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1.
Int J Nanomedicine ; 15: 10045-10058, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33328733

RESUMO

Background: Radiotherapy (RT), one of the main treatments for cervical cancer, has tremendous potential for improvement in the efficacy. Poly (ADP-ribose) polymerase (PARP) is a key enzyme in the repair of DNA strand breaks (DSB). Olaparib (Ola) is a PARP inhibitor that is involved in preventing the release of PARP from RT-induced damaged DNA to potentiate the effect of RT. Although the basic mechanism of Ola's radiosensitization is well known, the radiosensitization mechanism of its nanomedicine is still unclear. In addition, the lack of tumor tissue targeting is a major obstacle for the clinical success of Ola. Materials and Methods: In this study, we developed folate-conjugated active targeting olaparib nanoparticles (ATO) and investigated the anti-tumor effect of ATO combined with radiotherapy (RT) in nude mice using cervical cancer xenograft models. We used folate (FA)-conjugated poly (ε-caprolactone)-poly (ethyleneglycol)-poly (e-caprolactone) (PCEC) copolymer to prepare ATO via emulsification/solvent diffusion. Further, we evaluated ATO particle size, potential, encapsulation efficiency, and in vitro release characteristics, and evaluated the shape of ATO via transmission electron microscopy (TEM). We then performed MTT and cell uptake assays to detect cytotoxicity and targeting uptake in vitro. We investigated the anti-tumor properties of ATO in vivo by apoptosis test, 18 F-FDG PET/CT, and immunohistochemical analysis. Finally, the xenografted tumor in nude mice was subjected to RT and/or ATO treatment. Results: The results confirmed that ATO in combination with RT significantly inhibited tumor growth and prolonged survival time of tumor-bearing mice. This may be related to the inhibition of tumor proliferation and DNA damage repair and induction of cell apoptosis in vivo. Conclusion: The ATO developed in this study may represent a novel formulation for olaparib delivery and have promising potential for treating tumors with an over-expression of folate receptors.


Assuntos
Ácido Fólico/química , Nanopartículas/química , Ftalazinas/química , Ftalazinas/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/radioterapia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Terapia Combinada , Feminino , Humanos , Camundongos , Camundongos Nus , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
PLoS One ; 15(8): e0237196, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764777

RESUMO

Current antidepressant therapy has several disadvantages related to the properties of antidepressants. Considering their unfavourable features, the process of searching for new antidepressant drugs with better safety and tolerability requires consistent efforts and many complementary studies. Serotonin 5-HT1A receptor is considered as an interesting target of antidepressant therapy. In the present study, the intrinsic activity at different signaling pathways coupled to serotonin 5-HT1A receptor, antidepressant-like and pharmacokinetic properties, and the safety profile of two novel imidazopurine-2,4-dione derivatives, namely compounds AZ-853 (8-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)-1,3-dimethyl-1H- imidazo[2,1-f]purine-2,4(3H,8H)-dione) and AZ-861 (1,3-dimethyl-8-(4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione), were studied in animal models through in vitro and in vivo experiments. We demonstrated that AZ-853 and AZ-861, which structurally differ by one substituent and its placement in the phenyl ring, showed varied functional, pharmacological, and pharmacokinetic properties as well as side effect profiles. AZ-861 exhibited stronger agonistic action in all functional assays. After acute and repeated administration in mice, both compounds showed antidepressant-like activity in the forced swim test, which was partially mediated by 5-HT1A receptor activation. AZ-853 showed a more potent antidepressant-like effect, presumably due to its better penetration into brain structures. Both compounds did not show anticholinergic properties, but after repeated administration, they induced weak sedation and lipid metabolism disturbances without affecting serum glucose level. The stronger α1-adrenolytic effect of AZ-853 is responsible for decreased systolic blood pressure, and in contrast to AZ-861, AZ-853 induced weight gain in mice. The interesting comparative pharmacological profiles of AZ-853 and AZ-861 encourage to conduct further experiments to fully understand their mechanisms and differences in action.


Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Receptor 5-HT1A de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Animais , Antidepressivos/química , Técnicas de Observação do Comportamento , Comportamento Animal/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Depressão/diagnóstico , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Piperazinas/química , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Agonistas do Receptor 5-HT1 de Serotonina/química , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Relação Estrutura-Atividade , Ganho de Peso/efeitos dos fármacos
3.
Nat Commun ; 11(1): 4249, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843618

RESUMO

Aberrant cell cycle machinery and loss of the CDKN2A tumor suppressor locus make CDK4/6 a potential target in pancreatic ductal adenocarcinoma (PDAC). However, a vast majority of PDAC cases do not harbor a durable response to monotherapy of CDK4/6 inhibitor. Utilizing remote loading to co-encapsulate CDK4/6 inhibitor palbociclib (PAL) and an autophagy inhibitor hydroxychloroquine (HCQ), we demonstrate a ratiometrically designed mesoporous silica nanoformulation with synergistic efficacy in subcutaneous and orthotopic PDAC mouse models. The synergism is attributed to the effective intratumoral buildup of PAL/HCQ, which otherwise exhibit distinctly different circulatory and biodistribution profile. PAL/HCQ co-delivery nanoparticles lead to the most effective shrinkage of PDAC compared to various controls, including free drug mixture. Immunohistochemistry reveals that PAL/HCQ co-delivery nanoparticles trigger anti-apoptotic pathway after repetitive intravenous administrations in mice. When combined with a Bcl inhibitor, the performance of co-delivery nanoparticles is further improved, leading to a long-lasting anti-PDAC effect in vivo.


Assuntos
Autofagia/efeitos dos fármacos , Carcinoma Ductal Pancreático/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Sistemas de Liberação de Medicamentos , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sinergismo Farmacológico , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/química , Hidroxicloroquina/farmacologia , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Piperazinas/administração & dosagem , Piperazinas/química , Piperazinas/farmacologia , Piridinas/administração & dosagem , Piridinas/química , Piridinas/farmacologia , Dióxido de Silício/administração & dosagem , Dióxido de Silício/química , Dióxido de Silício/farmacologia , Resultado do Tratamento
4.
Chem Biol Interact ; 325: 109127, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32437695

RESUMO

Inhibition of mouse double minute 2 homolog (MDM2)-p53 interaction and reactivation of p53 signaling have been explored as effective anticancer therapeutic strategy. The potent and specific antitumor activity shown by Nutlins, first class of MDM2-p53 inhibitors discovered, has made these compounds potential antitumor candidates. To this end, we synthesized Nutlin-1 and Nutlin-2 analogs through molecular simplification and selected the compound with the most efficient antitumoral activity. Cytotoxicity of Nutlin-2 analog LQFM126 on B16F10 melanoma cells induced intense cytoplasmic vacuolization, reduction of cell size, chromatin condensation, cytoplasmic degeneration and nuclear fragmentation. LQFM126 antiproliferative effects mediated cell cycle retention in G0/G1 phase and increased the levels of cell cycle regulatory proteins p21 and p27. This Nutlin analog increased mitochondrial membrane potential, activated caspase-8, -9 and -3/7 and reduced VEGF levels in B16F10 cells. Therefore, LQFM126 promoted alterations suggestive of apoptosis, G0/G1 cell cycle arrest and suppression of angiogenesis through modulation of VEGF expression in B16F10 cells. Additionally, LQFM126 was classified as UN GHS category 4 (LD50 > 300-2000 mg/kg), suggesting it has low acute systemic toxicity. LQFM126 can be a promising prototype for anticancer therapy.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Melanoma Experimental/patologia , Pirazóis/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Caspases/metabolismo , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imidazóis/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Piperazinas/química , Pirazóis/síntese química , Pirazóis/química , Pirazóis/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo
5.
AAPS PharmSciTech ; 21(3): 115, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32296987

RESUMO

The objective of the current study was to develop ziprasidone hydrochloride monohydrate (ZHM) nanocrystal-based orally dispersible tablet (ODT) formulations. Design of experiment approach was used to develop ODTs. The tablets were compressed using direct compression method and characterized with quality control tests. In vitro dissolution studies and Caco-2 cell permeability tests were executed. The hardness and friability values of nanocrystal-based ODTs were found 31.2 N and 1.05%, respectively. The disintegration time was below 10 s. Dissolution profile in pH 7.4 phosphate buffer showed that nanocrystal-based ODTs and commercial product were dissolved in 120 min 58.98% and 16%, respectively. In pH 7.4 phosphate buffer with SLS, sample groups dissolved above 85% at the end of the study. Permeability value and cumulative ZHM amount on the cells were improved with nanocrystals. In conclusion, the novel formulation of ZHM nanocrystal-based ODTs was successfully developed for alternative dosage form.


Assuntos
Piperazinas/administração & dosagem , Tiazóis/administração & dosagem , Administração Oral , Células CACO-2 , Humanos , Concentração de Íons de Hidrogênio , Nanopartículas , Permeabilidade , Piperazinas/química , Solubilidade , Comprimidos , Tiazóis/química
6.
Science ; 368(6486)2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32241924

RESUMO

The success of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (PARPi) to treat cancer relates to their ability to trap PARP-1 at the site of a DNA break. Although different forms of PARPi all target the catalytic center of the enzyme, they have variable abilities to trap PARP-1. We found that several structurally distinct PARPi drive PARP-1 allostery to promote release from a DNA break. Other inhibitors drive allostery to retain PARP-1 on a DNA break. Further, we generated a new PARPi compound, converting an allosteric pro-release compound to a pro-retention compound and increasing its ability to kill cancer cells. These developments are pertinent to clinical applications where PARP-1 trapping is either desirable or undesirable.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Quebras de DNA/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Neoplasias/enzimologia , Poli(ADP-Ribose) Polimerase-1/química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Benzimidazóis/química , Benzimidazóis/farmacologia , Linhagem Celular Tumoral , Humanos , Isoindóis/química , Isoindóis/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Domínios Proteicos
7.
Mar Drugs ; 18(3)2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32110865

RESUMO

Aspergillus terreus has been reported to produce many secondary metabolites that exhibit potential bioactivities, such as antibiotic, hypoglycemic, and lipid-lowering activities. In the present study, two new thiodiketopiperazines, emestrins L (1) and M (2), together with five known analogues (3-7), and five known dihydroisocoumarins (8-12), were obtained from the marine-derived fungus Aspergillus terreus RA2905. The structures of the new compounds were elucidated by analysis of the comprehensive spectroscopic data, including high-resolution electrospray ionization mass spectrometry (HRESIMS), one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR), and electronic circular dichroism (ECD) data. This is the first time that the spectroscopic data of compounds 3, 8, and 9 have been reported. Compound 3 displayed antibacterial activity against Pseudomonas aeruginosa (minimum inhibitory concentration (MIC) = 32 µg/mL) and antifungal activity against Candida albicans (MIC = 32 µg/mL). In addition, compound 3 exhibited an inhibitory effect on protein tyrosine phosphatase 1 B (PTP1B), an important hypoglycemic target, with an inhibitory concentration (IC)50 value of 12.25 µM.


Assuntos
Antibacterianos/farmacologia , Aspergillus/química , Animais , Candida albicans/efeitos dos fármacos , Cumarínicos/química , Testes de Sensibilidade Microbiana , Oceanos e Mares , Piperazinas/química , Pseudomonas aeruginosa/efeitos dos fármacos
8.
Nat Protoc ; 15(4): 1525-1541, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32111986

RESUMO

Positron emission tomography (PET) is a diagnostic nuclear imaging modality that relies on automated protocols to prepare agents labeled with a positron-emitting radionuclide (e.g., 18F). In recent years, new reactions have appeared for the 18F-labeling of agents that are difficult to access by applying traditional radiochemistry, for example those requiring 18F incorporation into unactivated (hetero)arenes. However, automation of these new methods for translation to the clinic has progressed slowly because extensive modification of manual protocols is typically required when implementing novel 18F-labeling methodologies within automated modules. Here, we describe the workflow that led to the automated radiosynthesis of the poly(ADP-ribose) polymerase (PARP) inhibitor [18F]olaparib. First, we established a robust manual protocol to prepare [18F]olaparib from the protected N-[2-(trimethylsilyl)ethoxy]methyl (SEM) arylboronate ester precursor in a 17% ± 5% (n = 15; synthesis time, 135 min) non-decay-corrected (NDC) activity yield, with molar activity (Am) up to 34.6 GBq/µmol. Automation of the process, consisting of copper-mediated 18F-fluorodeboronation followed by deprotection, was achieved on an Eckert & Ziegler Modular-Lab radiosynthesis platform, affording [18F]olaparib in a 6% ± 5% (n = 3; synthesis time, 120 min) NDC activity yield with Am up to 319 GBq/µmol.


Assuntos
Técnicas de Química Sintética/métodos , Cobre/química , Radioisótopos de Flúor/química , Ftalazinas , Piperazinas , Inibidores de Poli(ADP-Ribose) Polimerases , Automação , Ftalazinas/síntese química , Ftalazinas/química , Piperazinas/síntese química , Piperazinas/química , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Tomografia por Emissão de Pósitrons , Radioquímica , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química
9.
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
10.
Eur J Med Chem ; 191: 112140, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32088494

RESUMO

2,3-Dihydro-5,6-dimethoxy-2-[4-(4-alkyl-4-methylpiperazinium-1-yl)benzylidine]-1H-inden-1-one halide salt derivatives as a novel donepezil hybrid analogs with the property of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzyme inhibition were designed and synthesized via N-alkylation reaction of 2,3-dihydro-5,6-dimethoxy-2-[4-(4-methylpiperazin-1-yl)benzylidene]-1H-inden-1-one with some alkyl halides. Biological tests demonstrated that most of the synthesized compounds have moderate to good inhibitory activities effect on cholinesterase enzymes. Among them, 10e showed the best profile as a selected compound for inhibition of hAChE (IC50 = 0.32) and hBuChE (IC50 = 0.43 µM) enzymes. Kinetic analysis and molecular docking led to a better understanding of this compound. Kinetic studies disclosed that 10e inhibited acetylcholinesterase in mixed-type and butyrylcholinesterase in non-competitive type. The toxicity results showed that 10e is less toxic than donepezil and has better inhibitory activity against hBuChE when compared to donepezil or Galantamine. Other performed experiments revealed that 10e has an anti-ß amyloid effect which is capable of reducing ROS, LDH and MDA also possing positive effect on TAC. On the other hand, it has shown a good anti-inflammation effect.


Assuntos
Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Indenos/farmacologia , Piperazinas/farmacologia , Acetilcolinesterase/genética , Algoritmos , Butirilcolinesterase/genética , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Indenos/síntese química , Indenos/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Sais/síntese química , Sais/química , Sais/farmacologia , Relação Estrutura-Atividade
11.
J Med Chem ; 63(5): 2588-2619, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32037829

RESUMO

Synthetic lethality is an innovative framework for discovering novel anticancer drug candidates. One example is the use of PARP inhibitors (PARPi) in oncology patients with BRCA mutations. Here, we exploit a new paradigm based on the possibility of triggering synthetic lethality using only small organic molecules (dubbed "fully small-molecule-induced synthetic lethality"). We exploited this paradigm to target pancreatic cancer, one of the major unmet needs in oncology. We discovered a dihydroquinolone pyrazoline-based molecule (35d) that disrupts the RAD51-BRCA2 protein-protein interaction, thus mimicking the effect of BRCA2 mutation. 35d inhibits the homologous recombination in a human pancreatic adenocarcinoma cell line. In addition, it synergizes with olaparib (a PARPi) to trigger synthetic lethality. This strategy aims to widen the use of PARPi in BRCA-competent and olaparib-resistant cancers, making fully small-molecule-induced synthetic lethality an innovative approach toward unmet oncological needs.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Proteína BRCA2/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Ftalazinas/farmacologia , Piperazinas/farmacologia , Rad51 Recombinase/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Antineoplásicos/química , Proteína BRCA2/genética , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Descoberta de Drogas , Sinergismo Farmacológico , Recombinação Homóloga/efeitos dos fármacos , Humanos , Modelos Moleculares , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Ftalazinas/química , Piperazinas/química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Mutações Sintéticas Letais/efeitos dos fármacos
12.
Org Biomol Chem ; 18(8): 1577-1581, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-32039416

RESUMO

Functionalized 2-piperazinones play essential roles as conformationally-constrained peptidomimetics by mimicking inverse γ-turns in peptides. Here, we describe an efficient, scalable, stereoselective, modular, and chemoselective annulation protocol between a novel N-trifluoroacetyl anhydride and several reactive partners, including lactim ethers, imidoyl chlorides, aryl aldimines, and 1,3-azadienes, leading to vicinally functionalized (bicyclic) 2-piperazinones.


Assuntos
Anidridos/química , Piperazinas/química , Compostos Heterocíclicos/química , Conformação Molecular , Peptidomiméticos/química , Piperazinas/síntese química
13.
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
14.
Proc Natl Acad Sci U S A ; 117(8): 4109-4116, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32041866

RESUMO

The UDP-2,3-diacylglucosamine pyrophosphate hydrolase LpxH is an essential lipid A biosynthetic enzyme that is conserved in the majority of gram-negative bacteria. It has emerged as an attractive novel antibiotic target due to the recent discovery of an LpxH-targeting sulfonyl piperazine compound (referred to as AZ1) by AstraZeneca. However, the molecular details of AZ1 inhibition have remained unresolved, stymieing further development of this class of antibiotics. Here we report the crystal structure of Klebsiella pneumoniae LpxH in complex with AZ1. We show that AZ1 fits snugly into the L-shaped acyl chain-binding chamber of LpxH with its indoline ring situating adjacent to the active site, its sulfonyl group adopting a sharp kink, and its N-CF3-phenyl substituted piperazine group reaching out to the far side of the LpxH acyl chain-binding chamber. Intriguingly, despite the observation of a single AZ1 conformation in the crystal structure, our solution NMR investigation has revealed the presence of a second ligand conformation invisible in the crystalline state. Together, these distinct ligand conformations delineate a cryptic inhibitor envelope that expands the observed footprint of AZ1 in the LpxH-bound crystal structure and enables the design of AZ1 analogs with enhanced potency in enzymatic assays. These designed compounds display striking improvement in antibiotic activity over AZ1 against wild-type K. pneumoniae, and coadministration with outer membrane permeability enhancers profoundly sensitizes Escherichia coli to designed LpxH inhibitors. Remarkably, none of the sulfonyl piperazine compounds occupies the active site of LpxH, foretelling a straightforward path for rapid optimization of this class of antibiotics.


Assuntos
Aciltransferases/antagonistas & inibidores , Aciltransferases/metabolismo , Antibacterianos/química , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Pirofosfatases/antagonistas & inibidores , Pirofosfatases/metabolismo , Aciltransferases/genética , Proteínas de Bactérias/genética , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Escherichia coli/metabolismo , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/metabolismo , Metabolismo dos Lipídeos , Testes de Sensibilidade Microbiana , Mutação , Piperazinas/química , Piperazinas/farmacologia , Conformação Proteica , Pirofosfatases/genética
15.
Eur J Med Chem ; 189: 112076, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32007668

RESUMO

In this study, a series of thieno [2,3-d]pyrimidine derivatives were designed, synthesized and evaluated as novel AKT1 inhibitors. In vitro antitumor assay results showed that compounds 9d-g and 9i potently suppressed the enzymatic activities of AKT1 and potently inhibited the proliferation of HepG2, Hep3B, Huh-7 and SMMC-7721 cancer cell lines. Among these derivatives, the compound 9f demonstrated the best inhibitory activities on AKT1 (IC50 = 0.034 µM) and Huh-7 cell (IC50 = 0.076 µM). A panel of biological assays showed that compound 9f suppressed the cellular proliferation of Huh-7 through Akt/mTOR signaling pathway mediated autophagy mechanism. Furthermore, the antitumor capacity of 9f was validated in the subcutaneous Huh-7 xenograft models. Together, our results demonstrate that a novel small-molecule Akt1 inhibitor induces autophagy associated death in hepatocellular carcinoma, which may afford a potential drug candidate for targeted cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Morte Celular Autofágica , Carcinoma Hepatocelular/patologia , Descoberta de Drogas , Neoplasias Hepáticas/patologia , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Animais , Antineoplásicos/química , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/enzimologia , Proliferação de Células , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/enzimologia , Camundongos , Camundongos Nus , Piperazinas/química , Inibidores de Proteínas Quinases/química , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Chem Pharm Bull (Tokyo) ; 68(2): 117-128, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32009078

RESUMO

The total syntheses of dimeric indole alkaloids, haplophytine, and T988s are described. These dimeric compounds comprising two structurally different indole units are ubiquitous in nature, and many possess pharmaceutically important activities. To realize an efficient chemical synthesis of these dimeric indole alkaloids, the establishment of convergent synthetic strategies and development of new coupling methods are indispensable. The linkage of two highly functionalized units at a late stage of the synthesis frequently induces synthetic problems such as chemoselectivity and steric repulsion. Moreover, although transition metal-catalyzed reactions are usually an effective method for the cross-coupling of two units, the application of these cross-coupling reactions to bond formation involving a sterically hindered C(sp3) is often difficult. Thus, even with precise modern synthetic methods, it is currently difficult to realize convergent syntheses of dimeric indole alkaloids possessing a quaternary carbon linking two units. To combat these synthetic problems, we developed a synthetic method to link two indole units using an Ag-mediated nucleophilic substitution reaction. In this review, we provide a detailed discussion of convergent synthetic strategies and coupling methods for dimeric indole alkaloids.


Assuntos
Técnicas de Química Sintética/métodos , Alcaloides Indólicos/síntese química , Dimerização , Alcaloides Indólicos/química , Piperazinas/síntese química , Piperazinas/química , Estereoisomerismo
17.
Analyst ; 145(4): 1396-1407, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32016204

RESUMO

The evolution of Raman spectroscopy into a useful analytical technique has been due, in part, to the development of inexpensive, compact instrumentation and advancements in methodologies that enhance Raman intensities. Surface enhanced Raman scattering (SERS) is a primary methodology for quantitative and low detection limit measurements. While a broad array of applications using solid SERS substrates have been demonstrated, in-solution SERS measurements are not as widely pursued. This work seeks to optimize the synthesis of gold nanostars (AuNS) as a colloidal SERS substrate for in-solution measurements using handheld instrumentation. The types and concentrations of two buffers typically used for AuNS synthesis are examined to optimize the SERS intensity of a chemisorbed Raman probe. The observed SERS intensity primarily depends on conditions that allow higher surface coverage of the probe. Conditions that result in AuNS aggregates are found to be most optimal for SERS, similar to other nanoparticle shapes. A method to quantitate methimazole, an anti-hormone pharmaceutical, in urine is developed and reported. The primary impact of this work is the demonstration of the combination of water dispersible substrates and handheld instrumentation for rapid and sensitive analytical measurements.


Assuntos
Ouro/química , Nanopartículas Metálicas/química , Análise Espectral Raman/métodos , Antitireóideos/urina , Tampões (Química) , Coloides , HEPES/química , Humanos , Limite de Detecção , Metimazol/urina , Tamanho da Partícula , Piperazinas/química , Soluções , Propriedades de Superfície
18.
Molecules ; 25(3)2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31991816

RESUMO

The increasing risk of radiation exposure underlines the need for novel radioprotective agents. Hence, a series of novel 1-(2-hydroxyethyl)piperazine derivatives were designed and synthesized. Some of the compounds protected human cells against radiation-induced apoptosis and exhibited low cytotoxicity. Compared to the previous series of piperazine derivatives, compound 8 exhibited a radioprotective effect on cell survival in vitro and low toxicity in vivo. It also enhanced the survival of mice 30 days after whole-body irradiation (although this increase was not statistically significant). Taken together, our in vitro and in vivo data indicate that some of our compounds are valuable for further research as potential radioprotectors.


Assuntos
Piperazinas/química , Piperazinas/farmacologia , Protetores contra Radiação/química , Protetores contra Radiação/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta a Droga , Humanos , Dose Máxima Tolerável , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Radiação Ionizante , Protetores contra Radiação/administração & dosagem , Protetores contra Radiação/efeitos adversos , Relação Estrutura-Atividade , Análise de Sobrevida
19.
Eur J Med Chem ; 188: 112032, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31926467

RESUMO

Overexpression and amplification of cyclin-dependent kinase 4/6 (CDK4/6) occur in many cancers and may be the cause of resistance to CDK4/6 inhibitors in preclinical models. However, there are few investigations on the assessment of CDK4/6 expression in tumors or other tissues. Palbociclib, which was approved in 2015 to treat ER+/HER2-breast cancer in combination with letrozole, is a selective CDK4/6 inhibitor. In this study, an intermediate (compound 3), which could be hydrolyzed into the ligand (compound L) consisting of palbociclib as the bioactive molecule and 6-hydrazino nicotinamide (HYNIC) as the bifunctional chelator, was synthesized. Compound L was radiolabeled with 99mTc using tricine/TPPTS or tricine/TPPMS as co-ligands. 99mTc-tricine-TPPTS-L and 99mTc-tricine-TPPMS-L were prepared with high radiochemical purity without postlabeling purification. They had great in vitro stability. Both radiotracers were hydrophilic, but 99mTc-tricine-TPPTS-L had a lower log P value. In vitro cell uptake studies in MCF-7 cells showed that cellular uptake was blocked by preincubation with palbociclib, suggesting a CDK4/6-mediated uptake mechanism. Biodistribution in mice bearing MCF-7 tumors showed that 99mTc-tricine-TPPTS-L had higher tumor uptake than 99mTc-tricine-TPPMS-L, while they had comparable tumor-to-muscle and tumor-to-blood ratios. Radioactivity accumulation in tumors was obvious in micro-SPECT/CT images with 99mTc-tricine-TPPTS-L. When mice were preinjected with palbociclib, tumor uptake of 99mTc-tricine-TPPTS-L significantly decreased and the tumor accumulation was clearly lost, confirming CDK4/6 specificity. All results in this work indicated that 99mTc-tricine-TPPTS-L is a promising tumor imaging agent that targets CDK4/6.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Hidrazinas/química , Niacinamida/análogos & derivados , Compostos de Organotecnécio/química , Piperazinas/química , Piridinas/química , Compostos Radiofarmacêuticos/química , Neoplasias da Mama/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Humanos , Hidrazinas/farmacologia , Células MCF-7 , Estrutura Molecular , Niacinamida/química , Niacinamida/farmacologia , Compostos de Organotecnécio/síntese química , Compostos de Organotecnécio/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacologia , Relação Estrutura-Atividade , Distribuição Tecidual
20.
Eur J Med Chem ; 188: 111975, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31940507

RESUMO

Local changes in the structure of G-protein coupled receptors (GPCR) binders largely affect their pharmacological profile. While the sought efficacy can be empirically obtained by introducing local modifications, the underlining structural explanation can remain elusive. Here, molecular dynamics (MD) simulations of the eticlopride-bound inactive state of the Dopamine D3 Receptor (D3DR) have been clustered using a machine learning-based approach in the attempt to rationalize the efficacy change in four congeneric modulators. Accumulating extended MD trajectories of receptor-ligand complexes, we observed how the increase in ligand flexibility progressively destabilized the crystal structure of the inactivated receptor. To prospectively validate this model, a partial agonist was rationally designed based on structural insights and computational modeling, and eventually synthesized and tested. Results turned out to be in line with the predictions. This case study suggests that the investigation of ligand flexibility in the framework of extended MD simulations can assist and inform drug design strategies, highlighting its potential role as a powerful in silico counterpart to functional assays.


Assuntos
Carbamatos/metabolismo , Agonistas de Dopamina/metabolismo , Antagonistas de Dopamina/metabolismo , Piperazinas/metabolismo , Receptores de Dopamina D3/metabolismo , Animais , Sítios de Ligação , Células CHO , Carbamatos/química , Cricetulus , Agonistas de Dopamina/química , Antagonistas de Dopamina/química , Desenho de Fármacos , Humanos , Ligantes , Aprendizado de Máquina , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Piperazinas/química , Conformação Proteica , Receptores de Dopamina D3/química , Salicilamidas/metabolismo
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