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1.
J Med Chem ; 63(13): 7143-7162, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32551607

RESUMO

Two chemical series of novel protein kinase C ζ (PKCζ) inhibitors, 4,6-disubstituted and 5,7-disubstituted isoquinolines, were rapidly identified using our fragment merging strategy. This methodology involves biochemical screening of a high concentration of a monosubstituted isoquinoline fragment library, then merging hit isoquinoline fragments into a single compound. Our strategy can be applied to the discovery of other challenging kinase inhibitors without protein-ligand structural information. Furthermore, our optimization effort identified the highly potent and orally available 5,7-isoquinoline 37 from the second chemical series. Compound 37 showed good efficacy in a mouse collagen-induced arthritis model. The in vivo studies suggest that PKCζ inhibition is a novel target for rheumatoid arthritis (RA) and that 5,7-disubstituted isoquinoline 37 has the potential to elucidate the biological consequences of PKCζ inhibition, specifically in terms of therapeutic intervention for RA.


Assuntos
Desenho de Fármacos , Isoquinolinas/química , Isoquinolinas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Animais , Isoquinolinas/farmacocinética , Ligantes , Camundongos , Modelos Moleculares , Conformação Proteica , Proteína Quinase C/química , Inibidores de Proteínas Quinases/farmacocinética , Relação Estrutura-Atividade , Distribuição Tecidual
2.
Alkaloids Chem Biol ; 84: 125-199, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32416952

RESUMO

The jadomycins are an expanding class of compounds produced from Streptomyces venezuelae, by diverting the normal biosynthesis which provides the antibiotic chloramphenicol. In the presence of amino acids, and either by heat shock, supplementation with ethanol, or when phage SV1 is added to the culture, the formation of substituted jadomycins and benzo[b]phenanthridines can be achieved. The first part of this review provides details of intermediates involved in the biosynthesis of the jadomycins and the related benzo[b]phenanthridines. Both the jadomycins and the benzo[b]phenanthridines share biosynthetic pathways with a large class of naturally occurring compounds known as the angucyclines. The biosynthetic pathways diverge when it is postulated that an intermediate quinone, such as 3-(2-formyl-6-hydroxy-4-methylphenyl)-8-hydroxy-1,4-naphthoquinone-2-carboxylic acid is formed. The quinone then undergoes reactions with amino acids and derivatives in the culture medium to ultimately afford a library of jadomycins and a few benzo[b]phenanthridines. The second part of the review initially details synthetic efforts toward the synthesis of the naturally occurring benzo[b]phenanthridine, phenanthroviridin, and then outlines methods that have been used to assemble a selection of jadomycins. Total syntheses of jadomycin A and B, derived from l-isoleucine, are described. In addition, the synthesis of the aglycon of jadomycins M, W, S, and T is outlined. These four jadomycins were derived from l-methionine, l-tryptophan, l-serine and l-threonine respectively. As a result of these synthetic efforts, the structures of jadomycin S and T have been revised. The third part of the review describes the reported antibacterial and anticancer activities of both the jadomycins and some naturally occurring benzo[b]phenanthridines.


Assuntos
Alcaloides/farmacologia , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Alcaloides/biossíntese , Alcaloides/química , Antibacterianos/biossíntese , Antibacterianos/química , Antifúngicos/química , Antifúngicos/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Bactérias/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Humanos , Isoquinolinas/química , Isoquinolinas/metabolismo , Isoquinolinas/farmacologia , Naftoquinonas/química , Naftoquinonas/metabolismo , Naftoquinonas/farmacologia , Fenantridinas/química , Fenantridinas/metabolismo , Fenantridinas/farmacologia
3.
Eur J Med Chem ; 200: 112415, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32454229

RESUMO

As simple analogues of the natural compound chelerythrine, a novel anti-cholinesterase 2-phenylisoquinolin-2-ium scaffold was designed by structure imitation. The activity evaluation led to the discovery of seven compounds with potent anti-acetylcholinesterase activity with IC50 values of ≤0.72 µM, superior to chelerythrine and standard drugs galantamine. Particularly, compound 8y showed the excellent dual acetylcholinesterase-butyrylcholinesterase inhibition activity, superior to rivastigmine, a dual cholinesterase inhibitor drug. Furthermore, the compounds displayed a competitive anti-acetylcholinesterase mechanism with the substrate and low cytotoxicity. Molecular docking showed that the isoquinoline moiety is embedded in a cavity surrounded by four aromatic residues of acetylcholinesterase by the π-π action. Structure-activity relationship showed that the p-substituents on the C-ring can dramatically improve the anti-acetylcholinesterase activity, while 8-OMe can increase the activity against the two cholinesterases simultaneously. Thus, the title compounds emerged as promising lead compounds for the development of novel cholinesterase inhibitor agents.


Assuntos
Benzofenantridinas/química , Inibidores da Colinesterase/química , Descoberta de Drogas , Sítios de Ligação , Butirilcolinesterase , Inibidores da Colinesterase/metabolismo , Humanos , Concentração Inibidora 50 , Isoquinolinas/química , Isoquinolinas/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
4.
Colloids Surf B Biointerfaces ; 191: 111003, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32276211

RESUMO

The increasing prevalence of fungal infections coupled with emerging drug resistance has stimulated an urgent need to explore new and effective antifungal agents. Sanguinarine and chelerythrine constitute alkaloids that have exhibited antifungal activities. However, the effects of a 1:1 mixture of these agents against Candida albicans and Cryptococcus neoformans have remained largely unexplored. The purpose of this study was to assess the anti-fungal and anti-biofilm efficacy of combined chelerythrine-sanguinarine against C. albicans and C. neoformans in vitro. Combined chelerythrine-sanguinarine inhibited C. albicans and C. neoformans growth with minimum inhibitory concentrations (MICs) of 2 and 16 µg/mL, respectively, and effectively inhibited adhesion and biofilm formation of these pathogens at minimum biofilm inhibitory concentrations of 1 and 8 µg/mL. Notably, the mixture significantly eradicated mature C. albicans and C. neoformans biofilms at 8 and 128 µg/mL, respectively. In particular, the mixture was found to disrupt cell membrane integrity and enhance penetration of antibiotics into fungal cells, suggesting its antifungal mode of action. Hence, combined chelerythrine-sanguinarine shows promise as a potential anti-fungal and anti-biofilm agent for the management of serious infections caused by C. albicans and C. neoformans.


Assuntos
Antifúngicos/farmacologia , Benzofenantridinas/farmacologia , Biofilmes/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Isoquinolinas/farmacologia , Antifúngicos/química , Benzofenantridinas/química , Isoquinolinas/química , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Propriedades de Superfície
5.
Molecules ; 25(7)2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32290229

RESUMO

Cancers are the leading cause of deaths worldwide. In 2018, an estimated 18.1 million new cancer cases and 9.6 million cancer-related deaths occurred globally. Several previous studies have shown that the enzyme, leucine aminopeptidase is involved in pathological conditions such as cancer. On the basis of the knowledge that isoquinoline alkaloids have antiproliferative activity and inhibitory activity towards leucine aminopeptidase, the present study was conducted a study which involved database search, virtual screening, and design of new potential leucine aminopeptidase inhibitors with a scaffold based on 3,4-dihydroisoquinoline. These compounds were then filtered through Lipinski's "rule of five," and 25 081 of them were then subjected to molecular docking. Next, three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed for the selected group of compounds with the best binding score results. The developed model, calculated by leave-one-out method, showed acceptable predictive and descriptive capability as represented by standard statistical parameters r2 (0.997) and q2 (0.717). Further, 35 compounds were identified to have an excellent predictive reliability. Finally, nine selected compounds were evaluated for drug-likeness and different pharmacokinetics parameters such as absorption, distribution, metabolism, excretion, and toxicity. Our methodology suggested that compounds with 3,4-dihydroisoquinoline moiety were potentially active in inhibiting leucine aminopeptidase and could be used for further in-depth in vitro and in vivo studies.


Assuntos
Isoquinolinas/química , Leucil Aminopeptidase/química , Modelos Moleculares , Inibidores de Proteases/química , Relação Quantitativa Estrutura-Atividade , Desenho de Fármacos , Humanos , Leucil Aminopeptidase/antagonistas & inibidores , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Inibidores de Proteases/farmacologia , Reprodutibilidade dos Testes
6.
Int J Mol Sci ; 21(7)2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32230861

RESUMO

Eleven novel isoquinoline-1-carboxamides (HSR1101~1111) were synthesized and evaluated for their effects on lipopolysaccharide (LPS)-induced production of pro-inflammatory mediators and cell migration in BV2 microglial cells. Three compounds (HSR1101~1103) exhibited the most potent suppression of LPS-induced pro-inflammatory mediators, including interleukin (IL)-6, tumor necrosis factor-alpha, and nitric oxide (NO), without significant cytotoxicity. Among them, only N-(2-hydroxyphenyl) isoquinoline-1-carboxamide (HSR1101) was found to reverse LPS-suppressed anti-inflammatory cytokine IL-10, so it was selected for further characterization. HSR1101 attenuated LPS-induced expression of inducible NO synthase and cyclooxygenase-2. Particularly, HSR1101 abated LPS-induced nuclear translocation of NF-κB through inhibition of IκB phosphorylation. Furthermore, HSR1101 inhibited LPS-induced cell migration and phosphorylation of mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 MAPK. The specific MAPK inhibitors, U0126, SP600125, and SB203580, suppressed LPS-stimulated pro-inflammatory mediators, cell migration, and NF-κB nuclear translocation, indicating that MAPKs may be the upstream kinase of NF-κB signaling. Collectively, these results demonstrate that HSR1101 is a potent and promising compound suppressing LPS-induced inflammation and cell migration in BV2 microglial cells, and that inhibition of the MAPKs/NF-κB pathway mediates its anti-inflammatory and anti-migratory effects. Based on our findings, HSR1101 may have beneficial impacts on various neurodegenerative disorders associated with neuroinflammation and microglial activation.


Assuntos
Anti-Inflamatórios/farmacologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Animais , Anti-Inflamatórios/química , Movimento Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Concentração Inibidora 50 , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Isoquinolinas/química , Isoquinolinas/farmacologia , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Doenças Neurodegenerativas/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Cicatrização/efeitos dos fármacos
7.
J Med Chem ; 63(10): 5458-5476, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32329342

RESUMO

SIS3 is a specific inhibitor of Smad3 that inhibits the TGFß1-induced phosphorylation of Smad3. In this article, a variety of SIS3 derivatives were designed and synthesized to discover potential inhibitors against P-glycoprotein-mediated multidrug resistance aided by late-stage functionalization of a 2-(4-(pyridin-2-yl)phenoxy)pyridine analogue. A novel class of potent P-gp reversal agents were investigated, and a lead compound 37 was identified as a potent P-gp reversal agent with strong bioactivity and outstanding affinity for P-gp.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Descoberta de Drogas/métodos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Isoquinolinas/química , Isoquinolinas/farmacologia , Piridinas/química , Piridinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Resistência a Múltiplos Medicamentos/fisiologia , Humanos , Isoquinolinas/metabolismo , Células K562 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular/métodos , Piridinas/metabolismo , Pirróis/metabolismo , Proteína Smad3/antagonistas & inibidores , Proteína Smad3/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
8.
Spectrochim Acta A Mol Biomol Spectrosc ; 234: 118261, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32213458

RESUMO

Encapsulation of a persuasive anticancer drug (Sanguinarine, SGR) within microheterogeneous environment of niosome has been investigated. Utilizing steady-state and time-resolved spectroscopic methods the effects of extrinsically added salts and temperature on the photophysical properties of niosome-bound bio-active drug have been explored thoroughly. The prototropic (alkanolamine⇌ iminium) equilibrium of SGR is found to be preferentially favored toward the neutral form inside the hydrophobic interior of niosome. With addition of salts and increment of temperature the reverse tendency of stabilization of the cationic species is observed which can be explained on the basis of degree of water penetration of water molecules to the hydration layer of niosome. Furthermore, drug sequestration has been investigated via disruption of niosome applying cyclodextrins (CDs). Exploration of the effect of CDs (ß-CD and γ-CD) on the niosome aids to have knowledge of the effect of CDs on cell membrane. In addition, the differential rotational relaxation behavior of SGR at various environmental circumstances has been observed to substantiate with other experimental results.


Assuntos
Antineoplásicos/farmacologia , Ciclodextrinas/química , Sais/química , Temperatura , Benzofenantridinas/química , Difusão Dinâmica da Luz , Isoquinolinas/química , Lipossomos , Tamanho da Partícula , Rotação , Espectrometria de Fluorescência , Tensoativos/química , Fatores de Tempo
9.
Nat Chem ; 12(4): 399-404, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32123338

RESUMO

Site-selective functionalization of C-H bonds will ultimately afford chemists transformative tools for editing and constructing complex molecular architectures. Towards this goal, it is essential to develop strategies to activate C-H bonds that are distal from a functional group. In this context, distinguishing remote C-H bonds on adjacent carbon atoms is an extraordinary challenge due to the lack of electronic or steric bias between the two positions. Herein, we report the design of a catalytic system leveraging a remote directing template and a transient norbornene mediator to selectively activate a previously inaccessible remote C-H bond that is one bond further away. The generality of this approach has been demonstrated with a range of heterocycles, including a complex anti-leukaemia agent and hydrocinnamic acid substrates.


Assuntos
Carbono/química , Hidrogênio/química , Isoquinolinas/química , Quinolinas/química , Catálise , Complexos de Coordenação/química , Estrutura Molecular , Norbornanos/química , Paládio/química
10.
Appl Environ Microbiol ; 86(8)2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32033956

RESUMO

The recently characterized strain Pseudomonas orientalis F9, an isolate from apple flowers in a Swiss orchard, exhibits antagonistic traits against phytopathogens. At high colonization densities, it exhibits phytotoxicity against apple flowers. P. orientalis F9 harbors biosynthesis genes for the siderophore pyoverdine as well as for the antibiotics safracin and phenazine. To elucidate the role of the three compounds in biocontrol, we screened a large random knockout library of P. orientalis F9 strains for lack of pyoverdine production or in vitro antagonism. Transposon mutants that lacked the ability for fluorescence carried transposons in pyoverdine production genes. Mutants unable to antagonize Erwinia amylovora in an in vitro double-layer assay carried transposon insertions in the safracin gene cluster. As no phenazine transposon mutant could be identified using the chosen selection criteria, we constructed a site-directed deletion mutant. Pyoverdine-, safracin-, and phenazine mutants were tested for their abilities to counteract the fire blight pathogen Erwinia amylovora ex vivo on apple flowers or the soilborne pathogen Pythium ultimum in vivo in a soil microcosm. In contrast to some in vitro assays, ex vivo and in vivo assays did not reveal significant differences between parental and mutant strains in their antagonistic activities. This suggests that, ex vivo and in vivo, other factors, such as competition for resources or space, are more important than the tested antibiotics or pyoverdine for successful antagonism of P. orientalis F9 against phytopathogens in the performed assays.IMPORTANCE Pseudomonas orientalis F9 is an antagonist of the economically important phytopathogen Erwinia amylovora, the causal agent of fire blight in pomme fruit. On King's B medium, P. orientalis F9 produces a pyoverdine siderophore and the antibiotic safracin. P. orientalis F9 transposon mutants lacking these factors fail to antagonize E. amylovora, depending on the in vitro assay. On isolated flowers and in soil microcosms, however, pyoverdine, safracin, and phenazine mutants control phytopathogens as clearly as their parental strains.


Assuntos
Agentes de Controle Biológico/química , Erwinia amylovora/fisiologia , Malus/microbiologia , Doenças das Plantas/prevenção & controle , Pseudomonas/química , Flores/microbiologia , Isoquinolinas/química , Oligopeptídeos/química , Fenazinas/química , Doenças das Plantas/microbiologia , Pseudomonas/genética
11.
Molecules ; 25(3)2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32028607

RESUMO

Accumulation of ß-amyloid (Aß) in the brain has been implicated in the pathology of Alzheimer's disease (AD). Aß is produced from the Aß precursor protein (APP) through the amyloidogenic pathway by ß-, and γ-secretase. Alternatively, APP can be cleaved by α-, and γ-secretase, precluding the production of Aß. Thus, stimulating α-secretase mediated APP processing is considered a therapeutic option not only for decreasing Aß production but for increasing neuroprotective sAPPα. We have previously reported that 7-deoxy-trans-dihydronarciclasine (E144), the active component of Lycoris chejuensis, decreases Aß production by attenuating APP level, and retarding APP maturation. It can also improve cognitive function in the AD model mouse. In this study, we further analyzed the activating effect of E144 on α-secretase. Treatment of E144 increased sAPPα, but decreased ß-secretase products from HeLa cells stably transfected with APP. E144 directly activated ADAM10 and ADAM17 in a substrate-specific manner both in cell-based and in cell-free assays. The Lineweaver-Burk plot analysis revealed that E144 enhanced the affinities of A Disintegrin and Metalloproteinases (ADAMs) towards the substrate. Consistent with this result, immunoprecipitation analysis showed that interactions of APP with ADAM10 and ADAM17 were increased by E144. Our results indicate that E144 might be a novel agent for AD treatment as a substrate-specific activator of α-secretase.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Isoquinolinas/farmacologia , Proteína ADAM10/antagonistas & inibidores , Proteína ADAM10/metabolismo , Proteína ADAM17/antagonistas & inibidores , Proteína ADAM17/metabolismo , Ativação Enzimática , Humanos , Isoquinolinas/química , Estrutura Molecular , Ligação Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Especificidade por Substrato
12.
J Enzyme Inhib Med Chem ; 35(1): 478-488, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31910701

RESUMO

The series of symmetrical and unsymmetrical isoquinolinium-5-carbaldoximes was designed and prepared for cholinesterase reactivation purposes. The novel compounds were evaluated for intrinsic acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) inhibition, when the majority of novel compounds resulted with high inhibition of both enzymes and only weak inhibitors were selected for reactivation experiments on human AChE or BChE inhibited by sarin, VX, or paraoxon. The AChE reactivation for all used organophosphates was found negligible if compared to the reactivation ability of obidoxime. Importantly, two compounds were found to reactivate BChE inhibited by sarin or VX better to obidoxime at human attainable concentration. One compound resulted as better reactivator of NEMP (VX surrogate)-inhibited BChE than obidoxime. The in vitro results were further rationalized by molecular docking studies showing future directions on designing potent BChE reactivators.


Assuntos
Acetilcolinesterase/efeitos dos fármacos , Butirilcolinesterase/efeitos dos fármacos , Reativadores da Colinesterase/farmacologia , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Inibidores da Colinesterase/farmacologia , Humanos , Isoquinolinas/química , Simulação de Acoplamento Molecular
13.
Fitoterapia ; 140: 104412, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31698060

RESUMO

Aconitum carmichaelii has been used in traditional Chinese medicine for treating various diseases for several thousand years. Based on the biosynthetic pathway of some alkaloids such as C19-diterpenoid alkaloids and obvious differences in alkaloid content between leaves of two A. carmichaelii varieties has been reported, we performed leaves transcriptome analysis of two A. carmichaelii varieties. Besides we characterized the biosynthetic pathway of salsolinol. A total of 56 million raw reads (8.28 G) and 55 million clean reads (8.24 G) were obtained from two varieties (Z175 and R184) leaves transcriptome, respectively, and 176,793 unigenes were annotated. 281 and 843 unigenes are involved in the salsolinol biosynthetic pathway and the formation of C19-diterpenoid alkaloids respectively. And including 34 and 24 unigenes are the differentially expressed genes (DEGs) in the biosynthesis pathway for C19-diterpenoid alkaloids and salsolinol between Z175 and R184 respectively, which were target genes to explore differences in C19-diterpenoid alkaloid and salsolinol biosynthesis in Z175 and R184. Thus genes involved in alkaloid biosynthesis and accumulation differ between varieties leaves. The mechanisms underlying the differences and their relevance require further exploration. The results expand our knowledge of alkaloids biosynthesis in A. carmichaelii leaves, and provide a theoretical basis for analysis differences in alkaloids biosynthesis patterns in different varieties.


Assuntos
Aconitum/química , Vias Biossintéticas , Isoquinolinas/química , Transcriptoma , Alcaloides/biossíntese , China , Diterpenos/química , Perfilação da Expressão Gênica , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Folhas de Planta/química , Plantas Medicinais/química
14.
J Med Chem ; 63(12): 6547-6560, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31682434

RESUMO

Pharmacological activation of NRF2 (nuclear factor erythroid 2-related factor 2) arises from blocking the interaction of NRF2 with its negative regulator, KEAP1 (Kelch-like ECH-associated protein 1). We previously reported an isoquinoline-based NRF2 activator, but this compound showed negative logD7.4 and a -2 charge at physiological pH, which may have limited its membrane permeability. In this work, we report potent, metabolically stable analogs that result from replacing a carboxymethyl group at the 4-position with a fluoroalkyl group.


Assuntos
Descoberta de Drogas , Isoquinolinas/química , Isoquinolinas/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Estabilidade de Medicamentos , Humanos , Ligação Proteica
15.
Eur J Med Chem ; 186: 111865, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31735573

RESUMO

We here report the discovery of isoquinoline-based biaryls as a new scaffold for colchicine domain tubulin inhibitors. Colchicinoid inhibitors offer highly desirable cytotoxic and vascular disrupting bioactivities, but their further development requires improving in vivo robustness and tolerability: properties that both depend on the scaffold structure employed. We have developed isoquinoline-based biaryls as a novel scaffold for high-potency tubulin inhibitors, with excellent robustness, druglikeness, and facile late-stage structural diversification, accessible through a tolerant synthetic route. We confirmed their bioactivity mechanism in vitro, developed soluble prodrugs, and established safe in vivo dosing in mice. By addressing several problems facing the current families of inhibitors, we expect that this new scaffold will find a range of in vivo applications towards translational use in cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Isoquinolinas/farmacologia , Microtúbulos/efeitos dos fármacos , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Células HeLa , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Microscopia Confocal , Microtúbulos/metabolismo , Estrutura Molecular , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
16.
Med Chem ; 16(2): 202-211, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31241438

RESUMO

BACKGROUND: The inhibition of transient receptor potential vanilloid receptor 1 (TRPV1) has emerged as a novel approach for the treatment of various pain states. Pyrrolidinyl urea, SB 705498 with pKb = 7.3 in guinea pig TRPV1 receptor has been investigated in Phase II clinical trials for pain and chronic cough. Another heteroaryl urea derivative, A-425619 1, has been reported to be a potent and selective TRPV1 antagonist of capsaicin-evoked receptor activation with an IC50 value of 4 nM in hTRPV1. OBJECTIVE: A series of thirteen A-425619 1 analogues with modifications centered around the Cregion were synthesized to understand the binding site characteristics of TRPV1 receptors. METHODS: We synthesized a series of isoquinoline ureas and evaluated their antagonist potency using smooth muscle assay using guinea pig trachea along with the evaluation of the molecular properties and molecular modeling using CoMFA studies. RESULTS: p-Chloro 4, p-bromo 5, m-isothiocyanate 15, and p-isothiocyanate 16 derivatives were found to be the most potent members of the series with pKb values in the range of 7.3-7.4 in the functional assay using guinea pig trachea. The lead compound A-425619 1 exhibited a pKb value of 8.1 in this assay. CONCLUSION: The para-substituted analogues were found to be more potent than the ortho- and meta- analogues in the biological assay. This observation was further supported by molecular modeling studies using CoMFA.


Assuntos
Desenho de Fármacos , Isoquinolinas/química , Canais de Cátion TRPV/antagonistas & inibidores , Ureia/síntese química , Ureia/farmacologia , Animais , Técnicas de Química Sintética , Cobaias , Masculino , Modelos Moleculares , Conformação Molecular , Relação Estrutura-Atividade , Ureia/química
17.
J Hum Genet ; 65(2): 143-153, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31645655

RESUMO

Direct-acting antivirals, asunaprevir (ASV), daclatasvir (DCV), and beclabuvir (BCV) are known to be mainly metabolized by CYP3A enzymes; however, the differences in the detailed metabolic activities of CYP3A4 and CYP3A5 on these drugs are not well clarified. The aim of the present study was to elucidate the relative contributions of CYP3A4 and CYP3A5 to the metabolism of ASV, DCV, and BCV, as well as the effect of CYP3A5*3 genetic variant in vitro. The amount of each drug and their major metabolites were determined using LC-MS/MS. Recombinant CYP3As and CYP3A5*3-genotyped human liver microsomes (CYP3A5 expressers or non-expressers) were used for the determination of their metabolic activities. The contribution of CYP3A5 to ASV metabolism was considerable compared to that of CYP3A4. Consistently, ASV metabolic activity in CYP3A5 expressers was higher than those in CYP3A5 non-expresser. Moreover, CYP3A5 expression level was significantly correlated with ASV metabolism. In contrast, these observations were not found in DCV and BCV metabolism. To our knowledge, this is the first study to directly demonstrate the effect of CYP3A5*3 genetic variants on the metabolism of ASV. The findings of the present study may provide basic information on ASV, DCV, and BCV metabolisms.


Assuntos
Antivirais/metabolismo , Benzazepinas/metabolismo , Citocromo P-450 CYP3A/genética , Imidazóis/metabolismo , Indóis/metabolismo , Isoquinolinas/metabolismo , Sulfonamidas/metabolismo , Benzazepinas/química , Cromatografia Líquida , Citocromo P-450 CYP3A/metabolismo , Variação Genética , Genótipo , Humanos , Imidazóis/química , Indóis/química , Isoquinolinas/química , Fígado/metabolismo , Microssomos Hepáticos , Proteínas Recombinantes , Sulfonamidas/química , Espectrometria de Massas em Tandem
18.
Org Biomol Chem ; 18(2): 237-249, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31782476

RESUMO

Two series of novel hexacyclic skeletons and their thirty-four derivatives were prepared from l-tryptophan and l-DOPA. The cytotoxicities of these compounds were tested against four human cancer cell lines HCT-116, HepG2, BGC-823 and A2780. Compounds with the tetrahydro-ß-carboline moiety in the left-half of the hexacyclic skeleton showed more potent cytotoxicity with IC50 values in the range of 10-7-10-9 M. Compound 20 with the 4-methoxybenzamide side chain showed potent cytotoxicity towards HepG2 with an IC50 value of 1.32 nM. Compounds 29 and 30 with 2-pyridine amide and (2E)-3-(3-thifluoromethyl-phenyl)acrylic amide side chains showed selective cytotoxicity towards A2780 with IC50 values of 1.73 nM and 7 nM, respectively.


Assuntos
Antineoplásicos/síntese química , Citotoxinas/síntese química , Desenho de Fármacos , Levodopa/química , Triptofano/química , Antibióticos Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Citotoxinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Isoquinolinas/química , Relação Estrutura-Atividade
19.
Nat Prod Res ; 34(5): 668-674, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30117330

RESUMO

New isoquinoline alkaloid hypepontine (1) together with a five known compounds, were identified in Hypecoum ponticum Velen, the partial synonym of Hypecoum procumbens L. The structure of the new substance was elucidated based on spectroscopic evidence. The tertiary and quaternary alkaloid mixtures as well as the isolated alkaloids were evaluated for their antibacterial and antifungal activity. The result revealed that the crude alkaloid mixture containing quaternary isoquinoline alkaloids showed potent antifungal and antibacterial activity.


Assuntos
Alcaloides/isolamento & purificação , Antibacterianos/isolamento & purificação , Antifúngicos/isolamento & purificação , Alcaloides/química , Alcaloides/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Medicamentos de Ervas Chinesas , Isoquinolinas/química , Isoquinolinas/isolamento & purificação , Isoquinolinas/farmacologia , Estrutura Molecular
20.
Anticancer Drugs ; 31(1): 55-59, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31609767

RESUMO

Heterocyclic organobismuth compounds, such as N-tert-butyl-bi-chlorodibenzo[c,f][1,5]azabismocine (compound 1) and bi-chlorodibenzo[c,f ][1,5]thiabismocine (compound 3), exert potent antiproliferative activities in vitro in human cancer cell lines. We showed that compound 3 induced both apoptotic and nonapoptotic cell death via reactive oxygen species production and mitotic arrest in a dose-dependent manner. The mechanisms underlying the dose-dependent effect of these organobismuth compounds were not clear. In the present study, we examined the dose-dependent mechanism underlying cell death induced by compound 1 in a human pancreatic cancer cell line, SUIT-2, and a human colorectal cancer cell line, DLD-1. Compound 1 inhibited cell growth in a dose-dependent manner and induced cell death. Treatment with the pan-caspase inhibitor zVAD-fmk reduced cell death induced by compound 1, whereas the inhibitory effect of zVAD-fmk was limited. Moreover, compound 1 significantly induced lipid peroxidation with concomitant induction of caspase-independent cell death. Our results suggested that eight-membered ring organobismuth compounds induce nonapoptotic cell death via lipid peroxidation.


Assuntos
Antineoplásicos/farmacologia , Bismuto/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Isoquinolinas/farmacologia , Compostos Organometálicos/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Clorometilcetonas de Aminoácidos/farmacologia , Bismuto/química , Inibidores de Caspase/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Isoquinolinas/química , Peroxidação de Lipídeos/efeitos dos fármacos , Compostos Organometálicos/química , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Espécies Reativas de Oxigênio/metabolismo , alfa-Tocoferol/farmacologia
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