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1.
Eur J Med Chem ; 182: 111670, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31499359

RESUMO

A series of novel structurally-related tubulin polymerization inhibitors based on benzodiazepine were designed, synthesized, and evaluated for anticancer activity. Extensive structure modifications were performed to investigate the detailed structure and activity relationships (SARs). Most compounds exhibited potent antiproliferative activity against a panel of cancer cell lines. Among these compounds, the optimal compound, 9a, possessed the most superior activity, including cytotoxicity against five cancer cell lines (IC50 = 6-15 nM) and inhibition of tubulin polymerization (IC50 = 1.65 ±â€¯0.11 µM). Mechanistic studies revealed that 9a could disrupt intracellular microtubule organization, arrest cell cycle at the G2/M phase and eventually induce cell apoptosis. Compound 9a exhibited good metabolic stability with a t1/2 of 161.2 min, which was much better than the reference compound CA-4. Moreover, the disodium salt of 9a, 9a-P, exhibited excellent in vivo antitumor activity in xenograft mice model with inhibitory rate of 89.3%, which was better than the reference compounds CA-4P (inhibitory rate: 52.8%) and Y-01P (inhibitory rate: 77.7%). Altogether, 9a could serve as a promising lead compound for the development of highly efficient anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Benzodiazepinas/farmacologia , Desenho de Drogas , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Benzodiazepinas/química , Benzodiazepinas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismo
2.
Chem Commun (Camb) ; 55(68): 10128-10131, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31386708

RESUMO

Fueled by the therapeutic potential of the epigenetic machinery, BET bromodomains have seen high interest as drug targets. Herein, we introduce different linkers to a BET bromodomain benzodiazepine ligand (I-BET762) to gauge its implications in the development of hybrid drugs, imaging probes and small molecule drug conjugates. Biophysical studies confirmed minimal disruption to binding of the BRD4 cavity by the synthesized entities, which includes imaging probes. Target engagement was confirmed in a cellular context, but poor membrane diffusion was found despite efficient localization in the nuclei after membrane disruption. Our study highlights challenges and opportunities for the successful design of benzodiazepine-derived drug-delivery systems.


Assuntos
Benzodiazepinas/farmacologia , Fluoresceínas/farmacologia , Corantes Fluorescentes/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Benzodiazepinas/síntese química , Benzodiazepinas/química , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Desenho de Drogas , Fluoresceínas/síntese química , Fluoresceínas/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Ligantes , Estrutura Molecular , Proteínas Nucleares/química , Domínios Proteicos
3.
J Photochem Photobiol B ; 199: 111588, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31450132

RESUMO

Green synthesis of zinc oxide has gained extensive attention as a reliable, sustainable, and eco-friendly protocol to reduce the destructive effects associated with the traditional synthesis methods commonly utilized in laboratory and industry. Here for the first time, we have synthesized quaker ladies flower type ZnO (ZnO/QNF) from panos extract (extract from four panax plants such as Panax ginseng, Acanthopanax senticosus, Kalopanax septemlobus and Dendropanax morbifera). The synthesized ZnO materials was characterized using powder X-ray diffraction, Fourier infrared spectroscopy, X-ray photoelectron spectroscopy and Transmission electron microscope. The newly synthesized ZnO/QNF was applied for the removal of industrial dyes such as methylene blue (MB), Eosin Y (EY) and Malachite green (MG) under UV illumination. The photocatalyst degraded the 15 mg L-1 MB, EY and MG to >99% within 80, 90 and 110 min of contact time, respectively. In addition, the ZnO/QNF photocatalyst removed the low concentrated 5 mg L-1 of MB, EY, and MG within 30, 35 and 40 min of contact time, respectively. The pedal structure provided all the active sites available for the easy interaction with dye molecule under UV, and that enabled fast kinetics of dye degradation than the many other benchmark materials reported previously. The ZnO photocatalyst could be reused minimum of five cycles without any significant loss in degradation efficiency.


Assuntos
Benzodiazepinas/química , Corantes/química , Nanoestruturas/química , Extratos Vegetais/química , Óxido de Zinco/química , Catálise , Amarelo de Eosina-(YS)/química , Química Verde/métodos , Cinética , Azul de Metileno/química , Processos Fotoquímicos , Corantes de Rosanilina/química , Raios Ultravioleta
4.
Eur J Med Chem ; 179: 591-607, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279293

RESUMO

Antibody-drug conjugates (ADCs) containing pyrrolobenzodiazepine (PBD) dimers are currently being evaluated in human oncology clinical trials with encouraging results. To further improve the therapeutic window, next-generation PBD drug-linker design has focused on the inclusion of additional tumor-selective triggers and use of lower-potency PBDs. ß-Glucuronidase is a well-known target for discovery prodrugs due to increased presence in tumor cells and microenvironment. In this study, a ß-glucuronidase cleavable cap was investigated at the PBD N10-position and compared with corresponding free imine ADCs. SG3600 (glucuronide) ADCs showed in vitro and in vivo efficacy/tolerability comparable to SG3400 (imine) ADCs, and good 50% inhibitory concentration differentials were observed in vitro between control non-antigen-targeted ADCs and targeted ADCs. Dependence on ß-glucuronidase for SG3600 activity was demonstrated through CRISPRCas9 knockdown studies and addition of exogenous ß-glucuronidase. SG3600 showed better serum stability, improved conjugation efficiency and was able to reach high drug-to-antibody ratio without aggregation.


Assuntos
Benzodiazepinas/farmacologia , Dipeptídeos/farmacologia , Glucuronídeos/farmacologia , Imunoconjugados/farmacologia , Pirróis/farmacologia , Benzodiazepinas/síntese química , Benzodiazepinas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dipeptídeos/química , Relação Dose-Resposta a Droga , Glucuronídeos/química , Humanos , Imunoconjugados/química , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
5.
Analyst ; 144(14): 4320-4330, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31192335

RESUMO

Restricted access molecularly imprinted polymers (RAMIPs) are hybrid materials that present selective binding sites for a template (or similar molecules), and an external hydrophilic layer that avoids the binding of proteins to the material, making them appropriate for the sample preparation of protein fluids. RAMIPs have been used successfully in online and offline solid phase extractions, but there is no application as a fiber in solid phase microextraction (SPME), to the best of our knowledge. In this paper, molecularly imprinted fibers were synthesized inside glass capillary tubes (0.53 mm i.d.), using diazepam and methacrylic acid as template and functional monomer, respectively. The MIP fibers were coated with a cross-linked bovine serum albumin (BSA) layer, resulting in RAMIP fibers that were used in the SPME of benzodiazepines directly from biological fluids. The BSA layer acts as a protective barrier that avoids the binding of proteins from the sample by an electrostatic repulsion mechanism. The protein exclusion capacity of the RAMIP fiber was about 98%, which is selective to benzodiazepines in comparison with other drugs (citalopram and fluoxetine). The SPME was optimized and the extraction conditions were set as follows: 1000 µL of the sample diluted with water (1 : 0.5, v : v), no pH adjustment, an extraction time of 20 min at 500 rpm, and elution with 200 µL of acetonitrile for 5 min at 500 rpm. The fibers were used in the SPME of benzodiazepines directly from plasma samples, followed by HPLC-DAD analyses. The method was linear for bromazepam (50-750 µg L-1), clonazepam (15-250 µg L-1), alprazolam (15-350 µg L-1), nordiazepam (100-2100 µg L-1) and diazepam (100-2600 µg L-1), with correlation coefficients higher than 0.97. Relative standard deviations (precision) and relative errors (accuracy) ranged from 0.5 to 20.0%, and -15.6 to 21.6%, respectively.


Assuntos
Benzodiazepinas/sangue , Ácidos Polimetacrílicos/química , Adsorção , Animais , Benzodiazepinas/química , Bovinos , Diazepam/química , Humanos , Cinética , Metacrilatos/química , Impressão Molecular/métodos , Ácidos Polimetacrílicos/síntese química , Estudo de Prova de Conceito , Soroalbumina Bovina/química , Microextração em Fase Sólida/instrumentação , Microextração em Fase Sólida/métodos
6.
PLoS Negl Trop Dis ; 13(5): e0007373, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31120889

RESUMO

Infections of humans and livestock with African trypanosomes are treated with drugs introduced decades ago that are not always fully effective and often have severe side effects. Here, the trypanosome haptoglobin-haemoglobin receptor (HpHbR) has been exploited as a route of uptake for an antibody-drug conjugate (ADC) that is completely effective against Trypanosoma brucei in the standard mouse model of infection. Recombinant human anti-HpHbR monoclonal antibodies were isolated and shown to be internalised in a receptor-dependent manner. Antibodies were conjugated to a pyrrolobenzodiazepine (PBD) toxin and killed T. brucei in vitro at picomolar concentrations. A single therapeutic dose (0.25 mg/kg) of a HpHbR antibody-PBD conjugate completely cured a T. brucei mouse infection within 2 days with no re-emergence of infection over a subsequent time course of 77 days. These experiments provide a demonstration of how ADCs can be exploited to treat protozoal diseases that desperately require new therapeutics.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antiprotozoários/administração & dosagem , Benzodiazepinas/administração & dosagem , Pirróis/administração & dosagem , Tripanossomíase Africana/tratamento farmacológico , Animais , Anticorpos Monoclonais/química , Antiprotozoários/química , Benzodiazepinas/química , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Pirróis/química , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/parasitologia
7.
Curr Top Med Chem ; 19(9): 741-752, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30931859

RESUMO

Background & Introduction: Pyrrolobenzodiazepine (PBD) dimers are highly potent DNA cross-linking agents used as warheads in Antibody Drug Conjugates (ADCs) for cancer therapy. We propose to investigate the correlation existing between the lipophilicity of those molecules and their activity (both in vitro and in vivo) as well as any effect observed during conjugation. MATERIALS AND METHODS: Reaction progress was monitored by Thin-Layer Chromatography (TLC) using Merck Kieselgel 60 F254 silica gel, with a fluorescent indicator on aluminium plates. Visualisation of TLC was achieved with UV light or iodine vapour unless otherwise stated. Flash chromatography was performed using Merck Kieselgel 60 F254 silica gel. RESULTS: We have successfully designed and synthesized a novel PBD warhead (SG3312) with enhanced physicochemical properties. The warhead also displayed increased potency in vitro. After overcoming some epimerization issues, the synthesis of enantiomerically pure payload was achieved (SG3259) and fulfilled our criteria for a simplified and more efficient conjugation. No addition of propylene glycol was required, and high DAR and excellent monomeric purity were achieved. CONCLUSION: The ADC (Herceptin-maia-SG3259) has been shown to release the active warhead (SG3312) upon exposure to Cathepsin B and demonstrated encouraging activity both in vitro and in vivo.


Assuntos
Antineoplásicos/farmacologia , Benzodiazepinas/farmacologia , Pirróis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Benzodiazepinas/síntese química , Benzodiazepinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromatografia em Camada Delgada , Dimerização , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Géis/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Dióxido de Silício/química , Relação Estrutura-Atividade
8.
Prog Med Chem ; 58: 1-62, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30879472

RESUMO

Covalent modulation of protein function can have multiple utilities including therapeutics, and probes to interrogate biology. While this field is still viewed with scepticism due to the potential for (idiosyncratic) toxicities, significant strides have been made in terms of understanding how to tune electrophilicity to selectively target specific residues. Progress has also been made in harnessing the potential of covalent binders to uncover novel biology and to provide an enhanced utility as payloads for Antibody Drug Conjugates. This perspective covers the tenets and applications of covalent binders.


Assuntos
Descoberta de Drogas , Proteínas/química , Aminoglicosídeos/química , Aminoglicosídeos/metabolismo , Benzodiazepinas/química , Benzodiazepinas/metabolismo , Camptotecina/química , Camptotecina/metabolismo , Indóis/química , Indóis/metabolismo , Simulação de Dinâmica Molecular , Ligação Proteica , Proteínas/metabolismo , Piranos/química , Piranos/metabolismo , Pirróis/química , Pirróis/metabolismo
9.
Molecules ; 24(5)2019 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-30857362

RESUMO

The hemi-synthesis of chiral imine, benzimidazole and benzodiazepine structures is reported by the condensation of (S)-(-)-perillaldehyde, the major phytochemical of Ammodaucus leucotrichus subsp. leucotrichus essential oil, with different amine derivatives of 2,3-diaminomaleonitrile, o-phenylenediamine and 3-[(2-aminoaryl)amino]dimedone. The reaction proceeds in situ at ambient temperature without prior isolation of the natural (S)-(-)-perillaldehyde. Final products precipitate in the ethanolic reaction medium. 2D NMR and single-crystal X-ray diffraction studies were used to unequivocally characterize the structures in solution and in the solid state, respectively. Chiral HPLC analysis confirms the formation of unique enantiomers and diastereomeric mixtures.


Assuntos
Apiaceae/química , Benzodiazepinas/química , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Óleos Voláteis/química , Difração de Raios X
10.
MAbs ; 11(3): 500-515, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30835621

RESUMO

Most strategies used to prepare homogeneous site-specific antibody-drug conjugates (ADCs) result in ADCs with a drug-to-antibody ratio (DAR) of two. Here, we report a disulfide re-bridging strategy to prepare homogeneous ADCs with DAR of one using a dual-maleimide pyrrolobenzodiazepine (PBD) dimer (SG3710) and an engineered antibody (Flexmab), which has only one intrachain disulfide bridge at the hinge. We demonstrate that SG3710 efficiently re-bridge a Flexmab targeting human epidermal growth factor receptor 2 (HER2), and the resulting ADC was highly resistant to payload loss in serum and exhibited potent anti-tumor activity in a HER2-positive gastric carcinoma xenograft model. Moreover, this ADC was tolerated in rats at twice the dose compared to a site-specific ADC with DAR of two prepared using a single-maleimide PBD dimer (SG3249). Flexmab technologies, in combination with SG3710, provide a platform for generating site-specific homogenous PBD-based ADCs with DAR of one, which have improved biophysical properties and tolerability compared to conventional site-specific PBD-based ADCs with DAR of two.


Assuntos
Antineoplásicos , Benzodiazepinas/química , Imunoconjugados , Pirróis/química , Receptor ErbB-2/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Trastuzumab , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Feminino , Humanos , Imunoconjugados/química , Imunoconjugados/farmacologia , Células MCF-7 , Camundongos Nus , Ratos , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Trastuzumab/química , Trastuzumab/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
J Pharm Biomed Anal ; 167: 1-6, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30731352

RESUMO

This manuscript presents a novel methodology for calculating the relative response factors (RRFs) of unstable degradation impurities of molibresib (1). The degradation impurities were observed by HPLC during stress testing and were accompanied by large mass balance deficits. However, the impurities could not be isolated for traditional RRF determination due to their instability. The RRFs of two degradation impurities were determined without isolation by multiple linear regression analysis of HPLC-UV data. The results permitted accurate quantification of the degradants. The benefits and drawbacks of the approach are discussed, including suggested validation acceptance criteria.


Assuntos
Benzodiazepinas/análise , Contaminação de Medicamentos , Modelos Teóricos , Benzodiazepinas/química , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Modelos Lineares , Análise Multivariada
12.
Ann Pharm Fr ; 77(2): 121-125, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30678803

RESUMO

The crystal structure of tetrazepam, a benzodiazepine derivative formerly used for its muscle relaxant properties, has been solved and found to be monoclinic, space group P21/c, with lattice parameters a=12.7386(7)Å, b=11.3774(7)Å, c=10.3084(7)Å, ß=103.175(5) and Vunit-cell=1454.69(16) Å3 at room temperature (293K) with Z=4 molecules in the unit-cell. A network of weak hydrogen bonds involving aliphatic hydrogen atoms plays an important role in the formation of this structure.


Assuntos
Benzodiazepinas/química , Ligações de Hidrogênio , Relaxantes Musculares Centrais/química , Cristalização , Cristalografia por Raios X , Hidrogênio/química , Modelos Moleculares , Temperatura Ambiente , Difração de Raios X
13.
Nature ; 565(7740): 454-459, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30602790

RESUMO

Type-A γ-aminobutyric (GABAA) receptors are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among the most successful drugs in clinical use and are common substances of abuse. Without reliable structural data, the mechanistic basis for the pharmacological modulation of GABAA receptors remains largely unknown. Here we report several high-resolution cryo-electron microscopy structures in which the full-length human α1ß3γ2L GABAA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (γ-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam. We describe the binding modes and mechanistic effects of these ligands, the closed and desensitized states of the GABAA receptor gating cycle, and the basis for allosteric coupling between the extracellular, agonist-binding region and the transmembrane, pore-forming region. This work provides a structural framework in which to integrate previous physiology and pharmacology research and a rational basis for the development of GABAA receptor modulators.


Assuntos
Alprazolam/química , Bicuculina/química , Microscopia Crioeletrônica , Diazepam/química , Picrotoxina/química , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Alprazolam/farmacologia , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Bicuculina/farmacologia , Ligação Competitiva/efeitos dos fármacos , Diazepam/farmacologia , Moduladores GABAérgicos/química , Moduladores GABAérgicos/farmacologia , Humanos , Ligantes , Modelos Moleculares , Nanoestruturas/química , Picrotoxina/farmacologia
14.
Drug Test Anal ; 11(1): 45-50, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29996009

RESUMO

Multiple new psychoactive substances (NPS) are released into the recreational drug market each year. One NPS drug class that has become more common in recent years is that of the benzodiazepines (designer benzodiazepines, DBZ). Several metabolism studies have been performed to improve their bioanalytical detection via the best target. These studies have shown the presence of parent glucuronides and, as polymorphisms have been noted for the catalyzing enzymes (UDP-glucuronyltransferases) responsible for glucuronide conjugation reactions, it is important to keep this in mind when interpreting DBZ cases in clinical and/or forensic toxicology. Therefore, the aim of this study was to determine the UDP-glucuronyltransferases (UGTs) responsible for parent compound conjugation of nine DBZ to facilitate interpretation of related cases. Clonazolam, deschloroetizolam, etizolam, flubromazolam, flunitrazolam, metizolam, nifoxipam, nitrazolam, and pyrazolam were incubated with pooled human liver microsomes (pHLM) or 13 different human UGTs. The samples were analyzed using liquid chromatography-high resolution tandem mass spectrometry (LC-HRMS/MS). Glucuronide conjugates of flunitrazolam and nifoxipam were only detected in pHLM, suggesting that these reactions are performed by dimer complexes of several UGTs or complexes between UGTs and other metabolizing enzymes contained in pHLM. Nitrazolam or pyrazolam glucuronides were not detected. Glucuronidation of clonazolam, deschloroetizolam, etizolam, flubromazolam, and metizolam was catalyzed exclusively by UGT1A4. The conjugation of the majority of the DBZ was performed by the UGT isoform 1A4 for which polymorphisms have been described. This underlines the importance of taking glucuronidation polymorphism into consideration when interpreting intoxication cases.


Assuntos
Benzodiazepinas/metabolismo , Drogas Desenhadas/metabolismo , Glucuronídeos/metabolismo , Glucuronosiltransferase/metabolismo , Espectrometria de Massas em Tandem/métodos , Animais , Benzodiazepinas/análise , Benzodiazepinas/química , Cromatografia Líquida/métodos , Drogas Desenhadas/análise , Drogas Desenhadas/química , Glucuronídeos/química , Glucuronosiltransferase/química , Humanos , Insetos , Microssomos/metabolismo , Detecção do Abuso de Substâncias/métodos
15.
Invest New Drugs ; 37(2): 297-306, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30132271

RESUMO

Purpose This first-in-human study evaluated SGN-CD70A, an antibody-drug conjugate (ADC) directed against the integral plasma membrane protein CD70 and linked to a pyrrolobenzodiazepine (PBD) dimer, in patients with relapsed or refractory (R/R) CD70-positive non-Hodgkin lymphoma (NHL) including diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and Grade 3b follicular lymphoma (FL3b). Methods SGN-CD70A was administered intravenously on Day 1 of 3-week cycles beginning at 8 mcg/kg with planned dose escalation to 200 mcg/kg. Due to observations of prolonged thrombocytopenia, the study was amended to dose every 6 weeks (q6wk). Results Twenty patients were enrolled and treated with SGN-CD70A. The maximum tolerated dose of SGN-CD70A was 30 mcg/kg q6wk. The most common adverse events (AEs) reported were thrombocytopenia (75%), nausea (55%), anemia (50%), and fatigue (50%). The onset for treatment-related thrombocytopenia typically occurred during Cycle 1. Most of the treatment-related events of thrombocytopenia were ≥ Grade 3. Antitumor activity in patients included 1 complete remission (CR) and 3 partial remissions (PRs), 2 of which were ongoing for at least 42.9 weeks. SGN-CD70A exposures were approximately dose proportional, with a mean terminal half-life of 3 to 5 days. Conclusions While modest single-agent activity was observed in heavily pretreated NHL patients, the applicability of SGN-CD70A is limited by the frequency and severity of thrombocytopenia, despite the long-term response with limited drug exposure.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Ligante CD27/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Linfoma de Células B/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/farmacocinética , Benzodiazepinas/química , Biomarcadores Tumorais/metabolismo , Ligante CD27/imunologia , Ligante CD27/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Seguimentos , Humanos , Imunoconjugados/farmacocinética , Imunoconjugados/uso terapêutico , Linfoma de Células B/imunologia , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Linfoma de Célula do Manto/imunologia , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Pirróis/química , Distribuição Tecidual
16.
Neurosci Lett ; 691: 35-43, 2019 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-30102960

RESUMO

In this review, we summarize the recent development of positron emission tomography (PET) radioligands for γ-aminobutyric acid A (GABAA) receptors and their potential to measure changes in endogenous GABA levels and highlight the clinical and translational applications of GABA-sensitive PET radioligands. We review the basic physiology of the GABA system with a focus on the importance of GABAA receptors in the brain and specifically the benzodiazepine binding site. Challenges for the development of central nervous system radioligands and particularly for radioligands with increased GABA sensitivity are outlined, as well as the status of established benzodiazepine site PET radioligands and agonist GABAA radioligands. We underline the challenge of using allosteric interactions to measure GABA concentrations and review the current state of PET imaging of changes in GABA levels. We conclude that PET tracers with increased GABA sensitivity are required to efficiently measure GABA release and that such a tool could be broadly applied to assess GABA transmission in vivo across several disorders.


Assuntos
Transtornos Mentais/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Receptores de GABA-A/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Benzodiazepinas/química , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Radioisótopos de Carbono , Flumazenil , Radioisótopos de Flúor , Humanos , Ligantes , Transtornos Mentais/metabolismo , Ácido gama-Aminobutírico/análise
17.
J Pharm Biomed Anal ; 164: 57-61, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30343244

RESUMO

The analysis of biological samples, such as whole blood, comes with several sample preparation challenges. Biological matrices often contain a variety of endogenous components that can interfere with the determination of xenobiotics. Especially blood plasma proteins (e.g. serum albumin) are known to interfere with electrospray ionization and result in analyte ion suppression. Sample preparation techniques should guarantee adequate removal of these biomolecules. The current study aims to determine to which extent proteins are removed from whole blood samples, using ionic liquid-based dispersive liquid-liquid microextraction (IL-DLLME). A qualitative comparison of the protein presence in extracts of IL-DLLME, solid-phase extraction (SPE) and protein precipitation (PP) was performed, using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Additionally, UV/VIS spectrophotometry was used to determine the protein content of a whole blood sample and IL-DLLME, SPE and PP extracts of the same sample. Finally, a quantitative comparison of matrix effects of benzodiazepines present in both whole blood and water samples. SDS-PAGE results showed that IL-DLLME extracts still contained proteins (i.e. albumin, hemoglobin); however, band intensities were comparable to SPE extracts. Spectrophotometric tests showed a total protein content of approximately 2 mg/mL in the final extracts. PP showed the highest protein extraction rate (19 mg/mL). Quantitative ME results showed no significant differences (α = 0.05) between blood and water IL-DLLME extracts. Overall, this is the first study to conclude that IL-DLLME is able to sufficiently remove blood proteins from whole blood samples, in order to avoid significant ion suppression.


Assuntos
Proteínas Sanguíneas/análise , Líquidos Iônicos/química , Microextração em Fase Líquida/métodos , Xenobióticos/sangue , Benzodiazepinas/sangue , Benzodiazepinas/química , Proteínas Sanguíneas/química , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Limite de Detecção , Microextração em Fase Líquida/instrumentação , Extração em Fase Sólida/instrumentação , Extração em Fase Sólida/métodos
18.
Mol Cancer Ther ; 18(1): 89-99, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30352801

RESUMO

Pyrrolobenzodiazepine dimers (PBD) form cross-links within the minor groove of DNA causing double-strand breaks (DSB). DNA repair genes such as BRCA1 and BRCA2 play important roles in homologous recombination repair of DSB. We hypothesized that PBD-based antibody-drug conjugates (ADC) will have enhanced killing of cells in which homologous recombination processes are defective by inactivation of BRCA1 or BRCA2 genes. To support this hypothesis, we found 5T4-PBD, a PBD-dimer conjugated to anti-5T4 antibody, elicited more potent antitumor activity in tumor xenografts that carry defects in DNA repair due to BRCA mutations compared with BRCA wild-type xenografts. To delineate the role of BRCA1/2 mutations in determining sensitivity to PBD, we used siRNA knockdown and isogenic BRCA1/2 knockout models to demonstrate that BRCA deficiency markedly increased cell sensitivity to PBD-based ADCs. To understand the translational potential of treating patients with BRCA deficiency using PBD-based ADCs, we conducted a "mouse clinical trial" on 23 patient-derived xenograft (PDX) models bearing mutations in BRCA1 or BRCA2 Of these PDX models, 61% to 74% had tumor stasis or regression when treated with a single dose of 0.3 mg/kg or three fractionated doses of 0.1 mg/kg of a PBD-based ADC. Furthermore, a suboptimal dose of PBD-based ADC in combination with olaparib resulted in significantly improved antitumor effects, was not associated with myelotoxicity, and was well tolerated. In conclusion, PBD-based ADC alone or in combination with a PARP inhibitor may have improved therapeutic window in patients with cancer carrying BRCA mutations.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Benzodiazepinas/química , Imunoconjugados/administração & dosagem , Neoplasias Experimentais/tratamento farmacológico , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Pirróis/química , Administração Intravenosa , Animais , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacologia , Proteína BRCA1/genética , Proteína BRCA2/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Células HeLa , Humanos , Imunoconjugados/química , Imunoconjugados/farmacologia , Glicoproteínas de Membrana/antagonistas & inibidores , Camundongos , Mutação , Neoplasias Experimentais/genética , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Sequenciamento Completo do Exoma , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Pharmacol Biochem Behav ; 176: 63-71, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30500330

RESUMO

The anxiolytic effect of earlier reported piperazinediones was assessed by elevated plus maze (EPM), hole-board and open-field (OFT) tests. The rats were administered pretreatment of three different doses i.e. 2, 1 and 0.5 mg/kg of compounds 52, 53 and 55 for seven consecutive days. Compound 52 and diazepam showed increase in open arm entries, increase in time spent therein and total arm entries at 1 mg/kg dose. The compound also produced increase in the number of head dip, sniffing behavior and total number of squares crossed compared to diazepam. In OFT paradigm grooming behavior, number of central squares crossed and the time spent in central area did not reveal statistical differences for diazepam and compound 52 at 1 mg/kg dose. Flumazenil mediated antagonism experiments of these showed that they were acting through benzodiazepine site on GABAA receptor. The levels of 5HT and 5HIAA were estimated in amygdalar region. Level of 5HT was found to be equivalent in case of compound 52 and diazepam treatment at dose of 1 mg/kg. Interestingly, compound 52 did not display sedative effect at higher dose in both animal models. Thus, present study indicated that compound 52 produced anti-anxiety property through modulation of GABAergic transmission.


Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Dicetopiperazinas/uso terapêutico , Moduladores GABAérgicos/uso terapêutico , Tonsila do Cerebelo/metabolismo , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/efeitos adversos , Ansiolíticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Benzodiazepinas/química , Domínio Catalítico , Diazepam/administração & dosagem , Diazepam/farmacologia , Dicetopiperazinas/administração & dosagem , Dicetopiperazinas/efeitos adversos , Dicetopiperazinas/farmacologia , Flumazenil/administração & dosagem , Flumazenil/farmacologia , Moduladores GABAérgicos/administração & dosagem , Moduladores GABAérgicos/efeitos adversos , Moduladores GABAérgicos/farmacologia , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Modelos Animais , Norepinefrina/metabolismo , Ratos , Ratos Wistar , Receptores de GABA-A/metabolismo , Serotonina/metabolismo
20.
Invest New Drugs ; 37(2): 331-337, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30402678

RESUMO

Background Mammalian target of rapamycin (mTOR) pathway and angiogenesis through vascular endothelial growth factor (VEGF) have been shown to play important roles in prostate cancer progression. Preclinical data in prostate cancer has suggested the potential additive effect dual inhibition of VEGF and mTOR pathways. In this phase I/II trial we assessed the safety and efficacy of bevacizumab in combination with temsirolimus for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC). Methods In the phase I portion, eligible patients received temsirolimus (20 mg or 25 mg IV weekly) in combination with a fixed dose of IV bevacizumab (10 mg/kg every 2 weeks). The primary endpoint for the phase II portion was objective response measured by either PSA or RECIST criteria. Exploratory endpoints included changes in circulating tumor cells (CTC) and their correlation with PSA response to treatment. Results Twenty-one patients, median age 64 (53-82), with pre-treatment PSA of 205.3 (11.1-1801.0), previously treated with a median of 2 (0-5) lines of therapy for mCRPC received the combination of temsirolimus weekly at 20 mg (n = 4) or 25 mg (n = 17) with bevacizumab 10 mg/kg every 2 weeks (n = 21). Median time to progression was 2.6 months (95% CI, 1.2-3.9) and the median best PSA change from baseline to 12 weeks was a 32% increase (-40-632%) which met the predefined futility rule and led to early termination of the study. Nine patients (43%) had ≥ grade 3 toxicity that included fatigue (24%), anorexia (10%), nausea/vomiting (5%) and lymphopenia (5%). In exploratory analysis, a decrease in CTC levels was observed in 9 out of 11 patients. No association between PSA levels and CTC levels was detected. Conclusions The combination of temsirolimus and bevacizumab showed limited clinical activity in mCRPC patients previously treated with chemotherapy and was associated with significant adverse events (AEs). Transient decrease in CTC levels was independent from PSA response. NCT01083368.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Terapia de Salvação , Serina-Treonina Quinases TOR/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzodiazepinas/química , Bevacizumab/administração & dosagem , Biomarcadores Tumorais/metabolismo , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Pirróis/química , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Distribuição Tecidual
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