to the development of new drugs for this neglected disease. Here, we explored the phenotypic response of S. mansoni to b-AP15, a bis-benzylidine piperidone that inhibits 26S proteasome deubiquitinases (DUBs), ubiquitin-specific protease 14 (USP14), and ubiquitin carboxyl-terminal hydrolase 5 (UCHL5). b-AP15 induces a modest decrease in egg production in vitro and reduces viability, leading to the death of parasite couples. This inhibitor also induces a twofold increase in the accumulation of polyubiquitinated proteins in S. mansoni adult worms and causes tegument changes such as disintegration, wrinkling, and bubble formation, both throughout the length of the parasite and in the oral sucker. b-AP15 alters the cell organelles of adult S. mansoni worms, and we specifically observed mitochondrial alterations, which are suggestive of proteotoxic stress leading to autophagy. Taken together, these results indicate that the deubiquitinase function of the proteasome is essential for the parasite and support the hypothesis that the proteasome constitutes an interesting drug target for the treatment of schistosomiasis.


Assuntos
Enzimas Desubiquitinantes/antagonistas & inibidores , Oviposição/efeitos dos fármacos , Inibidores de Proteassoma/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Animais , Feminino , Proteínas de Helminto/metabolismo , Piperidonas/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Schistosoma mansoni/metabolismo , Schistosoma mansoni/fisiologia , Ubiquitinação/efeitos dos fármacos
18.
Cell Biochem Biophys ; 78(2): 191-202, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32449075

RESUMO

Pancreatic adenocarcinoma is an aggressive cancer with poor clinical prognosis and limited therapeutic options. There is a significant lack of effective, safe, and targeted therapies for successful treatment of pancreatic cancer. In this report, we describe the anticancer efficacy of two novel compounds, N-methylpiperazinyl diarylidenylpiperidone (L-2663) and its pro-nitroxide conjugate (HO-4589) evaluated on human pancreatic adenocarcinoma (AsPC-1) cell line and xenograft tumor in mice. Using flow cytometry, we determined the effect of the L-2663 and HO-4589 drugs in inducing mitochondrial toxicity, triggering cell-cycle arrest, and apoptosis. EPR spectroscopy was used to quantify cellular uptake, metabolic conversion and stability of HO-4589 in cells and in vivo monitoring of tumor oxygenation as a function of growth. The results established different antiproliferative efficacy of the L-2663 and HO-4589 compounds, with a targeted action on cancer cells while being less toxic to noncancerous cells. The study may have important implications in the future designs of safe and effective chemotherapeutic agents for the treatment of pancreatic cancer.


Assuntos
Antineoplásicos/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Piperazinas/farmacologia , Piperidonas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Divisão Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Ensaios de Seleção de Medicamentos Antitumorais , Espectroscopia de Ressonância de Spin Eletrônica , Fase G2 , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Oximetria , Espécies Reativas de Oxigênio/metabolismo
19.
Bioorg Chem ; 100: 103865, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32361055

RESUMO

Invasive fungal infections along with rising incidence of resistance to antifungal drugs pose increasing threat to immunocompromised individuals, including cancer patients. In this study, we examined the antifungal activity of dispiropyrrolidine tethered piperidone heterocyclic hybrids. Results indicate that compounds 5a and 6i have demonstrated a potent antifungal effect on multiple fungal strains, including Candida albicans, without exhibiting cytotoxicity to mammalian cells. Furthermore, these two compounds exhibited significant inhibition on Candida albicans hyphae and biofilm development that surpasses the FDA-approved antifungal drug currently used for treatment. Taken together, our results suggest that 5a and 6i are promising candidates for development into new antifungal drugs.


Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Piperidonas/química , Piperidonas/farmacologia , Antifúngicos/síntese química , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Linhagem Celular , Criptococose/tratamento farmacológico , Criptococose/microbiologia , Humanos , Modelos Moleculares , Piperidonas/síntese química , Pirrolidinas/síntese química , Pirrolidinas/química , Pirrolidinas/farmacologia
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