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1.
PLoS One ; 15(7): e0235483, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32697773

RESUMO

A series of potent HIV-1 protease inhibitors, containing diverse piperidine analogues as the P2-ligands, 4-substituted phenylsulfonamides as the P2'-ligands and a hydrophobic cyclopropyl group as the P1'-ligand, were designed, synthesized and evaluated in this work. Among these twenty-four target compounds, many of them exhibited excellent activity against HIV-1 protease with half maximal inhibitory concentration (IC50) values below 20 nM. Particularly, compound 22a containing a (R)-piperidine-3-carboxamide as the P2-ligand and a 4-methoxylphenylsulfonamide as the P2'-ligand exhibited the most effective inhibitory activity with an IC50 value of 3.61 nM. More importantly, 22a exhibited activity with inhibition of 42% and 26% against wild-type and Darunavir (DRV)-resistant HIV-1 variants, respectively. Additionally, the molecular docking of 22a with HIV-1 protease provided insight into the ligand-binding properties, which was of great value for further study.


Assuntos
Inibidores Enzimáticos/química , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/química , HIV-1/efeitos dos fármacos , Piperidinas/farmacologia , Cristalografia por Raios X , Darunavir/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Infecções por HIV/virologia , Protease de HIV/química , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , HIV-1/química , HIV-1/patogenicidade , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia
2.
Proc Natl Acad Sci U S A ; 117(26): 14926-14935, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32554495

RESUMO

Molecular ON-switches in which a chemical compound induces protein-protein interactions can allow cellular function to be controlled with small molecules. ON-switches based on clinically applicable compounds and human proteins would greatly facilitate their therapeutic use. Here, we developed an ON-switch system in which the human retinol binding protein 4 (hRBP4) of the lipocalin family interacts with engineered hRBP4 binders in a small molecule-dependent manner. Two different protein scaffolds were engineered to bind to hRBP4 when loaded with the orally available small molecule A1120. The crystal structure of an assembled ON-switch shows that the engineered binder specifically recognizes the conformational changes induced by A1120 in two loop regions of hRBP4. We demonstrate that this conformation-specific ON-switch is highly dependent on the presence of A1120, as demonstrated by an ∼500-fold increase in affinity upon addition of the small molecule drug. Furthermore, the ON-switch successfully regulated the activity of primary human CAR T cells in vitro. We anticipate that lipocalin-based ON-switches have the potential to be broadly applied for the safe pharmacological control of cellular therapeutics.


Assuntos
Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linhagem Celular , Citocinas/imunologia , Humanos , Lipocalinas/genética , Lipocalinas/imunologia , Conformação Molecular , Piperidinas/química , Piperidinas/farmacologia , Receptores de Antígenos Quiméricos/genética , Proteínas Plasmáticas de Ligação ao Retinol/genética , Proteínas Plasmáticas de Ligação ao Retinol/imunologia , Linfócitos T/efeitos dos fármacos
3.
J Med Chem ; 63(11): 5783-5796, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32429662

RESUMO

Most of the current monoacylglycerol lipase (MAGL) inhibitors function by an irreversible mechanism of action, causing a series of side effects. Herein, starting from irreversible inhibitors, 25 compounds were synthesized and evaluated in vitro for MAGL inhibition, among which, compound 36 showed the most potent inhibitory activity (IC50 = 15 nM). Crucially, docking studies demonstrated that the m-chlorine-substituted aniline fragment occupied a hydrophobic subpocket enclosed by side chains of Val191, Tyr194, Val270, and Lys273, which creatively identify a new key anchoring point for the development of new MAGL inhibitors. Furthermore, in vivo evaluation innovatively revealed that this reversible inhibitor 36 significantly ameliorated depressive-like behaviors induced by reserpine. To the best of our knowledge, this is the first time that reversible inhibitors of MAGL were developed to support MAGL as a potential therapeutic target for depression.


Assuntos
Inibidores Enzimáticos/química , Monoacilglicerol Lipases/antagonistas & inibidores , Piperidinas/química , Animais , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Meia-Vida , Humanos , Cinética , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Monoacilglicerol Lipases/metabolismo , Piperidinas/metabolismo , Piperidinas/farmacologia , Estrutura Terciária de Proteína , Ratos , Relação Estrutura-Atividade
4.
BMC Complement Med Ther ; 20(1): 134, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32370771

RESUMO

BACKGROUND: Piper chaba Hunt. is used as an ingredient in Thai traditional preparation for arthritis. Its isolated compound is piperine which shows anti-inflammatory activity. Piperine produces a burning sensation because it activates TRPV1 receptor. The TRPV1 activation involved with the analgesic and adjuvant effect. P. chaba Hunt. has not been reported about TRPV1 activation and adjuvant effect. The aim of this study was to investigate the effect of P. chaba extract and piperine on TRPV1 receptor, which is considered as a target for analgesic and their adjuvant effects to support the development of an analgesic drug from herbal medicine. METHODS: The effect of P. chaba extract and piperine on HEK cells expressing TRPV1 channel was examined by calcium imaging assay. Adjuvant effects of P. chaba extract and piperine were investigated by a fluorescein isothiocyanate (FITC)-induced contact hypersensitivity (CHS) model in mice. RESULTS: P. chaba extract induced calcium influx with EC50 value of 0.67 µg/ml. Piperine induced calcium influx with EC50 value of 0.31 µg/ml or 1.08 µM. For mouse CHS model, we found that 1% piperine, 5% piperine, 1% P. chaba extract and 5% P. chaba extract significantly enhanced sensitization to FITC as revealed by ear swelling responses. CONCLUSION: P. chaba extract and piperine activated TRPV1 channel and enhanced contact sensitization to FITC.


Assuntos
Adjuvantes Farmacêuticos/farmacologia , Alcaloides/farmacologia , Benzodioxóis/farmacologia , Piper , Piperidinas/farmacologia , Extratos Vegetais/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Canais de Cátion TRPV/metabolismo , Adjuvantes Farmacêuticos/química , Alcaloides/química , Animais , Benzodioxóis/química , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Piperidinas/química , Extratos Vegetais/química , Alcamidas Poli-Insaturadas/química , Tailândia
5.
Chemosphere ; 250: 126250, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32234618

RESUMO

Presence of even small amount of active pharmaceutical ingredients in the environment carries risks to human and animal health, presenting an important issue. The paper presents issues related to the new drug - pimavanserin (PMV). Biological treatment efficiency of pimavanserin (PMV) was evaluated using lab-scale Sequencing Batch Reactor (SBR). It has been shown to have a negative effect on aquatic organisms by classifying it as a toxic compound (EC50 = 8 mgL-1). The level of biological degradation of PMV was insufficient (37%) and intensively foam formation caused operational problems. For this reason, in this study polymers based on cyclodextrins (CDs) were synthesized and used as adsorbents alternative to active carbons to effectively separate PMV from real industrial waste streams. Crosslinked ß- and γ-CD polymers (ß- and γ-NS), obtained in reaction with 1,1'-carbonyldiimidazole (CDI), were fully characterized by physicochemical methods. The adsorption equilibrium data were interpreted using Freundlich and Langmuir models. The sorption process was fast (60 s) and the efficiency of PMV separation from model waste waters was 93% and 81% for ß- and γ-NS, respectively. Maximum polymer capacity was found at 52.08 mg g-1 for ß-NS and 23.26 mg g-1 for γ-NS. The interactions of PMV with CDs have been studied and indicate that major mechanism of the sorption is based on supramolecular interaction and capture to polymer network. Described biodegradable and reusable materials are perfect example of correctly selected adsorbent for separation of target substance from postproduction aqueous media.


Assuntos
Piperidinas/química , Ureia/análogos & derivados , Eliminação de Resíduos Líquidos/métodos , Poluentes Químicos da Água/química , Adsorção , Celulose/química , Ciclodextrinas/química , Resíduos Industriais , Preparações Farmacêuticas , Polímeros/química , Ureia/química , Águas Residuárias , beta-Ciclodextrinas/química
6.
Ecotoxicol Environ Saf ; 194: 110391, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32155480

RESUMO

Corpse-removal behavior of the red imported fire ant (RIFA) and the effects of lethal substances on RIFA signal communication were investigated in this study. The RIFA corpses, obtained through freezing, ether, 0.25 mg/L thiamethoxam, and starvation to death treatments, and naturally dead red fire ants were subjected to gas chromatography-mass spectrometry to identify the cuticular hydrocarbon profiles that had an effect on the corpse-removal behavior. The results showed that lethal toxic substances altered the epidermal compounds of RIFA and affected their corpse-removal behavior. Lethal toxic substances increased the number of worker touches with corpses and identification time of corpses. In addition, the content of piperidine (1,1'-(1,2-ethanediyl)bis-) on the surface of the corpse was different following the various treatments. Contamination with toxic substances resulted in the increased secretion of piperidine and led to increased identification time of corpses, number of touch with corpses, and total time for removal of corpses. Piperidine content was higher under conditions of natural death (4.67 ± 0.55%) and with thiamethoxam (10.43 ± 0.78%), freezing (0.83 ± 0.25%), and ether treatment (12.50 ± 0.70%) than under starvation treatment (0). The higher content of piperidine led to a longer number of touches with corpses and identification time. Piperidine compounds may be an element in warning information, which could affect the occurrence of different corpse-removal behaviors.


Assuntos
Formigas/fisiologia , Comportamento Animal/fisiologia , Epiderme/química , Piperidinas/análise , Comportamento Social , Animais , Formigas/química , Formigas/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Cadáver , Congelamento , Cromatografia Gasosa-Espectrometria de Massas , Inseticidas/farmacologia , Piperidinas/química , Inanição , Tiametoxam/farmacologia
7.
Nat Commun ; 11(1): 1145, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32123179

RESUMO

Recent studies show that GPCRs rapidly interconvert between multiple states although our ability to interrogate, monitor and visualize them is limited by a relative lack of suitable tools. We previously reported two nanobodies (Nb39 and Nb6) that stabilize distinct ligand- and efficacy-delimited conformations of the kappa opioid receptor. Here, we demonstrate via X-ray crystallography a nanobody-targeted allosteric binding site by which Nb6 stabilizes a ligand-dependent inactive state. As Nb39 stabilizes an active-like state, we show how these two state-dependent nanobodies can provide real-time reporting of ligand stabilized states in cells in situ. Significantly, we demonstrate that chimeric GPCRs can be created with engineered nanobody binding sites to report ligand-stabilized states. Our results provide both insights regarding potential mechanisms for allosterically modulating KOR with nanobodies and a tool for reporting the real-time, in situ dynamic range of GPCR activity.


Assuntos
Receptores Opioides kappa/química , Receptores Opioides kappa/metabolismo , Anticorpos de Domínio Único/química , Sítio Alostérico , Sítios de Ligação , Técnicas Biossensoriais , Cristalografia por Raios X , AMP Cíclico/metabolismo , Dinorfinas/química , Dinorfinas/farmacologia , Células HEK293 , Humanos , Medições Luminescentes/métodos , Piperazinas/química , Piperazinas/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Conformação Proteica , Pirrolidinas/química , Pirrolidinas/farmacologia , Receptores Acoplados a Proteínas-G/química , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Anticorpos de Domínio Único/metabolismo , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacologia
8.
Nat Commun ; 11(1): 1273, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152321

RESUMO

The importance of N-heterocycles in drugs has stimulated diverse methods for their efficient syntheses. Methods that introduce significant stereochemical complexity are attractive for identifying new bioactive amine chemical space. Here, we report a [3 + 3] ring expansion of bicyclic aziridines and rhodium-bound vinyl carbenes to form complex dehydropiperidines in a highly stereocontrolled rearrangement. Mechanistic studies and DFT computations indicate that the reaction proceeds through formation of a vinyl aziridinium ylide; this reactive intermediate undergoes a pseudo-[1,4]-sigmatropic rearrangement to directly furnish heterocyclic products with net retention at the new C-C bond. In combination with asymmetric silver-catalyzed aziridination, enantioenriched scaffolds with up to three contiguous stereocenters are rapidly delivered. The mild reaction conditions, functional group tolerance, and high stereospecificity of this method are well-suited for appending piperidine motifs to natural product and complex molecules. Ultimately, our work establishes the value of underutilized aziridinium ylides as key intermediates for converting small, strained rings to larger N-heterocycles.


Assuntos
Aziridinas/química , Piperidinas/química , Catálise , Compostos Heterocíclicos/química , Estereoisomerismo
9.
J Agric Food Chem ; 68(14): 4227-4236, 2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32191454

RESUMO

Ten new cassane diterpenoids, caesalpulcherrins A-J (1-10), together with 11 known analogues (11-21) were isolated from the aerial parts of Caesalpinia pulcherrima. Their structures and relative stereochemistry were elucidated by spectrometric and spectroscopic methods, including one-dimensional (1D) and two-dimensional (2D) NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), and single-crystal X-ray diffraction analysis. Compounds 1-4 represent the first examples of 2,5-dimethoxyfuranocassane diterpenoids. Results of the antifeedant activity indicated that isovouacapenol C (12) and pulcherrin N (14) exhibited remarkable antifeedant activity against Mythimna separate with EC50 values of 3.43 and 4.20 µg/cm2, respectively. Meanwhile, pulcherrimin C (13) and 12-demethyl neocaesalpin F (18) exerted significant antifeedant activity against Plutella xylostella with an EC50 data of 4.00 and 3.05 µg/cm2, respectively. Some of the compounds showed obvious toxic activity against the plant-feeding generalist insect herbivores, M. separate and P. xylostella, at 0.8 mg/mL (800 ppm). Furthermore, the structure-activity relationships of antifeedant and insecticidal activities are also discussed in the article.


Assuntos
Caesalpinia/química , Diterpenos/química , Inseticidas/química , Componentes Aéreos da Planta/química , Extratos Vegetais/química , Aminoácidos Sulfúricos/química , Aminoácidos Sulfúricos/farmacologia , Animais , Cristalografia por Raios X , Diterpenos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Inseticidas/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Mariposas , Piperidinas/química , Piperidinas/farmacologia , Extratos Vegetais/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
10.
Anticancer Res ; 40(2): 689-694, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32014909

RESUMO

BACKGROUND/AIM: Piperine, a major alkaloid of the fruit of black pepper plants, selectively inhibits the growth of triple-negative breast cancer cells but its lipophilicity restricts possible clinical application. This study therefore determined the feasibility of encapsulating piperine in nanoparticles (NPs) to increase its solubility in an aqueous environment. MATERIALS AND METHODS: Piperine-loaded biodegradable methoxy poly(ethylene glycol)-poly(lactic-co-glycolic) acid copolymer-based NPs were produced by single emulsion solvent extraction and thin-film hydration. Growth and viability of triple-negative breast cancer (TNBC) cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Annexin-V-FLUOS/propidium iodide staining, respectively. RESULTS: Thin-film hydration was superior to single emulsion solvent extraction, yielding piperine-loaded NPs with an average size of 50 nm. Piperine-loaded NPs inhibited TNBC cell growth and induced apoptosis while sparing normal fibroblasts. CONCLUSION: It is feasible to deliver a cytotoxic concentration of piperine to TNBC cells via NPs with the potential for improved bioavailability and solubility in biological fluids.


Assuntos
Alcaloides/administração & dosagem , Benzodioxóis/administração & dosagem , Nanopartículas/administração & dosagem , Piperidinas/administração & dosagem , Alcamidas Poli-Insaturadas/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Alcaloides/química , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Benzodioxóis/química , Linhagem Celular Tumoral , Emulsões/administração & dosagem , Emulsões/química , Feminino , Humanos , Nanopartículas/química , Piperidinas/química , Poliésteres/administração & dosagem , Poliésteres/química , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Alcamidas Poli-Insaturadas/química , Neoplasias de Mama Triplo Negativas/patologia
11.
Ecotoxicol Environ Saf ; 192: 110321, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32061978

RESUMO

Day to day consumption of black pepper raise concern about the detailed information about their medicinal, pharmaceutical values and knowledge about the biocompatibility with respect to ecosystem. This study investigates the in vivo selective molecular biocompatibility of its seed cover (SC) and seed core (SP) powder extract using embryonic zebrafish model. Gas chromatography mass spectrometry (GCMS) analysis of the extract prepared by grinding showed presence of different components with "piperine" as principle component. Biocompatibility analysis showed dose and time dependent selective effect of SC and SP with LC50 of 30.4 µg/ml and 35.6 µg/ml, respectively on survivability, hatching and heartbeat rate in embryonic zebrafish. Mechanistic investigation elucidated it as effect of accumulation and internalization of black pepper leading to their influence on structure and function of cellular proteins hatching enzyme (he1a), superoxide dismutase (sod1) and tumor protein (tp53) responsible for delayed hatching, oxidative stress induction and apoptosis. The study provided insight to selective biocompatibility of black pepper expedient to produce higher quality spices with respect to pharmaceutical, clinical and environmental aspects.


Assuntos
Alcaloides/química , Apoptose/efeitos dos fármacos , Benzodioxóis/química , Estresse Oxidativo/efeitos dos fármacos , Piper nigrum/toxicidade , Piperidinas/química , Alcamidas Poli-Insaturadas/química , Alcaloides/análise , Animais , Benzodioxóis/análise , Piper nigrum/química , Piper nigrum/embriologia , Piperidinas/análise , Extratos Vegetais/química , Extratos Vegetais/toxicidade , Alcamidas Poli-Insaturadas/análise , Sementes/química , Sementes/toxicidade , Superóxido Dismutase/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/fisiologia , Proteínas de Peixe-Zebra/química , Proteínas de Peixe-Zebra/metabolismo
12.
J Photochem Photobiol B ; 205: 111805, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32092661

RESUMO

In recent days, reported researches demonstrated that encapsulation of natural hydrophobic drug molecules (Piperine) into the biodegradable polymer system with nanoformulations opens a novel prospect in bio-nanomedicine field. Generally, the nanostructured materials embedded with the drug molecules could render enhanced efficiency in therapies. Piperine is a chief alkaloid compound of natural black pepper exhibits excellent anti-convulsant efficiency in the anti-epileptic treatment. Nonetheless, the poor water solubility of the piperine molecules has some difficulties in drug delivery and clinical applications. Herein we report the synthesis of Copper oxide quantum dots coated Hyaluronic acid (HA)/ Poly(lactic-co-glycolic acid) (PLGA) with for the effective delivery of piperine in the targeted drug delivery for epilepsy treatment. The physicochemical characterization was performed using the as prepared material. The crystal structure, surface morphology and the elemental composition were investigated from XRD, SEM, TEM and EDX analyses respectively. The surface morphology clearly stated the loading of CuO QDs loaded HA/PLGA microspheres. The capping of the polymer matrix was also studied using FTIR analysis. A Photoluminescence spectrum is also recorded. This study was illustrating that Piperine loaded CuQDs@HA/PLGA nanostructures exhibit improved neuroprotection and encourage the activation of astrocytes in chemical kindling model of epilepsy. This proposed material could be a novel and effective therapeutic platform for the targeted drug delivery systems.


Assuntos
Alcaloides/administração & dosagem , Anticonvulsivantes/administração & dosagem , Benzodioxóis/administração & dosagem , Cobre/administração & dosagem , Sistemas de Liberação de Medicamentos , Epilepsia/tratamento farmacológico , Piperidinas/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Alcamidas Poli-Insaturadas/administração & dosagem , Pontos Quânticos/administração & dosagem , Alcaloides/química , Animais , Anticonvulsivantes/química , Benzodioxóis/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cobre/química , Desenho de Fármacos , Liberação Controlada de Fármacos , Epilepsia/induzido quimicamente , Humanos , Luminescência , Masculino , Pentilenotetrazol , Piperidinas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Alcamidas Poli-Insaturadas/química , Pontos Quânticos/química , Ratos Wistar
13.
Eur J Med Chem ; 191: 112144, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32087465

RESUMO

We designed and synthesized a novel series of piperidine propionamide derivatives as potent sigma-1 (σ1) receptor antagonists and mu (µ) opioid receptor agonists, and measured their affinity for σ1 and µ receptors in vitro through binding assays. The basic scaffold of the new compounds contained a 4-substituted piperidine ring and N-aryl propionamide. Compound 44, N-(2-(4-(4-fluorobenzyl) piperidin-1-yl) ethyl)-N-(4-methoxy-phenyl) propionamide, showed the highest affinity for σ1 receptor (Ki σ1 = 1.86 nM) and µ receptor (Ki µ = 2.1 nM). It exhibited potent analgesic activity in the formalin test (ED50 = 15.1 ± 1.67 mg/kg) and had equivalent analgesic effects to S1RA (σ1 antagonist) in a CCI model. Therefore, Compound 44, which has mixed σ1/µ receptor profiles, may be a potential candidate for treating neuropathic pain.


Assuntos
Amidas/farmacologia , Neuralgia/tratamento farmacológico , Piperidinas/farmacologia , Receptores Opioides mu/agonistas , Receptores sigma/antagonistas & inibidores , Amidas/administração & dosagem , Amidas/química , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Formaldeído , Cobaias , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Neuralgia/induzido quimicamente , Neuralgia/patologia , Piperidinas/administração & dosagem , Piperidinas/química , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/patologia , Relação Estrutura-Atividade
14.
Sci Rep ; 10(1): 2585, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066817

RESUMO

Polypharmacology plays an important role in defining response and adverse effects of drugs. For some mechanisms, experimentally mapping polypharmacology is commonplace, although this is typically done within the same protein class. Four PARP inhibitors have been approved by the FDA as cancer therapeutics, yet a precise mechanistic rationale to guide clinicians on which to choose for a particular patient is lacking. The four drugs have largely similar PARP family inhibition profiles, but several differences at the molecular and clinical level have been reported that remain poorly understood. Here, we report the first comprehensive characterization of the off-target kinase landscape of four FDA-approved PARP drugs. We demonstrate that all four PARP inhibitors have a unique polypharmacological profile across the kinome. Niraparib and rucaparib inhibit DYRK1s, CDK16 and PIM3 at clinically achievable, submicromolar concentrations. These kinases represent the most potently inhibited off-targets of PARP inhibitors identified to date and should be investigated further to clarify their potential implications for efficacy and safety in the clinic. Moreover, broad kinome profiling is recommended for the development of PARP inhibitors as PARP-kinase polypharmacology could potentially be exploited to modulate efficacy and side-effect profiles.


Assuntos
Antineoplásicos/química , Indazóis/química , Indóis/química , Ftalazinas/química , Piperazinas/química , Piperidinas/química , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/química , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Sítios de Ligação , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Células HEK293 , Humanos , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Indóis/administração & dosagem , Indóis/efeitos adversos , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/patologia , Ftalazinas/administração & dosagem , Ftalazinas/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Polifarmacologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Especificidade por Substrato
15.
J Med Chem ; 63(9): 4617-4627, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32105467

RESUMO

Selective inhibitors of gut bacterial ß-glucuronidases (GUSs) are of particular interest in the prevention of xenobiotic-induced toxicities. This study reports the first structure-activity relationships on potency and selectivity of several iminocyclitols (2-7) for the GUSs. Complex structures of Ruminococcus gnavus GUS with 2-7 explained how charge, conformation, and substituent of iminocyclitols affect their potency and selectivity. N1 of uronic isofagomine (2) made strong electrostatic interactions with two catalytic glutamates of GUSs, resulting in the most potent inhibition (Ki ≥ 11 nM). C6-propyl analogue of 2 (6) displayed 700-fold selectivity for opportunistic bacterial GUSs (Ki = 74 nM for E. coli GUS and 51.8 µM for RgGUS). In comparison with 2, there was 200-fold enhancement in the selectivity, which was attributed to differential interactions between the propyl group and loop 5 residues of the GUSs. The results provide useful insights to develop potent and selective inhibitors for undesired GUSs.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Ciclitóis/química , Microbioma Gastrointestinal/efeitos dos fármacos , Glucuronidase/antagonistas & inibidores , Piperidinas/química , Animais , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Domínio Catalítico , Bovinos , Clostridiales/enzimologia , Clostridium perfringens/enzimologia , Cristalografia por Raios X , Ciclitóis/síntese química , Ciclitóis/metabolismo , Ensaios Enzimáticos , Escherichia coli/enzimologia , Glucuronidase/química , Glucuronidase/metabolismo , Conformação Molecular , Piperidinas/síntese química , Piperidinas/metabolismo , Ligação Proteica , Relação Estrutura-Atividade
16.
Phytother Res ; 34(6): 1409-1420, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31989711

RESUMO

Mast cells play an important role in inflammatory and allergic diseases. MAS-related G protein-coupled receptor X2 (MRGPRX2) is a novel G protein-coupled receptor in mast cells that mediates drug-induced anaphylactoid reactions. Piperine has been reported to have anti-inflammatory and anti-allergic pharmacological activities. However, whether the pharmacological effects are regulated by MRGPRX2 has not yet been reported. The purpose of this study was to assess the anti-anaphylactoid effect of Piperine and to explore its potential mechanism. The anti-anaphylactoid effect of Piperine was assessed by an in vivo mouse hindpaw extravasation model. Mast cell intracellular calcium mobilization was measured by a calcium imaging assay. An enzyme immunoassay was used to evaluate the release of pro-inflammatory factors from stimulated mast cells. Activated mast cell related signals were assessed by western blot. A cell membrane chromatography assay was used to determine the binding characteristics of Piperine and MRGPRX2. The results showed that Piperine suppressed mast cell intracellular Ca2+ mobilization, inhibited cytokines and chemokines release, and down-regulated the phosphorylation level of phospholipase Cγ1, protein kinase C, inositol 1,4,5-triphate receptor, P38, protein kinase B, and ERK. Meanwhile, Piperine can bind to MRGPRX2 as a specific antagonist. Hence, Piperine can be served as a novel therapeutic drug candidate for MRGPRX2-mediated anaphylactoid reactions.


Assuntos
Alcaloides/química , Anafilaxia/tratamento farmacológico , Benzodioxóis/química , Mastócitos/metabolismo , Piperidinas/química , Alcamidas Poli-Insaturadas/química , Receptores Acoplados a Proteínas-G/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Humanos , Masculino , Camundongos
17.
J Med Chem ; 63(5): 2688-2704, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31951130

RESUMO

A novel series of C(3)-substituted piperdinylindoles were developed as nociceptin opioid receptor (NOP) partial agonists to explore a pharmacological hypothesis that NOP partial agonists would afford a dual pharmacological action of attenuating Parkinson's disease (PD) motor symptoms and development of levodopa-induced dyskinesias. SAR around the C-3 substituents investigated effects on NOP binding, intrinsic activity, and selectivity and showed that while the C(3)-substituted indoles are selective, high affinity NOP ligands, the steric, polar, and cationic nature of the C-3 substituents affected intrinsic activity to afford partial agonists with a range of efficacies. Compounds 4, 5, and 9 with agonist efficacies between 25% and 35% significantly attenuated motor deficits in the 6-OHDA-hemilesioned rat model of PD. Further, unlike NOP antagonists, which appear to worsen dyskinesia expression, these NOP partial agonists did not attenuate or worsen dyskinesia expression. The NOP partial agonists and their SAR reported here may be useful to develop nondopaminergic treatments for PD.


Assuntos
Antiparkinsonianos/uso terapêutico , Indóis/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Receptores Opioides/agonistas , Animais , Antiparkinsonianos/química , Antiparkinsonianos/farmacocinética , Células CACO-2 , Modelos Animais de Doenças , Humanos , Indóis/química , Indóis/farmacocinética , Masculino , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores Opioides/metabolismo , Relação Estrutura-Atividade
18.
Eur J Med Chem ; 188: 112017, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31926470

RESUMO

A series of xanthine compounds derived from the previous hit 20i with modification on the terminal side chain was discovered through ring formation strategy. Systematic optimization of the compounds with rigid heterocycles in the hydrophobic side chain led to the new lead compound HBK001 (21h) with the improved DPP-IV inhibition and moderate GPR119 agonism activity in vitro. As a continuing work to further study the PK and PD profiles, 21h and its hydrochloride (22) were synthesized on grams scale and evaluated on the ADME/T and oral glucose tolerance test (OGTT) in ICR mice. Compound 22 showed the improved bioavailability and blood glucose-lowering effect in vivo compared to its free base 21h probably attributed to its improved solubility and permeability. The preliminary toxicity studies on compound 22 exhibited that the result of mini-Ames was negative and the preliminary acute toxicity LD50 in mice was above 1.5 g/kg, while it showed moderate inhibition on hERG channel with IC50 4.9 µM maybe due to its high lipophilicity. These findings will be useful for the future drug design for more potent and safer dual ligand targeting DPP-IV and GPR119 for the treatment of diabetes.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Piperidinas/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Xantina/farmacologia , Animais , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/química , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Camundongos , Camundongos Endogâmicos ICR , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Receptores Acoplados a Proteínas-G/metabolismo , Relação Estrutura-Atividade , Xantina/síntese química , Xantina/química
19.
Org Lett ; 22(2): 666-669, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31909622

RESUMO

A catalytic conjunctive cross-coupling reaction is developed that allows the construction of chiral organoboronic esters from alkylboron ate complexes and alkyl iodide electrophiles. The process occurs most efficiently with a Ni/Pybox-comprised catalyst and with an acenapthoquinone-derived boron ligand. Because of the broad functional group tolerance of this reaction, it can be a versatile tool for organic synthesis. Applications to the construction of (R)-coniine and (-)-indolizidine 209D are described.


Assuntos
Alcaloides/síntese química , Ácidos Borônicos/síntese química , Ésteres/síntese química , Indolizinas/síntese química , Níquel/química , Piperidinas/síntese química , Alcaloides/química , Ácidos Borônicos/química , Catálise , Ésteres/química , Indolizinas/química , Estrutura Molecular , Piperidinas/química
20.
Molecules ; 25(2)2020 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-31940857

RESUMO

In order to prepare, at low cost, new compounds active against Plasmodium falciparum, and with a less side-effects, we have designed and synthesized a library of 1,4-disubstituted piperidine derivatives from 4-aminopiperidine derivatives 6. The resulting compound library has been evaluated against chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of P. falciparum. The most active molecules-compounds 12d (13.64 nM (3D7)), 13b (4.19 nM (3D7) and 13.30 nM (W2)), and 12a (11.6 nM (W2))-were comparable to chloroquine (22.38 nM (3D7) and 134.12 nM (W2)).


Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Antimaláricos/química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Piperidinas/química , Plasmodium falciparum/efeitos dos fármacos
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