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1.
Nat Protoc ; 14(10): 2972-2985, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31541227

RESUMO

Although Csp2-Csp2 Suzuki-Miyaura couplings (SMCs) are widely used in small-molecule synthesis, related methods that allow the incorporation of Csp3-hybridized coupling partners, particularly in an asymmetric manner, are less developed. This protocol describes catalytic asymmetric SMC reactions that provide access to enantiomerically enriched cyclic allylic products. The method couples racemic allyl halide starting materials with sp2-hybridized boronic acid derivatives and is compatible with heterocyclic coupling partners. These reactions are catalyzed by a rhodium-ligand complex and typically display very high levels of enantioselectivity (>95% enantiomeric excess (ee)). In this protocol, we detail a procedure using a dihydropyridine-derived allyl chloride for the synthesis of (-)-(S)-tert-butyl-3-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-carboxylate, an intermediate in the synthesis of the anticancer drug niraparib. This procedure affords 1.17 g (86% yield) of the coupling product with 96% ee. The initial experimental setup of the reaction takes 45-50 min, and the reaction is complete within 4-5 h.


Assuntos
Ácidos Borônicos/química , Técnicas de Química Sintética/métodos , Ródio/química , Compostos Alílicos/química , Catálise , Indazóis/síntese química , Piperidinas/síntese química , Estereoisomerismo
2.
Eur J Med Chem ; 182: 111571, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31425908

RESUMO

Anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase, is a therapeutic target in various cancers, including non-small cell lung cancer. Although several ALK inhibitors, including crizotinib, ceritinib, and alectinib, are approved for cancer treatment, their long-term benefit is often limited by the cancer's acquisition of resistance owing to secondary point mutations in ALK. Importantly, some ALK inhibitors cannot cross the blood-brain barrier (BBB) and thus have little or no efficacy against brain metastases. The introduction of a lipophilic moiety, such as a fluoroethyl group may improve the drug's BBB penetration. Herein, we report the synthesis of fluoroethyl analogues of crizotinib 1, alectinib 4, and ceritinib 9, and their radiolabeling with 18F for pharmacokinetic studies. The fluoroethyl derivatives and their radioactive analogues were obtained in good yields with high purity and good molar activity. A cytotoxicity screen in ALK-expressing H2228 lung cancer cells showed that the analogues had up to nanomolar potency and the addition of the fluorinated moiety had minimal impact overall on the potency of the original drugs. Positron emission tomography in healthy mice showed that the analogues had enhanced BBB penetration, suggesting that they have therapeutic potential against central nervous system metastases.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/farmacologia , Carbazóis/farmacologia , Crizotinibe/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfonas/farmacologia , Quinase do Linfoma Anaplásico/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Crizotinibe/síntese química , Crizotinibe/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Radioisótopos de Flúor , Humanos , Camundongos , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Tomografia por Emissão de Pósitrons , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Cintilografia , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química , Distribuição Tecidual
3.
Eur J Med Chem ; 179: 680-693, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31280020

RESUMO

A series of fifteen acetylcholinesterase inhibitors were designed and synthesised based upon the previously identified lead compound 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl 1-benzylpiperidine-4-carboxylate (5) which showed good inhibitory activity (IC50 0.03 ±â€¯0.07 µM) against acetylcholinesterase. A series of compounds were prepared wherein the ester linker in the original lead compound was exchanged for a more metabolically stable amide linker and the indanone moiety was exchanged for a range of aryl and aromatic heterocycles. The two most active analogues 1-benzyl-N-(5,6-dimethoxy-8H-indeno[1,2-d]thiazol-2-yl)piperidine-4-carboxamide (28) and 1-benzyl-N-(1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) piperidine-4-carboxamide (20) afforded in vitro IC50 values of 0.41 ±â€¯1.25 and 5.94 ±â€¯1.08 µM, respectively. In silico screening predicts that 20 will be a blood brain-barrier permeant, and molecular dynamic simulations are indicative of a close correlation between the binding of 20 and the Food and Drug Administration-approved cholinesterase inhibitor donepezil (1).


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Piperidinas/farmacologia , Doença de Alzheimer/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Enguias , Cavalos , Humanos , Modelos Moleculares , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade
4.
Mater Sci Eng C Mater Biol Appl ; 102: 45-52, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31147016

RESUMO

Tyrosinase inhibitors could effectively limit the activity of tyrosinase in melanocytes to reduce the excessive synthesis and deposition of melanin. However, low skin permeability and lacking in targeting greatly restricted their application. Herein, ZnO quantum dots were synthesized by gel-sol method and grafted with BQ-788, which have been employed as transdermal and targeting carrier to delivery ellagic acid to melanocytes. Ellagic acid loaded ZnO quantum dots with the size distribution of around 9 nm could targetedly bind to melanocytes and enter the melanocytes by endocytosis within 1 h. The ellagic acid release behavior was controlled by the decreasing of pH via the rapid dissolution of ZnO. When the concentration of BQ-788/EA@ZnO was 12.5 µg/mL, the inhibition rate on tyrosinase activity and melanin deposition were up to 44.23 ±â€¯4.97% and 37.50 ±â€¯5.23%, respectively. In view of their good biocompatibility, they were of great potential in clinically external application for tyrosinase inhibition.


Assuntos
Ácido Elágico/química , Inibidores Enzimáticos/farmacologia , Melanócitos/enzimologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacologia , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Pontos Quânticos/química , Óxido de Zinco/química , Administração Cutânea , Adulto , Materiais Biocompatíveis/farmacologia , Células Cultivadas , Preparações de Ação Retardada , Sistemas de Liberação de Medicamentos , Endocitose/efeitos dos fármacos , Humanos , Melaninas/metabolismo , Melanócitos/efeitos dos fármacos , Monofenol Mono-Oxigenase/metabolismo , Oligopeptídeos/síntese química , Oligopeptídeos/química , Piperidinas/síntese química , Piperidinas/química , Pontos Quânticos/ultraestrutura , Tirosina/metabolismo , Óxido de Zinco/síntese química
5.
Org Biomol Chem ; 17(25): 6229-6250, 2019 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-31183482

RESUMO

Tautomerism plays a pivotal role in structural stabilization and reactivity. Herein we investigate in detail, aided by DFT simulations, the case of gossypol, a naturally occurring atropisomeric dialdehyde showing promising properties as a male contraceptive and an antineoplasic agent. Its toxicity linked to reactive aldehydo groups can be reduced through amino conjugation. The occurrence of either imino or enamino structures is puzzling indeed and a clear-cut rationale is missing yet. N-enamine-N-enamine structures are prevalent or exclusive tautomers for Schiff bases from gossypol, while their corresponding hydrazones only possess N-imine-N-imine structures both in solution and the solid state. The modification of interactions between the lone pairs on the nitrogen atoms by altering the steric hindrance of the non-iminic nitrogen can favor enamine tautomers. This assumption has now been confirmed and, in the solid state, hydrazones from N-aminopiperidine and their cis-2,6-dimethylderivative present bis-imine and bis-enamine structures, respectively. In solution, these compounds exist in equilibrium between both structures. The tautomerization mechanism, analysis of axial chirality and aromaticity in such H-bonded pseudorings are discussed as well.


Assuntos
Gossipol/análogos & derivados , Gossipol/síntese química , Hidrazonas/síntese química , Piperidinas/química , Bases de Schiff/síntese química , Teoria da Densidade Funcional , Ligações de Hidrogênio , Isomerismo , Modelos Químicos , Conformação Molecular , Piperidinas/síntese química
6.
Eur J Med Chem ; 176: 149-161, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31103896

RESUMO

Plants are vital for the wellbeing of humankind in a variety of ways. Some plant extracts contain antimicrobial properties that can treat different pathogens. Most of the world's population relies on medicinal plants and natural products for their primary health care needs. Therefore, there is a growing interest in natural products, medicinal plants, and traditional medicine along with a desire to design and develop novel plant-based pharmaceuticals. These plant-based pharmaceuticals may address the concerns of reduced efficacy of synthetic antibiotics due to the emergence of drug-resistant pathogens. In this regard, some plant extracts from black pepper (Piper nigrum) with antimicrobial properties, including piperine, have the potential to be used as natural dietary supplements together with modern therapeutic approaches. This review highlights possible applications of piperine as the active compound in the fields of rational drug design and discovery, pharmaceutical chemistry, and biomedicine. We discuss different extraction methods and pharmacological effects of the analyzed substance to pave the way for further research strategies and perspectives towards the development of novel herbal products for better healthcare solutions.


Assuntos
Alcaloides/farmacologia , Benzodioxóis/farmacologia , Piper nigrum/química , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Alcaloides/análise , Alcaloides/síntese química , Alcaloides/isolamento & purificação , Animais , Benzodioxóis/análise , Benzodioxóis/síntese química , Benzodioxóis/isolamento & purificação , Linhagem Celular Tumoral , Humanos , Piperidinas/análise , Piperidinas/síntese química , Piperidinas/isolamento & purificação , Alcamidas Poli-Insaturadas/análise , Alcamidas Poli-Insaturadas/síntese química , Alcamidas Poli-Insaturadas/isolamento & purificação
7.
Cell Mol Neurobiol ; 39(6): 783-797, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31115733

RESUMO

Among gliomas types, glioblastoma is considered the most malignant and the worst form of primary brain tumor. It is characterized by high infiltration rate and great angiogenic capacity. The presence of an inflammatory microenvironment contributes to chemo/radioresistance, resulting in poor prognosis for patients. Recent data show that thiazolidinones have a wide range of pharmacological properties, including anti-inflammatory and antiglioma activities. Nanocapsules of biodegradable polymers become an alternative to cancer treatment since they provide targeted drug delivery and could overcome blood-brain barrier. Therefore, here we investigated the in vitro antiglioma activity and the potential in vivo toxicity of 2- (2-methoxyphenyl) -3- ((piperidin-1-yl) ethyl) thiazolidin-4-one-loaded polymeric nanocapsules (4L-N). Nanocapsules were prepared and characterized in terms of particle size, polydispersity index, zeta potential, pH, molecule content and encapsulation efficiency. Treatment with 4L-N selectively decreased human U138MG and rat C6 cell lines viability and proliferation, being even more efficient than the free-form molecule (4L). In addition, 4L-N did not promote toxicity to primary astrocytes. We further demonstrated that the treatment with sub-therapeutic dose of 4L-N did not alter weight, neither resulted in mortality, toxicity or peripheral damage to Wistar rats. Finally, 4L as well as 4L-N did not alter makers of oxidative damage, such as TBARS levels and total sulfhydryl content, and did not change antioxidant enzymes SOD and CAT activity in liver and brain of treated rats. Taken together, these data indicate that the nanoencapsulation of 4L has potentiated its antiglioma effect and does not cause in vivo toxicity.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Nanocápsulas/química , Piperidinas/toxicidade , Piperidinas/uso terapêutico , Polímeros/química , Tiazolidinas/toxicidade , Tiazolidinas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Biomarcadores Tumorais/sangue , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Glioma/sangue , Glioma/patologia , Humanos , Luz , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/síntese química , Piperidinas/química , Polímeros/síntese química , Ratos Wistar , Tiazolidinas/síntese química , Tiazolidinas/química , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Testes de Toxicidade , Perda de Peso/efeitos dos fármacos
8.
Amino Acids ; 51(7): 991-998, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31079215

RESUMO

DMDP acetic acid [N-carboxymethyl-2,5-dideoxy-2,5-imino-D-mannitol] 5 from Stevia rebaudiana is the first isolated natural amino acid derived from iminosugars bearing an N-alkyl acid side chain; it is clear from GCMS studies that such derivatives with acetic and propionic acids are common in a broad range of plants including mulberry, Baphia, and English bluebells, but that they are very difficult to purify. Reaction of unprotected pyrrolidine iminosugars with aqueous glyoxal gives the corresponding N-acetic acids in very high yield; Michael addition of both pyrrolidine and piperidine iminosugars and that of polyhydroxylated prolines to tert-butyl acrylate give the corresponding N-propionic acids in which the amino group of ß-alanine is incorporated into the heterocyclic ring. These easy syntheses allow the identification of this new class of amino acid in plant extracts and provide pure samples for biological evaluation. DMDP N-acetic and propionic acids are potent α-galactosidase inhibitors in contrast to potent ß-galactosidase inhibition by DMDP.


Assuntos
Acetatos/síntese química , Aminoácidos/química , Glicosídeo Hidrolases/antagonistas & inibidores , Imino Açúcares/isolamento & purificação , Propionatos/síntese química , Pirrolidinas/síntese química , Stevia/química , Aminoácidos/síntese química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Glicina/química , Glicosídeos/metabolismo , Hidroxiprolina/química , Imino Açúcares/química , Piperidinas/síntese química , alfa-Galactosidase/antagonistas & inibidores , beta-Alanina/química , beta-Galactosidase/antagonistas & inibidores
9.
Bull Exp Biol Med ; 166(6): 779-784, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31028582

RESUMO

The cytotoxicity and antioxidant effects of chitosan-(poly)nitoxides of different molecular weights containing a nitroxide radical of the piperidine structure were studied on tumor (HeLa, A172, and HepG2) and normal (Vero) cell lines. The chitosan-(poly)nitroxides exhibited low cytotoxicity. Under conditions of oxidative stress induced with tert-butyl hydroperoxide, the most pronounced decrease in ROS levels in the presence of chitosan-(poly)nitroxides was observed in normal cells. In cell homogenates, the decrease in malondialdehyde levels was observed only in the presence of low-molecular-weight chitosan-(poly)nitroxide irrespective of the cell line. Our data demonstrate that the cell-specific antioxidant properties of chitosan-(poly)nitroxides are related to their penetration into cells and interaction with intracellular membranes.


Assuntos
Antioxidantes/farmacologia , Quitosana/farmacologia , Óxidos de Nitrogênio/química , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/farmacologia , Animais , Antioxidantes/síntese química , Linhagem Celular Tumoral , Quitosana/análogos & derivados , Quitosana/síntese química , Células HeLa , Células Hep G2 , Humanos , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neuroglia/patologia , Especificidade de Órgãos , Piperidinas/síntese química , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Células Vero , terc-Butil Hidroperóxido/antagonistas & inibidores , terc-Butil Hidroperóxido/farmacologia
10.
Chem Pharm Bull (Tokyo) ; 67(3): 253-257, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30828001

RESUMO

The plant alkaloids, iso-6-spectaline and spectaline, isolated from the Cassia or Senna genera contain a characteristic 2,6-disubstituted piperidin-3-ol scaffold. Although both natural products are reported to exhibit a variety of interesting biological activities, few stereo-selective schemes for the construction of the 2,6-disubstituted scaffold have been reported. Following our previous studies regarding the synthesis of (+)-spectaline, herein we report the first convergent synthesis of (-)-iso-6-spectaline using a cross-metathesis under thermal conditions where the cis-2,6-disubstituted piperidin-3-ol scaffold is condensed with a long alkyl chain containing a terminal olefin. The cis-2,6-disubstituted piperidin-3-ol used in the synthesis was prepared simply via Pd(II)-catalyzed diastereoselective cyclization. It was confirmed that (+)-spectaline, an epimer of (-)-iso-6-spectaline, was selectively synthesized by the cross-metathesis reaction under less intense thermal conditions starting from the same cis-2,6-disubstituted piperidin-3-ol derivative.


Assuntos
Paládio/química , Piperidinas/síntese química , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Catálise , Cromatografia Líquida , Ciclização , Espectrometria de Massas , Testes de Sensibilidade Microbiana , Piperidinas/química , Piperidinas/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Staphylococcus epidermidis/efeitos dos fármacos , Relação Estrutura-Atividade , Termodinâmica
11.
Biosci Trends ; 13(1): 91-97, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30867374

RESUMO

In epigenetics, histone deacetylases (HDACs) are well validated targets for the development of anticancer drugs. In this work, we reported the design and synthesis of a series of twenty two novel (E)-N-hydroxycinnamamide-based HDAC inhibitors with 4-aminopiperidine1-carboxamide as the core structure. Most newly synthesized compounds displayed high inhibition rates toward HDAC at the concentration of 1 µM. Among them, the inhibition rates of compounds LYP-2, LYP-3, LYP-6, and LYP-15 were more than 75%. Furthermore, compounds LYP-2, LYP-3, and LYP-6 potently inhibited the activity of HDAC6 with selectivity over HDAC1. We chose LYP-2 and LYP-6 to test its antiproliferative effect on breast cancer cells MCF-7. Either LYP-2 or LYP-6 alone moderately suppressed the cell growth, but could synergistically enhance the inhibitory effect of bortezomib. These results suggested that combined HDAC6 inhibitor and bortezomib regimen might be an option for breast cancer treatment.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Bortezomib/farmacologia , Ácidos Cumáricos/farmacologia , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Piperidinas/farmacologia , Amidas/síntese química , Antineoplásicos/síntese química , Ácidos Cumáricos/síntese química , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Inibidores de Histona Desacetilases/síntese química , Humanos , Células MCF-7 , Piperidinas/síntese química
12.
ACS Appl Mater Interfaces ; 11(14): 13158-13167, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30901194

RESUMO

Photosensitizer is one of the most important elements of photodynamic therapy (PDT). Herein, we reported a novel strategy to prepare a new series of composite photosensitizers. The composite photosensitizer was prepared by simply mixing DNA G-quadruplexes with a hydrophilic porphyrin (TMPipEOPP)4+·4I-. Compared with the conventional porphyrin photosensitizers, the excitation wavelength of the composite one has been ∼50 nm redshifted (from 650 to 700 nm), which is beneficial to the penetration of the light. Moreover, the composite photosensitizer showed an about 7.4-fold increase of light absorption efficiency, thus greatly enhancing the singlet oxygen (1O2) generation capacity and PDT efficacy. What is more, the introduction of nucleic acids in the composite photosensitizer could also provide some extra charming properties, such as the targeted recognition ability conferred by aptamer and high capability to assemble with various drug carriers. We demonstrated that the composite photosensitizer could be easily assembled with MnO2 nanosheet. The obtained nanodevice integrated the merits of a composite photosensitizer and MnO2 nanosheet, thus showing strong near-infrared absorption, high 1O2 generation efficiency, avoidance of nonideal 1O2 consumption by glutathione, and in situ O2 generation to relieve tumor hypoxia. This nanodevice showed greatly improved PDT efficacy both in vitro and in vivo, presenting a huge potential for applications in clinical therapy for tumors.


Assuntos
Quadruplex G , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Piperidinas/química , Porfirinas/química , Portadores de Fármacos/química , Glutationa/química , Glutationa/metabolismo , Humanos , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/uso terapêutico , Piperidinas/síntese química , Piperidinas/uso terapêutico , Porfirinas/síntese química , Porfirinas/uso terapêutico , Oxigênio Singlete/química
13.
Bioorg Med Chem ; 27(6): 931-943, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30765302

RESUMO

Acetylcholinesterase (AChE) is the key enzyme targeted in Alzheimer's disease (AD) therapy, nevertheless butyrylcholinesterase (BuChE) has been drawing attention due to its role in the disease progression. Thus, we aimed to synthesize novel cholinesterases inhibitors considering structural differences in their peripheral site, exploiting a moiety replacement approach based on the potent and selective hAChE drug donepezil. Hence, two small series of N-benzylpiperidine based compounds have successfully been synthesized as novel potent and selective hBuChE inhibitors. The most promising compounds (9 and 11) were not cytotoxic and their kinetic study accounted for dual binding site mode of interaction, which is in agreement with further docking and molecular dynamics studies. Therefore, this study demonstrates how our strategy enabled the discovery of novel promising and privileged structures. Remarkably, compound 11 proved to be one of the most potent (0.17 nM) and selective (>58,000-fold) hBuChE inhibitor ever reported.


Assuntos
Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Inibidores da Colinesterase/síntese química , Química Click , Desenho de Drogas , Descoberta de Drogas , Humanos , Simulação de Acoplamento Molecular , Piperidinas/síntese química , Relação Estrutura-Atividade
14.
Eur J Med Chem ; 167: 510-524, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30784883

RESUMO

The multitarget-directed strategy offers an effective and promising paradigm to treat the complex neurodegenerative disorder, such as Alzheimer's disease (AD). Herein, a series of N-benzylpiperidine analogs (17-31 and 32-46) were designed and synthesized as multi-functional inhibitors of acetylcholinesterase (AChE) and ß-secretase-1 (BACE-1) with moderate to excellent inhibitory activities. Among the tested inhibitors, 25, 26, 40, and 41 presented the most significant and balanced inhibition against both the targets. Compounds 40 and 41 exhibited high brain permeability in the PAMPA-BBB assay, significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE, and were devoid of neurotoxicity towards SH-SY5Y neuroblastoma cell lines up to the maximum tested concentration of 80 µM. Meanwhile, both these compounds inhibited self- and AChE-induced Aß aggregation in thioflavin T assay, which was also re-affirmed by morphological characterization of Aß aggregates using atomic force microscopy (AFM). Moreover, 40 and 41 ameliorated the scopolamine-induced cognitive impairment in elevated plus and Y-maze experiments. Ex vivo and biochemical analysis established the brain AChE inhibitory potential and antioxidant properties of these compounds. Further, improvement in Aß1-42-induced cognitive impairment was also observed by compound 41 in the Morris water maze experiment with significant oral absorption characteristics ascertained by the pharmacokinetic studies.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores da Colinesterase/síntese química , Desenho de Drogas , Piperidinas/farmacologia , Doença de Alzheimer/enzimologia , Doença de Alzheimer/psicologia , Animais , Barreira Hematoencefálica/metabolismo , Linhagem Celular Tumoral , Inibidores da Colinesterase/farmacologia , Disfunção Cognitiva , Humanos , Camundongos , Piperidinas/síntese química , Agregação Patológica de Proteínas/tratamento farmacológico , Relação Estrutura-Atividade
15.
Bioorg Med Chem ; 27(4): 604-619, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30638966

RESUMO

5-Lipoxygenase (5-LOX) is a key enzyme involved in the biosynthesis of pro-inflammatory leukotrienes, leading to asthma. Developing potent 5-LOX inhibitors especially, natural product based ones, are highly attractive. Coumaperine, a natural product found in white pepper and its derivatives were herein developed as 5-LOX inhibitors. We have synthesized twenty four derivatives, characterized and evaluated their 5-LOX inhibition potential. Coumaperine derivatives substituted with multiple hydroxy and multiple methoxy groups exhibited best 5-LOX inhibition. CP-209, a catechol type dihydroxyl derivative and CP-262-F2, a vicinal trihydroxyl derivative exhibited, 82.7% and 82.5% inhibition of 5-LOX respectively at 20 µM. Their IC50 values are 2.1 ±â€¯0.2 µM and 2.3 ±â€¯0.2 µM respectively, and are comparable to zileuton, IC50 = 1.4 ±â€¯0.2 µM. CP-155, a methylenedioxy derivative (a natural product) and CP-194, a 2,4,6-trimethoxy derivative showed 76.0% and 77.1% inhibition of 5-LOX respectively at 20 µM. Antioxidant study revealed that CP-209 and 262-F2 (at 20 µM) scavenged DPPH radical by 76.8% and 71.3% respectively. On the other hand, CP-155 and 194 showed very poor DPPH radical scavenging activity. Pseudo peroxidase assay confirmed that the mode of action of CP-209 and 262-F2 were by redox process, similar to zileuton, affecting the oxidation state of the metal ion in the enzyme. On the contrary, CP-155 and 194 probably act through some other mechanism which does not involve the disruption of the oxidation state of the metal in the enzyme. Molecular docking of CP-155 and 194 to the active site of 5-LOX and binding energy calculation suggested that they are non-competitive inhibitors. The In-Silico ADME/TOX analysis shows the active compounds (CP-155, 194, 209 and 262-F2) are with good drug likeliness and reduced toxicity compared to existing drug. These studies indicate that there is a great potential for coumaperine derivatives to be developed as anti-inflammatory drug.


Assuntos
Antioxidantes/farmacologia , Araquidonato 5-Lipoxigenase/metabolismo , Inibidores de Lipoxigenase/farmacologia , Piperidinas/farmacologia , Antioxidantes/síntese química , Antioxidantes/farmacocinética , Araquidonato 5-Lipoxigenase/química , Domínio Catalítico , Desenho de Drogas , Ensaios Enzimáticos , Humanos , Hidroxiureia/análogos & derivados , Hidroxiureia/farmacologia , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/farmacocinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Peroxidases/química , Piperidinas/síntese química , Piperidinas/farmacocinética , Relação Estrutura-Atividade
16.
ACS Comb Sci ; 21(1): 1-5, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30485058

RESUMO

We present the solid-phase synthesis of 1,2-dihydroquinazoline-2-carboxylate derivatives with a quaternary carbon in position 2 and their subsequent cyclization in solution into compounds with unique 3D architectures and pharmacological relevance-spiroquinazolines, namely, 1' H-spiro[pyrrolidine-3,2'-quinazolin]-2-ones and 1' H-spiro[piperidine-3,2'-quinazolin]-2-ones. Acyclic precursors were prepared from commercially available building blocks: protected amino acids (2,4-diaminobutyric acid and ornithine), 2-nitrobenzensulfonyl chlorides and α-bromoacetophenones. The crucial step of the synthesis was a base-mediated tandem reaction including C-arylation followed by cyclization into indazole oxides, and the formation of a 5-membered heterocycle was accomplished by ring expansion into quinazolines. These derivatives were cyclized into spiro compounds in solution after cleavage from the resin.


Assuntos
Piperidinas/síntese química , Pirrolidinas/síntese química , Quinazolinas/síntese química , Técnicas de Síntese em Fase Sólida/métodos , Compostos de Espiro/síntese química , Acetofenonas/química , Aminobutiratos/química , Ciclização , Nitrobenzenos/química , Ornitina/química
17.
Bioorg Med Chem ; 27(1): 55-64, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30446439

RESUMO

Monoacylglycerol lipase (MGL) inhibition provides a potential treatment approach to glaucoma through the regulation of ocular 2-arachidonoylglycerol (2-AG) levels and the activation of CB1 receptors. Herein, we report the discovery of new series of carbamates as highly potent and selective MGL inhibitors. The new inhibitors showed potent nanomolar inhibitory activity against recombinant human and purified rat MGL, were selective (>1000-fold) against serine hydrolases FAAH and ABHD6 and lacked any affinity for the cannabinoid receptors CB1 and CB2. Protein-based 1H NMR experiments indicated that inhibitor 2 rapidly formed a covalent adduct with MGL with a residence time of about 6 h. This interconversion process "intrinsic reversibility" was exploited by modifications of the ligand's size (length and bulkiness) to generate analogs with "tunable' adduct residence time (τ). Inhibitor 2 was evaluated in a normotensive murine model for assessing intraocular pressure (IOP), which could lead to glaucoma, a major cause of blindness. Inhibitor 2 was found to decrease ocular pressure by ∼4.5 mmHg in a sustained manner for at least 12 h after a single ocular application, underscoring the potential for topically-administered MGL inhibitors as a novel therapeutic target for the treatment of glaucoma.


Assuntos
Carbamatos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Glaucoma/tratamento farmacológico , Monoacilglicerol Lipases/antagonistas & inibidores , Animais , Carbamatos/síntese química , Carbamatos/química , Carbamatos/farmacocinética , Domínio Catalítico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Masculino , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Monoacilglicerol Lipases/química , Piperazinas/síntese química , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Ratos , Relação Estrutura-Atividade
18.
Bioorg Med Chem ; 27(1): 65-78, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30502115

RESUMO

The Aurora kinases are a family of serine/threonine kinases that interact with components of the mitotic apparatus and serve as potential therapeutic targets in oncology. Herein, we reported a series of 2,4-bisanilinopyrimidines bearing 2,2,6,6-tetramethylpiperidine-N-oxyl with selective inhibition of Aurora A in either enzymatic assays or cellular phenotypic assays, and displaying more potent anti-proliferation compared with that of VX-680. The most potent compound 10a forms better interaction with Aurora A than Aurora B in molecular docking. Mechanistic studies revealed that 10a disrupt the spindle formation, block the cell cycle progression in the G2/M phase and induce apoptosis in HeLa cell. These results suggested that the produced series of compounds are potential anticancer agents for further development as selective Aurora A inhibitors.


Assuntos
Compostos de Anilina/farmacologia , Óxidos N-Cíclicos/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Compostos de Anilina/síntese química , Compostos de Anilina/química , Apoptose/efeitos dos fármacos , Aurora Quinase A/química , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Óxidos N-Cíclicos/síntese química , Óxidos N-Cíclicos/química , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Piperidinas/síntese química , Piperidinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Fuso Acromático/efeitos dos fármacos
19.
Bioorg Chem ; 83: 242-249, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30390553

RESUMO

Poly(ADP-ribose)polymerase-1 inhibitor (PARPi) AZD2461 was designed to be a weak P-glycoprotein (P-gp) analogue of FDA approved olaparib. With this chemical property in mind, we utilized the AZD2461 ligand architecture to develop a CNS penetrant and PARP-1 selective imaging probe, in order to investigate PARP-1 mediated neuroinflammation and neurodegenerative diseases, such as Alzheimer's and Parkinson's. Our work led to the identification of several high-affinity PARPi, including AZD2461 congener 9e (PARP-1 IC50 = 3.9 ±â€¯1.2 nM), which was further evaluated as a potential 18F-PET brain imaging probe. However, despite the similar molecular scaffolds of 9e and AZD2461, our studies revealed non-appreciable brain-uptake of [18F]9e in non-human primates, suggesting AZD2461 to be non-CNS penetrant.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Ftalazinas/farmacologia , Piperidinas/farmacologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/agonistas , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Radioisótopos de Flúor/química , Humanos , Macaca mulatta , Masculino , Camundongos Endogâmicos BALB C , Ftalazinas/síntese química , Piperidinas/síntese química
20.
Chem Commun (Camb) ; 55(3): 369-372, 2019 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-30540295
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