Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 279
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Oxid Med Cell Longev ; 2019: 2069250, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30906500

RESUMO

The newly synthesized coumarin derivative with dopamine, 3-(1-((3,4-dihydroxyphenethyl)amino)ethylidene)-chroman-2,4-dione, was completely structurally characterized by X-ray crystallography. It was shown that several types of hydrogen bonds are present, which additionally stabilize the structure. The compound was tested in vitro against different cell lines, healthy human keratinocyte HaCaT, cervical squamous cell carcinoma SiHa, breast carcinoma MCF7, and hepatocellular carcinoma HepG2. Compared to control, the new derivate showed a stronger effect on both healthy and carcinoma cell lines, with the most prominent effect on the breast carcinoma MCF7 cell line. The molecular docking study, obtained for ten different conformations of the new compound, showed its inhibitory nature against CDKS protein. Lower inhibition constant, relative to one of 4-OH-coumarine, proved stronger and more numerous interactions with CDKS protein. These interactions were carefully examined for both parent molecule and derivative and explained from a structural point of view.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Cromanos/síntese química , Cromanos/farmacologia , Antineoplásicos/química , Sobrevivência Celular/efeitos dos fármacos , Cromanos/química , Cristalografia por Raios X , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular
2.
Bioorg Med Chem ; 27(7): 1382-1390, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30819619

RESUMO

ROCK1 and ROCK2 are highly homologous isoforms. Accumulated studies indicate that they have distinct different functions, and the development of isoform selective ROCK inhibitors will pave new roads for the treatment of various diseases. In this work, a series of amide-chroman derivatives were synthesized and biologically evaluated in order to develop potent and isoform selective ROCK2 inhibitors. Remarkably, (S)-6-methoxy-chroman-3-carboxylic acid (4-pyridin-4-yl-phenyl)-amide ((S)-7c) possessed ROCK2 inhibitory activity with an IC50 value of 3 nM and 22.7-fold isoform selectivity (vs. ROCK1). Molecular docking indicated that hydrophobic interactions were the key element for the high potency and isoform selectivity of (S)-7c. The binding free energies predicted by MM/GBSA were in good agreement with the experimental bioactivities, and the analysis of individual energy terms suggested that residue Lys105 in ROCK1 or Lys121 in ROCK2 was the key residue for the isoform selectivity of (S)-7c.


Assuntos
Cromanos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Cromanos/síntese química , Cromanos/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Quinases Associadas a rho/metabolismo
3.
Eur J Med Chem ; 170: 16-27, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30878829

RESUMO

A series of Flexible Heteroarotinoid (Flex-Het) analogs was synthesized and their biological activities were evaluated against the A2780 ovarian cancer cell line. The objective of this study was to establish structure-activity relationships (SARs) for new Flex-Het derivatives, which were previously inaccessible due to the limited availability of aryl isothiocyanate precursors. The current work developed a synthesis of isothiocyanate 13 and used it to prepare 14 diverse thiourea analogs of the lead compound SHetA2 (1, NSC-721689) from a range of commercial amines. Additionally, five new ureas were prepared along with nine N-benzylthioureas, five derivatives incorporating hydrazine or hydrazide linkers and four desmethyl compounds. Potencies and efficacies were determined for each derivative. Some of the new Flex-Hets displayed high activity with IC50 values ranging from 1.86 to 4.70 µM and 85.6-95.9% efficacies, which are comparable to or better than the lead compound (IC50 3.17 µM, 84.3% efficacy). Although SHetA2 is scheduled to enter clinical trials in the near future, alternative backup drug candidates have been identified in this work. The new agents possess similar pharmacological properties and retain selective activity against A2780 ovarian cancer cells. Although a mixed SAR was obtained for these analogs, diversified, highly potent molecules were identified for further investigation. In particular, agents 2c-d and 3e-f, which incorporated CF3 and OCF3 groups in place of NO2 on the pendent aryl ring, displayed high activity and excellent differentiation between normal and cancerous cells.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cromanos/química , Cromanos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Tionas/química , Tionas/farmacologia , Tioureia/análogos & derivados , Tioureia/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromanos/síntese química , Feminino , Humanos , Neoplasias Ovarianas/patologia , Relação Estrutura-Atividade , Tionas/síntese química , Tioureia/síntese química
4.
AAPS PharmSciTech ; 20(1): 20, 2019 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-30604109

RESUMO

SHetA2 is a novel anticancer drug with poor aqueous solubility. In formal toxicological studies, Kolliphor HS 15 was used as a solubilizing agent to increase the oral bioavailability of SHetA2. The purpose of this study was to formulate SHetA2 and Kolliphor HS 15 as solid powders to facilitate their filling in hard gelatin capsules for clinical trials. Two manufacturing processes, ultra-rapid freeze-drying (URFD) and spray freeze drying (SFD), were employed to fabricate solid powders of SHetA2-Kolliphor HS 15 and trehalose. The morphology, size, flowability, and compressibility of URFD-SHetA2 and SFD-SHetA2 powders were characterized. The crystallinity and apparent maximum solubility of SHetA2 in both powders were also determined. SFD-SHetA2 powders were spherical in shape, small, and with a wide size distribution while the URFD-SHetA2 powders were irregularly shaped and big but with a narrower distribution. DSC and XRD analyses indicated that SHetA2 was mostly amorphous in both powders. The flow of both powders was categorized as "good" (angle of repose < 35°). The uniformity of drug content in URFD-SHetA2 powders was more variable than that in SFD-SHetA2 powders. The solubility profile of SHetA2 in both powders SGF exhibited a transient supersaturation "spring effect" due to the drug's amorphousness followed by extended supersaturation "parachute effect" at approximately 6 µg/ml for both powders compared to 0.02 ± 0.01 µg/ml for unprocessed drug. In conclusion, both URFD and SFD formed solid SHetA2 Kolliphor powders that are possible formulation candidates to be filled in hard gelatin capsules for clinical trials.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Cromanos/síntese química , Cromanos/farmacocinética , Tionas/síntese química , Tionas/farmacocinética , Administração Oral , Antineoplásicos/administração & dosagem , Disponibilidade Biológica , Cromanos/administração & dosagem , Dessecação , Liofilização/métodos , Ácido Gástrico/metabolismo , Humanos , Tamanho da Partícula , Pós , Solubilidade , Tionas/administração & dosagem , Difração de Raios X
5.
Cancer Lett ; 443: 157-166, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30503556

RESUMO

SL-1-39 [1-(4-chloro-3-methylphenyl)-3-(4-nitrophenyl)thiourea] is a new flexible heteroarotinoid (Flex-Het) analog derived from the parental compound, SHetA2, previously shown to inhibit cell growth across multiple cancer types. The current study aims to determine growth inhibitory effects of SL-1-39 across the different subtypes of breast cancer cells and delineate its molecular mechanism. Our results demonstrate that while SL-1-39 blocks cell proliferation of all breast cancer subtypes tested, it has the highest efficacy against HER2+ breast cancer cells. Molecular analyses suggest that SL-1-39 prevents S phase progression of HER2+ breast cancer cells (SKBR3 and MDA-MB-453), which is consistent with reduced expression of key cell-cycle regulators at both the protein and transcriptional levels. SL-1-39 treatment also decreases the protein levels of HER2 and pHER2 as well as its downstream effectors, pMAPK and pAKT. Reduction of HER2 and pHER2 at the protein level is attributed to increased lysosomal degradation of total HER2 levels. This is the first study to show that a flexible heteroarotinoid analog modulates the HER2 signaling pathway through lysosomal degradation, and thus further warrants the development of SL-1-39 as a therapeutic option for HER2+ breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Cromanos/síntese química , Lisossomos/metabolismo , Receptor ErbB-2/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Catecóis/química , Catecóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromanos/química , Cromanos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Proteólise , Receptor ErbB-2/genética , Tionas/química
6.
Chem Biol Drug Des ; 93(3): 254-261, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30264436

RESUMO

Sulfone/sulfoxide-containing carbohydrate derived thiochromans were found to be highly active antiplasmodial agents. However, the inability of the sulfone/sulfoxide functional groups for further derivatization and manipulation limited the potential for further exploration. In this study, based on the interesting and important physicochemical properties, as well as amenability of sulfoximines (isosters of sulfones) for further derivatization, a series of novel sulfoximine-type carbohydrate-derived thiochroman derivatives have been successfully synthesized, characterized, and evaluated for their antiplasmodial activity. Although the replacement of the sulfone functional group with a sulfoximine unit improved the antiplasmodial activity of the scaffolds, the activity was highly dependent on the configuration of the stereogenic centre at the sulfur atom. Moreover, analysis of the crystal structures of the sulfoximine analogues revealed that the bond between the sulfur and nitrogen atoms of the sulfoximine functional group is not a true double bond but rather a polarized single bond.


Assuntos
Antimaláricos/síntese química , Cromanos/química , Desenho de Fármacos , Safrol/análogos & derivados , Sulfonas/química , Alquilação , Antimaláricos/química , Antimaláricos/farmacologia , Carboidratos/química , Sobrevivência Celular/efeitos dos fármacos , Cromanos/síntese química , Cromanos/farmacologia , Células HeLa , Humanos , Plasmodium falciparum/efeitos dos fármacos , Safrol/síntese química , Safrol/química , Safrol/farmacologia , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/farmacologia
7.
Molecules ; 23(12)2018 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-30551624

RESUMO

Tyrosinase is a key enzyme in melanin synthesis, catalyzing the initial rate-limiting steps of melanin synthesis. Abnormal and excessive melanin synthesis is the primary cause of serious skin disorders including melasma, senile lentigo, freckles, and age spots. In attempts to find potent and safe tyrosinase inhibitors, we designed and synthesized a novel compound, (Z)-3-(3-bromo-4-hydroxybenzylidene)thiochroman-4-one (MHY1498), and evaluated its tyrosinase inhibitory activity in vitro and in silico. The chemical structures of (Z)-3-benzylidenethiochroman-4-one analogues, including the novel compound MHY1498, were rationally designed and synthesized as hybrid structures of reported potent tyrosinase inhibitors, which were confirmed both in vitro and in vivo: (Z)-5-(substituted benzylidene)thiazolidine-2,4-diones (Compound A) and 2-(substituted phenyl)benzo[d]thiazoles (Compound B). During screening, MHY1498 showed a strong dose-dependent inhibitory effect on mushroom tyrosinase. The IC50 value of MHY1498 (4.1 ± 0.6 µM) was significantly lower than that of the positive control, kojic acid (22.0 ± 4.7 µM). In silico molecular multi-docking simulation and inhibition mechanism studies indicated that MHY1498 interacts competitively with the tyrosinase enzyme, with greater affinity for the active site of tyrosinase than the positive control. Furthermore, in B16F10 melanoma cells treated with α-melanocyte-stimulating hormone, MHY1498 suppressed both melanin production and tyrosinase activity. In conclusion, our data demonstrate that MHY1498, a synthesized novel compound, effectively inhibits tyrosinase activity and has potential for treating hyperpigmentation and related disorders.


Assuntos
Cromanos/farmacologia , Simulação por Computador , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Agaricales/enzimologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Cromanos/síntese química , Cromanos/química , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Concentração Inibidora 50 , Cinética , Melaninas/biossíntese , Melanoma Experimental/patologia , Camundongos , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase/metabolismo , Pironas/farmacologia
8.
Org Biomol Chem ; 17(1): 151-155, 2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30525178

RESUMO

A highly enantio- and diastereoselective method for the synthesis of functionalized chroman-2-ones and chromanes was achieved by using an organocatalytic domino Michael/hemiacetalization reaction of aliphatic aldehydes and (E)-2-(2-nitrovinyl)phenols followed by a PCC oxidation and dehydroxylation, respectively. Using the modularly designed organocatalysts (MDOs) self-assembled from cinchona alkaloid derivatives and amino acids in the reaction media, the title products were obtained in good to high yields (up to 97%) and excellent diastereoselectivities (up to 99 : 1 dr) and enantioselectivities (up to 99% ee).


Assuntos
Cromanos/síntese química , Cromonas/síntese química , Aldeídos/química , Aminoácidos/química , Catálise , Alcaloides de Cinchona/química , Oxirredução , Fenóis/química , Estereoisomerismo
9.
Bioorg Med Chem ; 26(20): 5443-5461, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30270002

RESUMO

The non-canonical IκB kinases TANK-binding kinase 1 (TBK1) and inhibitor of nuclear factor kappa-B kinase ε (IKKε) play a key role in insulin-independent pathways that promote energy storage and block adaptive energy expenditure during obesity. Utilizing docking calculations and the x-ray structure of TBK1 bound to amlexanox, an inhibitor of these kinases with modest potency, a series of analogues was synthesized to develop a structure activity relationship (SAR) around the A- and C-rings of the core scaffold. A strategy was developed wherein R7 and R8 A-ring substituents were incorporated late in the synthetic sequence by utilizing palladium-catalyzed cross-coupling reactions on appropriate bromo precursors. Analogues display IC50 values as low as 210 nM and reveal A-ring substituents that enhance selectivity toward either kinase. In cell assays, selected analogues display enhanced phosphorylation of p38 or TBK1 and elicited IL-6 secretion in 3T3-L1 adipocytes better than amlexanox. An analogue bearing a R7 cyclohexyl modification demonstrated robust IL-6 production in 3T3-L1 cells as well as a phosphorylation marker of efficacy and was tested in obese mice where it promoted serum IL-6 response, weight loss, and insulin sensitizing effects comparable to amlexanox. These studies provide impetus to expand the SAR around the amlexanox core toward uncovering analogues with development potential.


Assuntos
Quinase I-kappa B/antagonistas & inibidores , Obesidade/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Células 3T3-L1 , Aminação , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Cromanos/síntese química , Cromanos/química , Cromanos/farmacologia , Cromanos/uso terapêutico , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Quinase I-kappa B/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Obesidade/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/metabolismo , Piridinas/síntese química , Piridinas/uso terapêutico
10.
Eur J Med Chem ; 158: 334-352, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30223121

RESUMO

Because of the complex biological networks, many pathologic disorders fail to be treated with a molecule directed towards a single target. Thus, combination therapies are often necessary, but they have many drawbacks. An alternative consists in building molecules intended to interact with multiple targets, called designed multiple ligands. We followed such a strategy in order to treat metabolic syndrome, by setting up molecules directed towards both type 1 angiotensin II (AT1) receptor and peroxisome proliferator-activated receptor-γ (PPAR-γ). For this purpose, many molecules were prepared by merging both pharmacophores following three different strategies. Their ability to activate PPAR-γ and to block AT1 receptors were evaluated in vitro. This strategy led to the preparation of many new PPAR-γ activating and AT1 blocking molecules. Among them, some exhibited both activities, highlighting the convenience of this approach.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Desenho de Fármacos , PPAR gama/agonistas , Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Animais , Cromanos/síntese química , Cromanos/química , Cromanos/farmacologia , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Ligantes , Células MCF-7 , Masculino , Simulação de Acoplamento Molecular , PPAR gama/metabolismo , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo , Triazóis/síntese química , Triazóis/química , Triazóis/farmacologia
11.
Eur J Med Chem ; 158: 720-732, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30245396

RESUMO

Five series of chromans with urea and thiourea linkers connecting a chroman unit (ring A) and a 4-substituted benzene unit (ring B) have been prepared and evaluated relative to SHetA2 (NSC 721689) for activity against the human A2780 ovarian cancer cell line. The lead compound SHetA2 had a sulfur in place of the oxygen in ring A and a thiourea linker to ring B. The 2-Me-4-Me series (two sets of geminal dimethyl groups at C2 and at C4 on the ring A unit) permitted direct comparison with SHetA2. Ring B in this series was evaluated with specific functional groups at C4 on the ring, including NO2, CO2Et, CF3, OCF3, CN and SO2NH2. The 2-H-4-Me series (only one geminal dimethyl group at the C4 position on ring A) permitted structure-activity relationship analysis to assess the importance of the hydrophobic geminal dimethyl groups on ring A to the activity of SHetA2. The remaining three series 2-Et-4-Me, 2-Me-4-Et and 2-Et-4-Et (ring A methyl groups replaced with ethyls at C2, at C4 and at both C2 and C4, respectively) offered the opportunity to modulate the hydrophobicity of the chroman moiety. Additionally, in all these series, the influence of a urea versus a thiourea linker was also investigated. The results of these modifications are summarized below. The exact analog of SHetA2 with oxygen substituted for sulfur in ring A (2a) showed comparable efficacy but a significantly lower IC50 against the ovarian cancer cell line. The urea linked analogs bearing CN, CF3 and OCF3 at C4 of ring B (3c,d and f) showed greater efficacy than SHetA2, but also had lower IC50 values. Removing the geminal dimethyl group at C2 (4a-c, 5a-c) caused a significant lowering of the efficacy and percent growth inhibition, indicating that the hydrophobic geminal dimethyl group at C2 in ring A is crucial for activity. Finally, replacing the geminal dimethyl groups with geminal diethyls on ring A in the urea derivatives gave 6b-c, 7c-d and 8b, all of which outperformed SHetA2 with respect to efficacy and IC50. The results for compounds 4-8 are in concurrence with modeling studies, which predicted that greater hydrophobicity in ring A would be beneficial. Binding energies were determined for compounds docked in silico to mortalin, the protein identified as a receptor of SHetA2. The urea linker promoted activity comparable to or, in some cases, greater than compounds with a thiourea linker. Several compounds achieved 94% efficacy and an IC50 of 2 µM, which were better than SHetA2 (84%, 3 µM).


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cromanos/química , Cromanos/farmacologia , Tionas/química , Tionas/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Cromanos/síntese química , Feminino , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Simulação de Acoplamento Molecular , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Oxigênio/química , Oxigênio/farmacologia , Enxofre/química , Enxofre/farmacologia , Tionas/síntese química , Tioureia/análogos & derivados , Tioureia/síntese química , Tioureia/farmacologia , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologia
12.
Chem Commun (Camb) ; 54(81): 11387-11390, 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30191239

RESUMO

In this study, we developed a multi-signal mitochondria-targeted fluorescent probe (NIR-Cys) for simultaneous detection of Cys and its metabolite, SO2. In the design of the probe, the acrylate group and the C[double bond, length as m-dash]C of the coumarin ring were used as the recognizing moiety for Cys and SO2, respectively. The probe exhibited high sensitivity, excellent specificity, and fast response. NIR-Cys was found to precisely target and visualize Cys metabolism in mitochondria of living cells with a multi-fluorescence signal. This probe is expected to be a useful tool for understanding Cys metabolism.


Assuntos
Acrilatos/química , Cromanos/química , Cumarínicos/química , Cisteína/análise , Corantes Fluorescentes/química , Mitocôndrias/metabolismo , Dióxido de Enxofre/análise , Acrilatos/síntese química , Acrilatos/metabolismo , Acrilatos/toxicidade , Animais , Linhagem Celular Tumoral , Cromanos/síntese química , Cromanos/metabolismo , Cromanos/toxicidade , Cumarínicos/síntese química , Cumarínicos/metabolismo , Cumarínicos/toxicidade , Cisteína/metabolismo , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Corantes Fluorescentes/toxicidade , Humanos , Limite de Detecção , Fígado/metabolismo , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Sulfitos/análise , Sulfitos/química , Dióxido de Enxofre/metabolismo , Peixe-Zebra
13.
Chem Pharm Bull (Tokyo) ; 66(9): 843-846, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30175739

RESUMO

The complete synthesis of D-α-tocopherol was achieved using our developed-Ullmann C-O coupling reaction as a key reaction. The synthesis of the core structure of D-α-tocopherol, which is a chiral chromane, has never been reported using intramolecular Ullmann C-O coupling reactions owing to the low reactivity of electron-rich iodoarenes with tertiary alcohols. Because the developed intramolecular C-O coupling reactions prefer electron-rich iodoarenes with tertiary alcohols, we successfully synthesized the chiral chromane core and achieved the total synthesis of D-α-tocopherol.


Assuntos
Cromanos/síntese química , alfa-Tocoferol/síntese química , Álcoois/química , Amidas/química , Catálise , Ciclização , Isomerismo , Estrutura Molecular , Oxirredução
14.
Sci Rep ; 8(1): 12784, 2018 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-30143727

RESUMO

Inflammation plays a major role in the onset and development of chronic non-communicable diseases like obesity, cardiovascular diseases and cancer. Combined, these diseases represent the most common causes of death worldwide, thus development of novel pharmacological approaches is crucial. Electrophilic nitroalkenes derived from fatty acids are formed endogenously and exert anti-inflammatory actions by the modification of proteins involved in inflammation signaling cascades. We have developed novel nitroalkenes derived from α-tocopherol aiming to increase its salutary actions by adding anti-inflammatory properties to a well-known nutraceutical. We synthesized and characterized an α-tocopherol-nitroalkene (NATOH) and two hydrosoluble analogues derived from Trolox (NATxME and NATx0). We analyzed the kinetics of the Michael addition reaction of these compounds with thiols in micellar systems aiming to understand the effect of hydrophobic partition on the reactivity of nitroalkenes. We studied NATxME in vitro showing it exerts non-conventional anti-inflammatory responses by inducing Nrf2-Keap1-dependent gene expression and inhibiting the secretion of NF-κB dependent pro-inflammatory cytokines. NATxME was also effective in vivo, inhibiting neutrophil recruitment in a zebrafish model of inflammation. This work lays the foundation for the rational design of a new therapeutic strategy for the prevention and treatment of metabolic and inflammation-related diseases.


Assuntos
Alcenos/síntese química , Alcenos/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Transdução de Sinais , Tocoferóis/síntese química , Tocoferóis/farmacologia , Alcenos/química , Animais , Anti-Inflamatórios/química , Cromanos/síntese química , Cromanos/química , Cromanos/farmacologia , Cinética , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Micelas , Infiltração de Neutrófilos/efeitos dos fármacos , Células RAW 264.7 , Tocoferóis/química , Peixe-Zebra
15.
Molecules ; 23(7)2018 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-29933627

RESUMO

Tuberculosis is the leading cause of death from a single infectious agent worldwide; therefore, the need for new antitubercular drugs is desperate. The recently validated target salicylate synthase MbtI is the first enzyme involved in the biosynthesis of mycobactins, compounds able to chelate iron, an essential cofactor for the survival of Mycobacterium tuberculosis in the host. Here, we report on the synthesis and biological evaluation of chromane-based compounds as new potential inhibitors of MbtI. Our approach successfully allowed the identification of a novel lead compound (1), endowed with a promising activity against this enzyme (IC50 = 55 µM). Molecular modeling studies were performed in order to evaluate the binding mode of 1 and rationalize the preliminary structure-activity relationships, thus providing crucial information to carry out further optimization studies.


Assuntos
Antituberculosos/química , Proteínas de Bactérias/antagonistas & inibidores , Ácido Corísmico/química , Cromanos/química , Inibidores Enzimáticos/química , Liases/antagonistas & inibidores , Mycobacterium tuberculosis/química , Motivos de Aminoácidos , Antituberculosos/síntese química , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Domínio Catalítico , Ácido Corísmico/metabolismo , Cromanos/síntese química , Inibidores Enzimáticos/síntese química , Expressão Gênica , Cinética , Liases/química , Liases/genética , Liases/metabolismo , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/enzimologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato , Termodinâmica
16.
J Org Chem ; 83(11): 6066-6085, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29728045

RESUMO

(+)-Psiguadial B is a diformyl phloroglucinol meroterpenoid that exhibits antiproliferative activity against the HepG2 human hepatoma cancer cell line. This full account details the evolution of a strategy that culminated in the first enantioselective total synthesis of (+)-psiguadial B. A key feature of the synthesis is the construction of the trans-cyclobutane motif by a Wolff rearrangement with in situ catalytic, asymmetric trapping of the ketene. An investigation of the substrate scope of this method to prepare enantioenriched 8-aminoquinolinamides is disclosed. Three routes toward (+)-psiguadial B were evaluated that featured the following key steps: (1) an ortho-quinone methide hetero-Diels-Alder cycloaddition to prepare the chroman framework, (2) a Prins cyclization to form the bridging bicyclo[4.3.1]decane system, and (3) a modified Norrish-Yang cyclization to generate the chroman. Ultimately, the successful strategy employed a ring-closing metathesis to form the seven-membered ring and an intramolecular O-arylation reaction to complete the polycyclic framework of the natural product.


Assuntos
Produtos Biológicos/síntese química , Terpenos/síntese química , Catálise , Cromanos/síntese química , Ciclização , Reação de Cicloadição , Ciclobutanos/química , Indolquinonas/química , Estrutura Molecular , Floroglucinol/química , Estereoisomerismo
17.
J Am Chem Soc ; 140(4): 1211-1214, 2018 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-29303567

RESUMO

This report describes the stereoselective synthesis of 3-azido-tetralins, -chromanes, and -tetrahydroquinolines via a tandem allylic azide rearrangement/Friedel-Crafts alkylation. Exposure of allylic azides with a pendant trichloroacetimidate to catalytic quantities of AgSbF6 proved optimal for this transformation. This cascade successfully differentiates the equilibrating azide isomers, providing products in excellent yield and selectivity (>25 examples, up to 94% yield and >25:1 dr). In many cases, the reactive isomer is only a trace fraction of the equilibrium mixture, keenly illustrating the dynamic nature of these systems. We demonstrate the utility of this process via a synthesis of hasubanan.


Assuntos
Compostos Alílicos/química , Azidas/química , Cromanos/síntese química , Quinolinas/síntese química , Tetra-Hidronaftalenos/síntese química , Cromanos/química , Ciclização , Estrutura Molecular , Quinolinas/química , Estereoisomerismo , Tetra-Hidronaftalenos/química
18.
Folia Med (Plovdiv) ; 60(4): 601-609, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31188774

RESUMO

BACKGROUND: Despite the use of traditional method, Ugi reaction currently is a well-established multicomponent reaction. Chromane motif itself possesses a variety of biological functions. In order to improve its anti-tubercular activity, it is necessary to modify it accordingly. AIM: To ensure relation between in silico and in vitro study, we have carried out in vitro screening against H37Rv anti-tubercular agent. MATERIALS AND METHODS: Ugi four-component condensation (U-4CCRs) between 6-fluorochroman-2-carboxylic acid, various aryl aldehyde, 3,4,5-trimethoxy amine and tert-butyl isocyanide, gave N-((tert-butylcarbamoyl)(4-substitutedphenyl) methyl)-6-fluoro-N-(3,4,5-trimethoxyphenyl) chroman-2-carboxamide. The molecular level insight of all compounds was carried out by molecular docking study against the receptor tyrosine phosphatase PtpB. All these newly synthesized compounds were screened for their anti-microbial activity against Mycobacterium tuberculosis H37Rv to determine the MIC, IC50 and IC90 of the compound. RESULTS: The compound 5d also shows large hydrophobic surface contact on the face of the α7-α8 (Ile 207, Phe 211, Met 206, Ile203, Phe161, Phe80, Met126, Tyr130, Val231 and Leu101) that lines one side of the entrance to the active site of the receptor. The compound 5d bind with tyrosine phosphatase PtpB with predicted docking geometric score of 4664, whereas a score of rifampicin was 6586 determined. CONCLUSION: From the docking studies, compound 5d, was considered to be the potent inhibitor, which gave strong supportive coordinate with the in vitro study. It is highly active against H37Rv, having MIC and IC50 value of was 70 µM and 53 µM respectively in in vitro study.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Cromanos/química , Cromanos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Cromanos/síntese química , Simulação por Computador , Cristalografia por Raios X , Ensaios de Triagem em Larga Escala/métodos , Humanos , Técnicas In Vitro , Testes de Sensibilidade Microbiana/métodos , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/enzimologia , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Rifampina/química , Rifampina/farmacologia
19.
J Med Chem ; 61(4): 1436-1449, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29251932

RESUMO

Cystic fibrosis (CF) is a multiorgan disease of the lungs, sinuses, pancreas, and gastrointestinal tract that is caused by a dysfunction or deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial anion channel that regulates salt and water balance in the tissues in which it is expressed. To effectively treat the most prevalent patient population (F508del mutation), two biomolecular modulators are required: correctors to increase CFTR levels at the cell surface, and potentiators to allow the effective opening of the CFTR channel. Despite approved potentiator and potentiator/corrector combination therapies, there remains a high need to develop more potent and efficacious correctors. Herein, we disclose the discovery of a highly potent series of CFTR correctors and the structure-activity relationship (SAR) studies that guided the discovery of ABBV/GLPG-2222 (22), which is currently in clinical trials in patients harboring the F508del CFTR mutation on at least one allele.


Assuntos
Benzoatos/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Descoberta de Drogas , Amidas/síntese química , Animais , Benzoatos/síntese química , Benzoatos/farmacocinética , Cromanos/síntese química , Cães , Humanos , Proteínas Mutantes/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
20.
Bioorg Med Chem Lett ; 28(2): 196-201, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29198904

RESUMO

We have developed a facile and efficient synthetic route to substituted isochromans for the first time by reacting 2-(2-bromoethyl)benzaldehyde with a variety of aryl, heteroaryl amines in AcOH. The reaction is catalyst/additive free and takes place at reflux conditions with short reaction time to furnish products in good to excellent yields. All the compounds have been characterized by spectral techniques such as IR, 1H NMR and Mass etc. Synthesized compounds were evaluated for antimicrobial activity against specific bacterial like 1) Staphylococcus strains aureus 2) Bacillus subtilis 3) Escherichia coli 4) Pseudomonas aeruginosa. Compounds 3e, 3n, 3 m, 3 l, 3 k, 3j and 3b showed most potent in vitro activity against bacterial strains.


Assuntos
Ácido Acético/química , Aminas/química , Antibacterianos/farmacologia , Benzaldeídos/química , Cromanos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Bacillus subtilis/efeitos dos fármacos , Benzaldeídos/síntese química , Cromanos/síntese química , Cromanos/química , Relação Dose-Resposta a Droga , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA