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1.
J Chromatogr A ; 1685: 463636, 2022 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-36401913

RESUMO

Effective quantitative analysis of BMAA (ß-N-methylamino-L-alanine) and its isomers without the need for derivatization has always been an analytical challenge due to their poor retention and separation on various liquid chromatography stationary phases. Previous studies that utilized conventional hydrophilic interaction chromatography (HILIC) demonstrate false negatives compared to reverse-phase workflows with derivatization. This work evaluates the chromatographic behavior of BMAA and its isomers, in their underivatized forms, on selected stationary phases, in particular fluorophenyl-based columns, to attain effective retention and separation. Detection and quantification were achieved with an ion-trap mass spectrometer. Extraction and preconcentration were achieved via solid phase microextraction (SPME) by assessing the effectiveness of multiple extraction phases, including hydrophilic-lipophilic balanced (HLB) and mixed-mode (MM). A MM extraction phase consisting of C8 and benzene sulfonic acid moieties provided ideal extraction performance for BMAA and its isomers (2,4-diaminobutyric acid, DABA; N-(2-aminoethyl) glycine, AEG). Chromatographic separation was achieved within 8 min on a fluorophenyl stationary phase, ensuring high throughput without derivatization, and showing exceptional improvement from conventional HILIC methods. Limits of quantification in water for BMAA and AEG were 2.5 µg L-1 and DABA was 5 µg L-1, with linear dynamic ranges from 2.5 µg L-1 - 200 µg L-1 for BMAA and AEG and 5 µg L-1 - 200 µg L-1 for DABA.


Assuntos
Aminoácidos , Neurotoxinas , Cromatografia Líquida
2.
J Med Chem ; 65(21): 14764-14791, 2022 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-36306372

RESUMO

HDAC inhibitors are an attractive class of cytotoxic agents for the design of hybrid molecules. Several HDAC hybrids have emerged over the years, but none combines HDAC inhibition with ferroptosis, a combination which is being extensively studied because it leads to enhanced cytotoxicity and attenuated neuronal toxicity. We combined the pharmacophores of SAHA and CETZOLE molecules to design the first-in-class dual mechanism hybrid molecules, which induce ferroptosis and inhibit HDAC proteins. The involvement of both mechanisms in cytotoxicity was confirmed by a series of biological assays. The cytotoxic effects were evaluated in a series of cancer and neuronal cell lines. Analogue HY-1 demonstrated the best cytotoxic profile with GI50 values as low as 20 nM. Although the increase in activity of the hybrids over the combinations is modest in cellular systems, they have the potential advantage of homogeneous spatiotemporal distribution in in vivo systems.


Assuntos
Antineoplásicos , Ferroptose , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Histona Desacetilases/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células
3.
J Med Chem ; 65(17): 11788-11817, 2022 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-35984756

RESUMO

Once considered potential liabilities, the modern era witnesses a renaissance of interest in covalent inhibitors in drug discovery. The available toolbox of electrophilic warheads is limited by constraints on tuning reactivity and selectivity. Following our work on a class of ferroptotic agents termed CETZOLEs, we discovered new tunable heterocyclic electrophiles which are capable of inducing ferroptosis. The biological evaluation demonstrated that thiazoles with an alkyne electrophile at the 2-position selectively induce ferroptosis with high potency. Density functional theory calculations and NMR kinetic studies demonstrated the ability of our heterocycles to undergo thiol addition, an apparent prerequisite for cytotoxicity. Chemoproteomic analysis indicated several potential targets, the most prominent among them being GPX4 protein. These results were further validated by western blot analysis and the cellular thermal shift assay. Incorporation of these heterocycles into appropriate pharmacophores generated highly cytotoxic agents such as the analogue BCP-T.A, with low nM IC50 values in ferroptosis-sensitive cell lines.


Assuntos
Cisteína , Ferroptose , Cisteína/química , Descoberta de Drogas , Cinética , Compostos de Sulfidrila/química
4.
Bioorg Med Chem ; 62: 116721, 2022 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-35358862

RESUMO

Small molecules remain an important category of therapeutic agents. Their binding to different proteins can lead to both desired and undesired biological effects. Identification of the proteins that a drug binds to has become an important step in drug development because it can lead to safer and more effective drugs. Parent bioactive molecules can be converted to appropriate probes that allow for visualization and identification of their target proteins. Typically, these probes are designed and synthesized utilizing some or all of five major tools; a photoactivatable group, a reporter tag, a linker, an affinity tag, and a bioorthogonal handle. This review covers two of the most challenging tools, photoactivation and bioorthogonal ligation. We provide a historical and theoretical background along with synthetic routes to prepare them. In addition, the review provides comparative analyses of the available tools that can assist decision making when designing such probes. A survey of most recent literature reports is included as well to identify recent trends in the field.


Assuntos
Marcadores de Fotoafinidade , Proteínas , Animais , Marcadores de Fotoafinidade/química , Proteínas/química
5.
Bioorg Chem ; 122: 105700, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35313238

RESUMO

We recently reported a new class of imidazole-based chalcones as potential antimitotic agents. In view of their promising cytotoxic activity, a comprehensive structure-activity relationship (SAR) of these compounds was undertaken focusing on four major structural variations: the length of the molecule, the Michael acceptor character, the nature and substitution pattern of ring B, and the nature of the amide functionality tethering ring B. These second-generation analogs (IBCs) demonstrated a superior bioactivity profile than the previously reported imidazole chalcones (referred to as IPEs). The analog IBC-2 with one less methylene group (nor series) and para-fluoro substituted ring B demonstrated the best cytotoxicity profile among the library of compounds. A computational analysis of the NCI-60 data associated both IBCs and the previously reported IPEs with the privileged pharmacological pharmacophore of chalcones. Interestingly, biological studies suggest that the imidazole ring is essential for cytotoxic activity of the elongated chalcone analogues. Immunofluorescence studies revealed that IBC-2, unlike IPEs, has the ability to induce microtubule catastrophe independently of Aurora-B inhibition. The effects of IBC-2 on microtubule dynamics are similar to those of Nocodazole, but the cell cycle effects appear to be different. In-silico studies demonstrate that the members of the new series have the ability to bind to the colchicine binding site of ß-tubulin with binding scores similar to those of IPEs, corresponding chalcones and Nocodazole. Although tubulin binding can partially explain the biological effects of IBC-2, on-going target identification studies are aimed at further investigation of its biological targets.


Assuntos
Antineoplásicos , Chalcona , Chalconas , Antineoplásicos/química , Chalcona/farmacologia , Chalconas/química , Imidazóis , Microtúbulos , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo
6.
Bioorg Chem ; 116: 105297, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34509798

RESUMO

Despite the advances in treatment strategies, cancer is still the second leading cause of death in the USA. A majority of the currently used cancer drugs have limitations in their clinical use due to poor selectivity, toxic side effects and multiple drug resistance, warranting the development of new anticancer drugs of different mechanisms of action. Here we describe the design, synthesis and initial biological evaluation of a new class of antimitotic agents that modulate tubulin polymerization. Structurally, these compounds are chalcone mimics containing a 1-(1H-imidazol-2-yl)ethan-1-one moiety, which was initially introduced to act as a metal-binding group and inhibit histone deacetylase enzymes. Although several analogues selectively inhibited purified HDAC8 with IC50 values in low micromolar range, tissue culture studies suggest that HDAC inhibition is not a major mechanism responsible for cytotoxicity. The compounds demonstrated cell growth inhibition with GI50 values of upper nanomolar to low micromolar potency with significant selectively for cancer over normal cells. Interestingly, several compounds arrested HeLaM cells in mitosis and seem to target tubulin to cause mitotic arrest. For example, when combined with inhibitors of Aurora B kinase, they led to dramatic disassembly of the mitotic spindle. In-vitro tubulin polymerization studies showed that the compounds reduced the rate of polymerization of microtubules during the elongation phase and lowered the amount of polymerized tubulin during the plateau phase. Finally, in silico docking studies identified binding of IPE-7 to the colchicine site with similar affinity as the test compound D64131. These compounds represent a new antimitotic pharmacophore with limited HDAC inhibitory activity.


Assuntos
Antineoplásicos/farmacologia , Citotoxinas/farmacologia , Etanol/farmacologia , Imidazóis/farmacologia , Microtúbulos/efeitos dos fármacos , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citotoxinas/síntese química , Citotoxinas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Etanol/análogos & derivados , Etanol/química , Células HCT116 , Humanos , Imidazóis/síntese química , Imidazóis/química , Microtúbulos/metabolismo , Estrutura Molecular , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Células Tumorais Cultivadas
7.
Bioorg Med Chem Lett ; 47: 128205, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34139326

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder, projected to be the second leading cause of mortality by 2040. AD is characterized by a progressive impairment of memory leading to dementia and loss of ability to carry out daily functions. In addition to the deficiency of acetylcholine release in synapse, there are other mechanisms explaining the etiology of the disease. The most disputing ones are associated with the accumulation of damaged proteins ß-amyloid (Aß) and hyperphosphorylated tau outside and inside neurons, respectively. Lysergic acid derivatives have been shown to possess promising anti-Alzheimer effect. Moreover, lysergic acid structure encompasses the general structural requirements for acetylcholinesterase inhibition. In this study, sixteen analogues, derived from lysergic acid structure, were synthesized. Heck and Mannich reactions were carried out to 4-bromo indole nucleus to generate potentially active analogues. Some of them were subsequently cyclized by nitromethane and zinc reduction procedures. Some of these compounds showed neuroprotective and anti-inflammatory effects stronger than the currently used anti-Alzheimer drug; donepezil. Some of the synthesized com-pounds showed a noticeable acetylcholinesterase inhibition. Twelve molecular targets attributed with AD etiology were tested versus the synthesized compounds by in silico modeling. Docking scores of modeling were plotted against in vitro activity of the compounds. The one afforded the strongest positive correlation was ULK-1 which has a significant role in autophagy.


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Produtos Biológicos/farmacologia , Inibidores da Colinesterase/farmacologia , Ácido Lisérgico/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Animais , Produtos Biológicos/síntese química , Produtos Biológicos/química , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Ácido Lisérgico/síntese química , Ácido Lisérgico/química , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Células PC12 , Ratos , Relação Estrutura-Atividade
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