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1.
Chem Biodivers ; 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31943757

RESUMO

In our search for new small molecules activating procaspase-3, we have designed and synthesized a series of new acetohydrazides incorporating both 2-oxoindoline and 4-oxoquinazoline scaffolds. Biological evaluation showed that a number of these acetohydrazides were comparably or even more cytotoxic against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer) in comparison to PAC-1, a first procaspase-3 activating compound, which was used as a positive control. One of those new compounds, 2-(6-chloro-4-oxoquinazolin-3(4H)-yl)-N'-[(3Z)-5-methyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene]acetohydrazide activated the caspase-3 activity in U937 human lymphoma cells by 5-fold higher than the untreated control. Three of the new compounds significantly induced necrosis and apoptosis in U937 cells.

2.
World J Gastroenterol ; 26(3): 366-374, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31988595

RESUMO

BACKGROUND: Despite an expanding number of studies on intraductal papillary neoplasm of the bile duct (IPNB), distant metastasis remains unexplained especially in cases of carcinoma in situ. In the present study, we report a rare and interesting case of IPNB without invasive components that later metastasized to lungs and brain. CASE SUMMARY: A 69-year-old male was referred to our hospital due to suspected cholangiocarcinoma. Laboratory tests on admission reported a mild elevation of alkaline phosphatase, γ-glutamyl transpeptidase, and total bilirubin in serum. Endoscopic retrograde cholangiography revealed a filling defect in the common bile duct (CBD) extending to the left hepatic duct. Peroral cholangioscopy delineated a tumor in the CBD that had a papillary pattern. Multidetector computed tomography and magnetic resonance cholangiopancreatography detected partial blockage ot interlude in the CBD leading to cholestasis without evidence of metastasis. Therefore, a diagnosis of IPNB cT1N0M0 was established. Left hepatectomy with bile duct reconstruction was performed. Pathological examination confirmed an intraepithelial neoplasia pattern without an invasive component and an R0 resection achievement. The patient was monitored carefully by regular examinations. However, at 32 mo after the operation, a 26 mm tumor in the lungs and a 12 mm lesion in the brain were detected following a suspicious elevated CA 19-9 level. Video-assisted thoracoscopic surgery of left upper lobectomy and stereotactic radiotherapy are indicated. In addition to histopathological results, a genomic profiling analysis using whole exome sequencing subsequently confirmed lung metastasis originating from bile duct cancer. CONCLUSION: This case highlights the important role of genomic profiling analysis using whole exome sequencing in identifying the origin of metastasis in patients with IPNB.

3.
Rev Med Virol ; : e2089, 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31811678

RESUMO

There is a need for improved treatment of patients with chronic hepatitis B (CHB). We reviewed the literature to explore the efficacy of HB vaccines alone or in combination therapy (CT) with antiviral drugs in CHB patients and to meta-analyze data from randomized controlled trials. We conducted a systematic search in ten databases. All studies investigating the efficacy of HBV vaccine in HBV infected patients were included with no restrictions. Among 1359 studies initially identified, 23 studies (n = 1956 patients) were included for the final analysis. CT showed a significant reduction of HBV DNA compared with analogue monotherapy (AM) at the 12-month follow-up period (odds ratio (OR) = 2.835, 95% confidence interval (CI) [1.275, 6.306], p = .011). Additionally, CT also remarkably induce HbsAg loss in comparison with AM (OR = 11.736, 95% CI [1.841, 74.794], p = .009). Our pooled data revealed no difference between treatment and control regarding alanine aminotransferase normalization, HBeAg seroconversion, and HBeAg disappearance. In addition, CT using vaccine and NAs resulted in a statistically significant higher incidence of adverse effects than AM. The therapeutic effects of combination therapy for patients with CHB were encouraging, but future studies need to investigate all possible treatment combinations and assess their cost-effectiveness.

4.
Clin Transplant ; 33(12)2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31651060

RESUMO

Sarcopenia frequently occurs in cirrhotic patients who are waiting for liver transplantation (LT). This disease is associated with increased morbidity and mortality rates during the LT period. Recently, the careful assessment of nutritional status for end-stage liver disease patients has received a great deal of attention; hence, numerous methods of evaluating sarcopenia have been proposed. However, most of the methods have limitations, including a lack of objectivity, reproducibility, and ability to discriminate prognoses. In addition, many reports suggest that sarcopenia be used as an adjustment factor for the selection criteria of LT and that sarcopenia be incorporated into the selection criteria for living donor LT in our center. In this article, based on a literature review, we aim to identify the current definition of sarcopenia, the available methods of measurement, the potential novel interventions for the treatment of malnutrition and the significance of sarcopenia in LT.

5.
Bioorg Chem ; 92: 103202, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31479984

RESUMO

In search for novel small molecules with antitumor cytotoxicity via activating procaspase-3, we have designed and synthesized three series of novel (E)-N'-benzylidene-4-oxoquinazolin-3(4H)-yl)acetohydrazides (5a-j, 6a-h, and 7a-h). On the phenyl ring ò the benzylidene part, three different substituents, including 2-OH-4-OCH3, 4-OCH3, and 4-N(CH3)2, were introduced, respectively. Biological evaluation showed that the acetohydrazides in series 5a-j, in which the phenyl ring of the benzylidene part was substituted by 2-OH-4-OCH3 substituent, exhibited potent cytotoxicity against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung). Most of the compounds, in this series, especially compounds 5c, 5b and 5h, also significantly activated caspase-3 activity. Among these, compound 5c displayed 1.61-fold more potent than PAC-1 as caspase-3 activator. Cell cycle analysis showed that compounds 5b, 5c, and 5h significantly arrested the cell cycle in G1 phase. Further apoptotic studies also demonstrated compounds 5b, 5c, and 5h as strong apoptotic cell death inducers. The docking simulation studies showed that these compounds could activate procaspase via chelating Zn2+ ion bound to the allosteric site of the zymogen.

7.
J Enzyme Inhib Med Chem ; 34(1): 465-478, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30734614

RESUMO

In our search for novel small molecules activating procaspase-3, we have designed and synthesised a series of novel acetohydrazides incorporating quinazolin-4(3H)-ones (5, 6, 7). Biological evaluation revealed eight compounds with significant cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). The most potent compound 5t displayed cytotoxicity up to 5-fold more potent than 5-FU. Analysis of structure-activity relationships showed that the introduction of different substituents at C-6 position on the quinazolin-4(3H)-4-one moiety, such as 6-chloro or 6-methoxy potentially increased the cytotoxicity of the compounds. In term of caspase activation activity, several compounds were found to exhibit potent effects, (e.g. compounds 7 b, 5n, and 5l). Especially, compound 7 b activated caspases activity by almost 200% in comparison to that of PAC-1. Further docking simulation also revealed that this compound potentially is a potent allosteric inhibitor of procaspase-3.


Assuntos
Antineoplásicos/farmacologia , Caspases/metabolismo , Hidrazinas/farmacologia , Quinazolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade
8.
Chem Biodivers ; 16(4): e1800502, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30653817

RESUMO

The present article describes the synthesis and biological activity of various series of novel hydroxamic acids incorporating quinazolin-4(3H)-ones as novel small molecules targeting histone deacetylases. Biological evaluation showed that these hydroxamic acids were potently cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung). Most compounds displayed superior cytotoxicity than SAHA (suberoylanilide hydroxamic acid, Vorinostat) in term of cytotoxicity. Especially, N-hydroxy-7-(7-methyl-4-oxoquinazolin-3(4H)-yl)heptanamide (5b) and N-hydroxy-7-(6-methyl-4-oxoquinazolin-3(4H)-yl)heptanamide (5c) (IC50 values, 0.10-0.16 µm) were found to be approximately 30-fold more cytotoxic than SAHA (IC50 values of 3.29-3.67 µm). N-Hydroxy-7-(4-oxoquinazolin-3(4H)-yl)heptanamide (5a; IC50 values of 0.21-0.38 µm) was approximately 10- to 15-fold more potent than SAHA in cytotoxicity assay. These compounds also showed comparable HDAC inhibition potency with IC50 values in sub-micromolar ranges. Molecular docking experiments indicated that most compounds, as represented by 5b and 5c, strictly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Quinazolinonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinazolinonas/síntese química , Quinazolinonas/química , Relação Estrutura-Atividade
9.
Anticancer Agents Med Chem ; 19(4): 546-556, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30426904

RESUMO

BACKGROUND: Histone Deacetylase (HDAC) inhibitors represent an extensive class of targeted anticancer agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as givinostat (ITF2357) and belinostat (PXD-101). AIMS: This study aims at developing novel HDAC inhibitors bearing N-hydroxybenzamides and Nhydroxypropenamides scaffolds with potential cytotoxicity against different cancer cell lines. METHODS: Two new series of N-hydroxybenzamides and N-hydroxypropenamides analogues (4a-j, 6a-j) designed based on the structural features of nexturastat A, AR-42, and PXD-101, were synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines (SW620 (colorectal adenocarcinoma), PC3 (prostate adenocarcinoma), and NCI-H23 (adenocarcinoma, non-small cell lung cancer). Molecular simulations were finally carried out to gain more insight into the structure-activity relationships. RESULTS: It was found that the N-hydroxypropenamides (6a-e) displayed very good HDAC inhibitory potency and cytotoxicity. Various compounds, e.g. 6a-e, especially compound 6e, were up to 5-fold more potent than suberanilohydroxamic acid (SAHA) in terms of cytotoxicity. These compounds also comparably inhibited HDACs with IC50 values in the sub-micromolar range. Docking experiments showed that these compounds bound to HDAC2 at the enzyme active binding site with the same binding mode of SAHA, but with higher binding affinities. CONCLUSIONS: The two series of N-hydroxybenzamides and N-hydroxypropenamides designed and synthesized were potential HDAC inhibitors and antitumor agents. Further development of these compounds should be warranted.

10.
Curr Top Med Chem ; 18(26): 2209-2229, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30499410

RESUMO

One of the main goals of in silico Caco-2 cell permeability models is to identify those drug substances with high intestinal absorption in human (HIA). For more than a decade, several in silico Caco-2 models have been made, applying a wide range of modeling techniques; nevertheless, their capacity for intestinal absorption extrapolation is still doubtful. There are three main problems related to the modest capacity of obtained models, including the existence of inter- and/or intra-laboratory variability of recollected data, the influence of the metabolism mechanism, and the inconsistent in vitro-in vivo correlation (IVIVC) of Caco-2 cell permeability. This review paper intends to sum up the recent advances and limitations of current modeling approaches, and revealed some possible solutions to improve the applicability of in silico Caco-2 permeability models for absorption property profiling, taking into account the above-mentioned issues.


Assuntos
Células CACO-2/citologia , Simulação por Computador , Modelos Biológicos , Humanos , Permeabilidade
11.
Chem Biodivers ; 15(10): e1800322, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30054973

RESUMO

In our search for novel small cytotoxic molecules potentially activating procaspase-3, we have designed and synthesized a series of novel N'-[(E)-arylidene]-2-(2,3-dihydro-3-oxo-4H-1,4-benzoxazin-4-yl)acetohydrazides (5, 6). Biological evaluation revealed that seven compounds, including 5h, 5j, 5k, 5l, 5n, 6a, and 6b, exhibited moderate to strong cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). Among these compounds, two most cytotoxic compounds (5h and 5j) displayed from 3- up to 10-fold higher potency than PAC-1 and 5-FU in three cancer cell lines tested. Three compounds 5j, 5k, and 5n were also found to display better caspases activation activity in comparison to PAC-1. Especially, compound 5k activated the level of caspases activity by 200% higher than that of PAC-1. From this study, three compounds 5j, 5k, and 5n could be considered as potential leads for further design and development of caspase activators and anticancer agents.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Caspases/metabolismo , Ativadores de Enzimas/química , Ativadores de Enzimas/farmacologia , Hidrazinas/química , Hidrazinas/farmacologia , Antineoplásicos/síntese química , Benzoxazinas/síntese química , Benzoxazinas/química , Benzoxazinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Ativadores de Enzimas/síntese química , Humanos , Hidrazinas/síntese química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Relação Estrutura-Atividade
12.
Med Chem ; 14(8): 831-850, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29807520

RESUMO

BACKGROUND: Histone deacetylases (HDAC) enzymes are emerging as potential targets for cancer treatments. In this study, several series of novel hydroxamic acids incorporating 1-((1H- 1,2,3-triazol-4-yl)methyl)-3-substituted-2-oxoindolines were explored. METHODS: The compounds were designed using Autodock Vina program, then synthesized and evaluated in vitro and in silico for their inhibitory activity against HDACs. The cytotoxicity was measured by SRB method. The enzyme inhibitory effects of the compounds were evaluated by the fluorescent assay. RESULTS: Biological evaluation showed that these hydroxamic acids were generally cytotoxic against four human cancer cell lines (SW620, colon; PC-3, prostate; AsPC-1, pancreas; NCI-H23, lung). Several compounds, e.g. 7g, 11c, and 11g, displayed up to 10-fold more potent than SAHA (suberoylanilide hydroxamic acid, vorinostat) in term of cytotoxicity. The synthesized compounds were also comparably potent to SAHA in inhibiting HDAC2. In particular, compound 11c displayed potential inhibitory effects against HDAC1, HDAC2, HDAC6, and HDAC8 with comparable or slightly higher potency than SAHA. Docking results on four class I and IIB isoenzymes indicated that these compounds tightly bound to HDACs at the active site with binding affinities much higher than that of SAHA. Finally, chemo-informatics approaches were employed to assess the pharmacokinetic and toxicity profiles of 7g and 11c. We identified degradation via phase II metabolism and toxicity two of the most serious problems that need further optimization. CONCLUSION: Taking altogether our findings are encouraging and current hydroxamate derivatives are worth being considered as potential HDAC inhibitors and could be useful for further research on the development of new anti-cancer agents.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Indóis/síntese química , Indóis/química , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Vorinostat/farmacologia
13.
Chem Biodivers ; 15(6): e1800027, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29667768

RESUMO

In our search for novel histone deacetylases inhibitors, we have designed and synthesized a series of novel hydroxamic acids and N-hydroxybenzamides incorporating quinazoline heterocycles (4a - 4i, 6a - 6i). Bioevaluation showed that these quinazoline-based hydroxamic acids and N-hydroxybenzamides were potently cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung). In term of cytotoxicity, several compounds, e.g., 4g, 4c, 4g - 4i, 6c, and 6h, displayed from 5- up to 10-fold higher potency than SAHA (suberoylanilidehydroxamic acid, vorinostat). The compounds were also generally comparable to SAHA in inhibiting HDACs with IC50 values in sub-micromolar range. Some compounds, e.g., 4g, 6c, 6e, and 6h, were even more potent HDAC inhibitors compared to SAHA in HeLa extract assay. Docking studies demonstrated that the compounds tightly bound to HDAC2 at the active binding site with binding affinities higher than that of SAHA. Detailed investigation on the estimation of absorption, distribution, metabolism, excretion, and toxicity (ADMET) suggested that compounds 4g, 6c, and 6g, while showing potent HDAC2 inhibitory activity and cytotoxicity, also potentially displayed ADMET characteristics desirable to be expected as promising anticancer drug candidates.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Quinazolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Simulação de Acoplamento Molecular , Quinazolinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
14.
Curr Top Med Chem ; 17(30): 3269-3288, 2018 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-29231145

RESUMO

Quantitative Structure - Activity Relationship (QSAR) modeling has been widely used in medicinal chemistry and computational toxicology for many years. Today, as the amount of chemicals is increasing dramatically, QSAR methods have become pivotal for the purpose of handling the data, identifying a decision, and gathering useful information from data processing. The advances in this field have paved a way for numerous alternative approaches that require deep mathematics in order to enhance the learning capability of QSAR models. One of these directions is the use of Multiple Classifier Systems (MCSs) that potentially provide a means to exploit the advantages of manifold learning through decomposition frameworks, while improving generalization and predictive performance. In this paper, we presented MCS as a next generation of QSAR modeling techniques and discuss the chance to mining the vast number of models already published in the literature. We systematically revisited the theoretical frameworks of MCS as well as current advances in MCS application for QSAR practice. Furthermore, we illustrated our idea by describing ensemble approaches on modeling histone deacetylase (HDACs) inhibitors. We expect that our analysis would contribute to a better understanding about MCS application and its future perspectives for improving the decision making of QSAR models.


Assuntos
Química Farmacêutica/métodos , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Relação Quantitativa Estrutura-Atividade , Animais , Tomada de Decisões , Humanos , Aprendizagem , Modelos Moleculares
15.
Bioorg Chem ; 76: 258-267, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29223029

RESUMO

In our search for novel small molecules targeting histone deacetylases, we have designed and synthesized several series of novel N-hydroxybenzamides/N-hydroxypropenamides incorporating quinazolin-4(3H)-ones (4a-h, 8a-d, 10a-d). Biological evaluation showed that these hydroxamic acids were generally cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung cancer). It was found that the N-hydroxypropenamides (10a-d) were the most potent, both in term of HDAC inhibition and cytotoxicity. Several compounds, e.g. 4e, 8b-c, and 10a-c, displayed up to 4-fold more potent than SAHA (suberoylanilide hydroxamic acid, vorinostat) in term of cytotoxicity. These compounds also comparably inhibited HDACs with IC50 values in sub-micromolar range. Docking experiments on HDAC2 isozyme revealed some important features contributing to the inhibitory activity of synthesized compounds, especially for propenamide analogues. Importantly, the free binding energy computed was found to have high quantitative correlation (R2 ∼ 95%) with experimental results.


Assuntos
Acrilamidas/farmacologia , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Acrilamidas/síntese química , Acrilamidas/química , Acrilamidas/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Benzamidas/síntese química , Benzamidas/química , Benzamidas/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Histona Desacetilase 2/química , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/metabolismo , Humanos , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade
16.
Asian Pac J Trop Med ; 10(6): 549-556, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28756918

RESUMO

OBJECTIVE: To screen Vietnamese medicinal plants for xanthine oxidase (XO) inhibitory activity and to isolate XO inhibitor(s) from the most active plant. METHODS: The plants materials were extracted by methanol. The active plant materials were fractionated using different organic solvents, including n-hexane, ethyl acetate, and n-butanol. Bioassay-guided fractionation and column chromatography were used to isolate compounds. The compounds structures were elucidated by analysis of spectroscopic data, including IR, MS, and NMR. RESULTS: Three hundreds and eleven methanol extracts (CME) belonging to 301 Vietnamese herbs were screened for XO inhibitory activity. Among these plants, 57 extracts displayed XO inhibitory activity at 100 µg/mL with inhibition rates of over 50%. The extracts of Archidendron clypearia (A. clypearia), Smilax poilanei, Linociera ramiflora and Passiflora foetida exhibited the greatest potency with IC50 values below 30 µg/mL. Chemical study performed on the extract of A. clypearia resulted in the isolation of six compounds, including 1-octacosanol, docosenoic acid, daucosterol, methyl gallate, quercitrin and (-)-7-O-galloyltricetiflavan. The compound (-)-7-O-galloyltricetiflavan showed the most potent XO inhibitory activity with an IC50 value of 25.5 µmol/L. CONCLUSIONS: From this investigation, four Vietnamese medicinal plants were identified to have XO inhibitory effects with IC50 values of the methanol extracts below 30 µg/mL. Compound (-)-7-O- galloyltricetiflavan was identified as an XO inhibitor from A. clypearia with IC50 value of 25.5 µmol/L.

17.
Bioorg Chem ; 71: 160-169, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28196602

RESUMO

In our search for novel small molecules targeting histone deacetylases, we have designed and synthesized two series of novel N-hydroxybenzamides incorporating 2-oxoindolines (4a-g, 6a-g). Biological evaluation showed that these benzamides potently inhibited HDAC2 with IC50 values in sub-micromolar range. In three human cancer cell lines the synthesized compounds were up to 4-fold more cytotoxic than SAHA. Docking experiments indicated that the compounds tightly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA. Our present results demonstrate that these novel and simple N-hydroxybenzamides are potential for further development as anticancer agents and further investigation of similarly simple N-hydroxybenzamides should be warranted to obtain more potent HDAC inhibitors.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Histona Desacetilase 2/antagonistas & inibidores , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Indóis/química , Indóis/farmacologia , Antineoplásicos/síntese química , Benzamidas/síntese química , Benzamidas/química , Benzamidas/farmacologia , Linhagem Celular Tumoral , Química Click , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/síntese química , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Indóis/síntese química , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Relação Estrutura-Atividade
18.
Bioorg Chem ; 66: 63-71, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27018835

RESUMO

A series of novel hydroxamic acids bearing artemisinin skeleton was designed and synthesized. Some compounds in this series exhibited moderate inhibition against the whole cell HDAC enzymes. Especially, compound 6g displayed potent cytotoxicity against three human cancer cell lines, including HepG2 (liver cancer), MCF-7 (breast cancer) and HL-60 (leukemia cancer), with IC50 values of 2.50, 2.62 and 1.28µg/mL, respectively. Docking studies performed with two potent compounds 6a and 6g using Autodock Vina showed that both compounds bound to HDAC2 with relatively high binding affinities from -7.1 to 7.0kcal/mol compared to SAHA (-7.4kcal/mol). It was found in this research that most of the target compounds seemed to be more cytotoxic toward blood cancer cells (HL-60) than liver (HepG2), and breast (MCF-7) cancer cells.


Assuntos
Antineoplásicos/farmacologia , Artemisininas/farmacologia , Desenho de Drogas , Ácidos Hidroxâmicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Artemisininas/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Células Hep G2 , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
19.
In Vitro Cell Dev Biol Anim ; 51(10): 1085-92, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26275888

RESUMO

Adipose-derived stem cells (ADSCs) have been put forward as promising therapeutics for end-stage liver disease (ESLD). In the present study, we compared the effects of defined chemicals and liver extract on the hepatic differentiation of ADSCs. ADSCs were isolated according to the method described in our previously published study. Subsequently, the differentiation of ADSCs was induced separately by chemicals (including hepatic growth factor (HGF), fibroblast growth factor (FGF), and oncostatin M (OSM)) and liver extract (30 µg/ml) in a total period of 21 d. The efficiency of hepatic differentiation was evaluated by changes in the cell morphology, gene expression, and cellular function. The results showed that the liver extract promoted the hepatic differentiation of ADSCs to a significantly greater extent than the chemicals. In the group of ADSCs treated with liver extract, changes in the cell morphology began sooner, and the expression of alpha-FP and albumin genes was higher than that in the chemically treated group. The ADSCs in both the groups stained positive for anti-alpha trypsin (AAT) and albumin markers. The cells also exhibited glycogen storage capacity. Therefore, we concluded that the liver extract could efficiently induce the differentiation of ADSCs into hepatocyte-like cells. This study reveals the potential of mesenchymal stem cell differentiation in the liver extract, which supports further preclinical and clinical research on the application of ADSCs in ESLD treatment.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Hepatopatias/terapia , Extratos Hepáticos/farmacologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Tecido Adiposo/citologia , Albuminas/biossíntese , Animais , Terapia Baseada em Transplante de Células e Tecidos/métodos , Células Cultivadas , Fatores de Crescimento de Fibroblastos/farmacologia , Glicogênio/metabolismo , Fator de Crescimento de Hepatócito/farmacologia , Humanos , Camundongos , Oncostatina M/farmacologia , alfa 1-Antitripsina/biossíntese , alfa-Fetoproteínas/biossíntese
20.
Med Chem ; 11(8): 725-35, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26133355

RESUMO

Histone deacetylases (HDAC) are currently a group of validated targets for anticancer drug discovery and development. In our research program to find novel small molecules targeting these enzymes, we designed and synthesized two series of 3-hydroxyimino-2-oxoindoline- and 3- methoxyimino-2-oxoindoline-based N-hydroxypropenamides (3a-g, 6a-g). The results show that these propenamides potently inhibited HDAC2 with IC50 values in sub-micromolar range, approximately 10-fold lower than that of SAHA (also known as suberoylanilohydroxamic acid). Evaluation of cytotoxicity of these compounds in three human cancer cell lines revealed that most of the synthesized compounds were up to 5-fold more cytotoxic than SAHA. Docking studies showed that the compounds bound to HDAC2 at the binding site with higher binding affinities compared to SAHA. Our present results demonstrate that these novel 3-substituted-2-oxoindoline-based N-hydroxypropenamides are potential for further development as anticancer agents.


Assuntos
Acrilamidas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Histona Desacetilase 2/antagonistas & inibidores , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Indóis/química , Indóis/farmacologia , Acrilamidas/síntese química , Acrilamidas/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/síntese química , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
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