RESUMO
Background: Anthraquinone drugs are widely used in the treatment of tumors. However, multidrug resistance and severe cardiac toxicity limit its use, which have led to the discovery of new analogues. In this paper, 4-Deoxy-ε-pyrromycinone (4-Deo), belonging to anthraquinone compounds, was first been studied with the anti-tumor effects and the safety in vitro and in vivo as a new anti-tumor drug or lead compound. Methods: The quantitative analysis of 4-Deo was established by UV methodology. The anti-cancer effect of 4-Deo in vitro was evaluated by cytotoxicity experiments of H22, HepG2 and Caco2, and the anti-cancer mechanism was explored by cell apoptosis and cycle. The tumor-bearing mouse model was established by subcutaneous inoculation of H22 cells to evaluate the anti-tumor effect of 4-Deo in vivo. The safety of 4-Deo was verified by the in vitro safety experiments of healthy cells and the in vivo safety experiments of H22 tumor-bearing mice. Tumor tissue sections were labeled with CRT, HMGB1, IL-6 and CD115 to explore the preliminary anti-cancer mechanism by immunohistochemistry. Results: In vitro experiments demonstrated that 4-Deo could inhibit the growth of H22 by inducing cell necrosis and blocking cells in S phase, and 4-Deo has less damage to healthy cells. In vivo experiments showed that 4-Deo increased the positive area of CRT and HMGB1, which may inhibit tumor growth by triggering immunogenic cell death (ICD). In addition, 4-Deo reduced the positive area of CSF1R, and the anti-tumor effect may be achieved by blocking the transformation of tumor-associated macrophages (TAMs) to M2 phenotype. Conclusion: In summary, this paper demonstrated the promise of 4-Deo for cancer treatment in vitro and in vivo. This paper lays the foundation for the study of 4-Deo, which is beneficial for the further development anti-tumor drugs based on the lead compound of 4-Deo.
Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Animais , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Camundongos , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Antraquinonas/farmacologia , Antraquinonas/química , Antraquinonas/síntese química , Relação Dose-Resposta a Droga , Estrutura Molecular , Relação Estrutura-Atividade , Camundongos Endogâmicos BALB CRESUMO
VEGFR-2 is a prominent therapeutic target in antitumor drug research to block tumor angiogenesis. This study focused on the synthesis and optimization of PROTACs based on the natural product rhein, resulting in the successful synthesis of 15 distinct molecules. In A549 cells, D9 exhibited remarkable antitumor efficacy with an IC50 of 5.88±0.50â µM, which was 15-fold higher compared to rhein (IC50=88.45±2.77â µM). An in-depth study of the effect of D9 on the degradation of VEGFR-2 revealed that D9 was able to induce the degradation of VEGFR-2 in A549 cells in a time-dependent manner. The observed effect was reversible, contingent upon the proteasome and ubiquitination system, and demonstrably linked to CRBN. Further experiments revealed that D9 induced apoptosis in A549 cells and led to cell cycle arrest in the G1 phase. Molecular docking simulations validated the binding mode of D9 to VEGFR, establishing the potential of D9 to bind to VEGFR-2 in its natural state. In summary, this study confirms the feasibility of natural product-bound PROTAC technology for the development of a new generation of VEGFR-2 degraders, offering a novel trajectory for the future development of pharmacological agents targeting VEGFR-2.
Assuntos
Antineoplásicos , Apoptose , Produtos Biológicos , Simulação de Acoplamento Molecular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Produtos Biológicos/síntese química , Apoptose/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Antraquinonas/farmacologia , Antraquinonas/química , Antraquinonas/síntese química , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , Relação Dose-Resposta a Droga , Estrutura Molecular , Células A549 , Proteólise/efeitos dos fármacos , Quimera de Direcionamento de ProteóliseRESUMO
The interaction of acetamidine and phenylamidine with peri-R-ethynyl-9,10-anthraquinones in refluxing n-butanol leads to the formation of cascade transformations products: addition/elimination/cyclization-2-R-7H-dibenzo[de,h]quinolin-7-ones and(or) 2-R-3-aroyl-7H-dibenzo[de,h]quinolin-7-ones. The anti-inflammatory and antitumor properties of the new 2-R-7H-dibenzo[de,h]quinolin-7-ones were investigated in vivo, in vitro, and in silico. The synthesized compounds exhibit high anti-inflammatory activity at dose 20 mg/kg (intraperitoneal injection) in the models of exudative (histamine-induced) and immunogenic (concanavalin A-induced) inflammation. Molecular docking data demonstrate that quinolinones can potentially intercalate into DNA similarly to the antitumor drug doxorubicin.
Assuntos
Amidinas/química , Antraquinonas/química , Anti-Inflamatórios/química , Antineoplásicos/química , Quinolinas/química , Alcaloides/síntese química , Alcaloides/química , Alcaloides/farmacologia , Amidinas/síntese química , Animais , Antraquinonas/síntese química , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Técnicas de Química Sintética , Humanos , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Quinolinas/síntese química , Quinolinas/farmacologiaRESUMO
Total syntheses of aturanosides A and B, two antiangiogenic anthraquinone glycosides, have been achieved in an expeditious manner, highlighting anthraquinone synthesis, phenol glycosylation, α-d-glucosaminoside installation, and judicious use of protecting groups.
Assuntos
Inibidores da Angiogênese/síntese química , Antraquinonas/síntese química , Glicosídeos/química , Glicosídeos/síntese química , Glicosilação , Estrutura MolecularRESUMO
Transthyretin is a tetrameric protein which functions as a transporter of thyroxine and retinol-binding protein. Misfolding and amyloid aggregation of transthyretin are known to cause wild-type and hereditary transthyretin amyloidosis. Stabilization of the transthyretin tetramer by low molecular weight compounds is an efficacious strategy to inhibit the aggregation pathway in the amyloidosis. Here, we investigated the inhibitory activities of anthraquinone and xanthone derivatives against amyloid aggregation, and found that xanthone-2-carboxylic acid with one chlorine or methyl group has strong inhibitory activity comparable with that of diflunisal, which is one of the best known stabilizers of transthyretin. X-ray crystallographic structures of transthyretin in complex with the compounds revealed that the introduction of chlorine, which is buried in a hydrophobic region, is important for the strong inhibitory effect of the stabilizer against amyloidogenesis. An in vitro absorption, distribution, metabolism and elimination (ADME) study and in vivo pharmacokinetic study demonstrated that the compounds have drug-like features, suggesting that they have potential as therapeutic agents to stabilize transthyretin.
Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Antraquinonas/uso terapêutico , Xantonas/uso terapêutico , Antraquinonas/síntese química , Antraquinonas/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Xantonas/síntese química , Xantonas/químicaRESUMO
The anthraquinone scaffold has long been known as a source of efficacious antitumor drugs. In particular, the various chemical modifications of the side chains in this scaffold have yielded the compounds potent for the wild type tumor cells, their counterparts with molecular determinants of altered drug response, as well as in vivo settings. Further exploring the chemotype of anticancer heteroarene-fused anthraquinones, we herein demonstrate that derivative of anthra[2,3-b]thiophene-2-carboxamide, (compound 8) is highly potent against a panel of human tumor cell lines and their drug resistant variants. Treatment with submicromolar or low micromolar concentrations of 8 for only 30 min was sufficient to trigger lethal damage of K562 chronic myelogenous leukemia cells. Compound 8 (2.5 µM, 3-6 h) induced an apoptotic cell death as determined by concomitant activation of caspases 3 and 9, cleavage of poly(ADP-ribose) polymerase, increase of Annexin V/propidium iodide double stained cells, DNA fragmentation (subG1 fraction) and a decrease of mitochondrial membrane potential. Neither a significant interaction with double stranded DNA nor strong inhibition of the DNA dependent enzyme topoisomerase 1 by 8 were detectable in cell free systems. Laser scanning confocal microscopy revealed that some amount of 8 was detectable in mitochondria as early as 5 min after the addition to the cells; exposure for 1 h caused significant morphological changes and clustering of mitochondria. The bioisosteric analog 2 in which the thiophene ring was replaced with furan was less active although the patterns of cytotoxicity of both derivatives were similar. These results point at the specific role of the sulfur atom in the antitumor properties of carboxamide derivatives of heteroarene-fused anthraquinone.
Assuntos
Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Tiofenos/farmacologia , Antraquinonas/síntese química , Antraquinonas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células K562 , Estrutura Molecular , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Células Tumorais CultivadasRESUMO
In this report, a new thermally activated delayed fluorescence (TADF) molecule [2-(4-triphenylvinyl-phenyl)-anthraquinone (TPE-AQ)] was synthesized. This nanomaterial has satisfactory photostability. Through In vitro analysis, it was found that these TADF nanoparticles (NPs) targeted lysosomes in oral cancer cells. ROS were released under irradiation with a 450-nm laser, and the growth of xenograft tumors in mouse models was inhibited in vivo. More interestingly, radiation exposure caused little damage to normal tissues due to the low irradiation intensity (mA) used in the photodynamic therapy (PDT) treatment of oral cancer. Therefore, these TADF NPs provide new possibilities for the development of new PDT drugs for biomedical applications. In future work, possible functional modifications of TADF NPs for increased potency in clinical applications will be addressed.
Assuntos
Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Materiais Biocompatíveis/farmacologia , Neoplasias Bucais/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Animais , Antraquinonas/síntese química , Antraquinonas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fluorescência , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Tamanho da Partícula , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Oxigênio Singlete/análise , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Temperatura , Células Tumorais CultivadasRESUMO
Gastric cancer is one of the most common and deadly cancers among men and women and is the third leading cause of cancer mortality worldwide. Thus, discovering and developing novel therapeutics for gastric cancer has become a global priority. In this study, we synthesized two novel anthraquinone-based aspirin derivatives, Asp-X3 and Asp-X3-CH3, with therapeutic potential for gastric cancer. The structures of the two compounds were determined by 1D, 2D-NMR, and High-Resolution Mass (HRSM). Asp-X3 and Asp-X3-CH3 could inhibit the growth of gastric cancer cells (SGC7901), yielding IC50 values 10-fold lower than that of Aspirin. Asp-X3 and Asp-X3-CH3 were less toxic to gastric mucosal cells, yielding IC50 values that were about 2-fold higher than the corresponding IC50 values determined with SGC7901 cells. Asp-X3-CH3 and Asp-X3 also induced SGC7901 cells to undergo apoptosis, yielding apoptotic rates that were about twice the rate induced by Aspirin. Asp-X3-CH3 did not cause significant loss of COX-1 expression in gastric mucosal cells, whereas Asp-X3 and Aspirin both caused significant loss of COX-1 expression as demonstrated by Western blot, consistent with their effects on the content of PGE2 in these cells as determined by ELISA assay. However, both Asp-X3-CH3 and Asp-X3 exerted a similar effect on the level of COX-2 in gastric cancer cells, causing as much as 90% and 95% reduction in COX-2 expression, respectively. Taken together, the results suggested that Asp-X3-CH3 and Asp-X3 were potentially better agents than Aspirin for the inhibition of gastric cancer cell growth, but Asp-X3-CH3 was more effective.
Assuntos
Antraquinonas/síntese química , Antraquinonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Aspirina/análogos & derivados , Aspirina/farmacologia , Neoplasias Gástricas/prevenção & controle , Apoptose/efeitos dos fármacos , Aspirina/síntese química , Linhagem Celular Tumoral , Ciclo-Oxigenase 1/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/metabolismo , Mucosa Gástrica/citologia , Mucosa Gástrica/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Neoplasias Gástricas/induzido quimicamente , Relação Estrutura-AtividadeRESUMO
Rheum ribes L. (Rhubarb) is one of the most important edible medicinal plants in the Eastern Anatolia region and is called "Iskin" by local people. Resveratrol and 6-O-methylalaternin were isolated from the Rhubarb for the first time in addition to well-known secondary metabolites including emodin, aloe-emodin, ß-sitosterol and rutin. The new semi-synthetic anthraquinone derivatives with the NαFmoc-l-Lys and ethynyl group were synthesized from the isolated anthraquinones emodin and aloe-emodin of Rhubarb to increase the bioactivities. Aloe-emodin derivative with NαFmoc-l-Lys shows the highest inhibition values by 94.11 ± 0.12 and 82.38 ± 0.00% against HT-29 and HeLa cell lines, respectively, at 25 µg/mL. Further, modification of the aloe-emodin with both the ethynyl and the NαFmoc-l-Lys groups showed an antioxidant activity-enhancing effect. From molecular docking studies, the relative binding energies of the emodin and aloe-emodin derivatives to human serum albumin ranged from -7.30 and -10.62 kcal/mol.
Assuntos
Antraquinonas/química , Antineoplásicos/síntese química , Resveratrol/química , Rheum/química , Antraquinonas/síntese química , Antraquinonas/isolamento & purificação , Antraquinonas/metabolismo , Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Emodina/química , Emodina/isolamento & purificação , Emodina/metabolismo , Emodina/farmacologia , Humanos , Simulação de Acoplamento Molecular , Componentes Aéreos da Planta/química , Componentes Aéreos da Planta/metabolismo , Resveratrol/isolamento & purificação , Resveratrol/farmacologia , Rheum/metabolismo , Albumina Sérica/química , Albumina Sérica/metabolismoRESUMO
The quest for effective anticancer therapeutics continues to be extensively pursued. Over the past century, several drugs have been developed, however, a majority of these drugs have a poor therapeutic index and increased toxicity profile. Hence, there still exists ample opportunity to discover safe and effective anticancer drugs. Aurora Kinase B (AurB), a member of the Aurora kinase family and a key regulator of mitotic cell division, is found to be frequently overexpressed in a variety of human cancers and has thus emerged as an attractive target for the design of anticancer therapeutics. In the present study, a structure-based scaffold hopping approach was utilized to modify the heterocyclic moiety of (S)-3-(3-aminopyrrolidine-1-carbonyl)-4,11-dihydroxy-2-methylanthra [2,3-b]furan-5,10-dione (anthrafuran 1) to generate a series of heteroarene-fused anthraquinone derivatives, which were then subjected to virtual screening for the identification of potential AurB inhibitors. The obtained hits were subsequently synthesized and evaluated by using a combination of in silico and biophysical techniques for elucidating their in vitro binding and inhibition activity with recombinantly expressed AurB. Four identified hits presented an improved binding profile as compared to their parent analog anthrafuran 1. One derivative, anthrathiophene 2 demonstrated excellent in vitro inhibition of AurB (7.3 µM).
Assuntos
Antraquinonas , Aurora Quinase B , Inibidores de Proteínas Quinases , Antraquinonas/síntese química , Antraquinonas/química , Antraquinonas/farmacologia , Aurora Quinase B/antagonistas & inibidores , Aurora Quinase B/química , Aurora Quinase B/metabolismo , Linhagem Celular Tumoral , Humanos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologiaRESUMO
We report the design, synthesis, and biological evaluation of 13 new and 1 known anthraquinone derivatives which exerted cytotoxicity against PC3, A549 and NTUB1 cell lines. The results indicate that, among these 14, compounds-1 and 14 showed the highest growth inhibitory effect on NTUB1 and PC3 cells, respectively. Compound-1 at lower doses targets DNA, induces DNA damage and subsequently triggers G2/M arrest and apoptotic cell death at 24 h. Previously we reported that 14 induced PC3 cell autophagy and in treated PC3 cells, cleaved caspase-3 and cleaved PARP, and survivin did not increase and increase, respectively. The autophagic and necrotic cell deaths mediated by 14-triggered ROS generation. Our study is the first to investigate the biological mechanism of 14 action in detail. We find that when 14 was co-administrated with Bafilomycin A1 (BAF) in PC3 cells, rapid necrotic cell death occurred with no cleaved caspase-3 and cleaved PARP activation and increasing the expression of survivin. We further show that necrotic signaling in these cells coincided with production of reactive oxygen species. In the present study, we developed methods to synthesize five new 14 analogues for studing the structure-activity relationships. This study could provide valuable sight to find new antitumor agents for cancer therapy.
Assuntos
Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Antraquinonas/síntese química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Estrutura Molecular , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
Hyperlipidaemia is one of the major risk factors for atherosclerosis, coronary heart disease, stroke and diabetes. In the present study, we synthesized a new anthraquinone compound, 1,8-dihydroxy-3-succinic acid monoethyl ester-6-methylanthraquinone, and named it Kanglexin (KLX). The aim of this study was to evaluate whether KLX has a lipid-lowering effect and to explore the potential molecular mechanism. In this study, Sprague-Dawley rats were fed a high fat diet (HFD) for 5 weeks to establish a hyperlipidaemia model; then, the rats were orally administered KLX (20, 40, and 80 mg kg-1·d-1) or atorvastatin calcium (AT, 10 mg kg-1·d-1) once a day for 2 weeks. KLX had prominent effects on reducing blood lipids, hepatic lipid accumulation, body weight and the ratio of liver weight/body weight. Furthermore, KLXdramatically reduced the total cholesterol (TC) and triglyceride (TG) levels and lipid accumulation in a HepG2 cell model of dyslipidaemia induced by 1 mmol/L oleic acid (OA). KLX may decrease lipid levels by phosphorylating adenosine monophosphate-activated protein kinase (AMPK) and the downstream sterol regulatory element binding protein 2 (SREBP-2)/proprotein convertase subtilisin/kexin type 9 (PCSK9)/low-density lipoprotein receptor (LDLR) signalling pathway in the HFD rats and OA-treated HepG2 cells. The effects of KLX on the AMPK/SREBP-2/PCSK9/LDLR signalling pathway were abolished when AMPK was inhibited by compound C (a specific AMPK inhibitor) in HepG2 cells. In summary, KLX has an efficient lipid-lowering effect mediated by activation of the AMPK/SREBP-2/PCSK9/LDLR signalling pathway. Our findings may provide new insight into and evidence for the discovery of a new lipid-lowering drug for the prevention and treatment of hyperlipidaemia, fatty liver, and cardiovascular disease in the clinic.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antraquinonas/farmacologia , Fígado Gorduroso/prevenção & controle , Hepatócitos/efeitos dos fármacos , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/farmacologia , Lipídeos/sangue , Fígado/efeitos dos fármacos , Pró-Proteína Convertase 9/metabolismo , Receptores de LDL/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Animais , Antraquinonas/síntese química , Biomarcadores/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Fígado Gorduroso/sangue , Fígado Gorduroso/enzimologia , Fígado Gorduroso/patologia , Células Hep G2 , Hepatócitos/enzimologia , Hepatócitos/patologia , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/enzimologia , Hipolipemiantes/síntese química , Fígado/enzimologia , Fígado/patologia , Masculino , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
Anthracycline antibiotics play an important role in cancer chemotherapy. The need to improve their therapeutic index has stimulated an ongoing search for anthracycline analogs with enhanced properties. This review aims to summarize the common synthetic approaches to benzo[g]quinoxaline-5,10-diones and their uses in heterocyclic chemistry. Because of the valuable biological activities of the 1,4-diazaanthraquinone compounds, a summary of the most promising heterocyclic quinones is provided together with their antitumor properties.
Assuntos
Antraquinonas/síntese química , Antineoplásicos/síntese química , Técnicas de Química Sintética , Quinoxalinas/síntese química , Inibidores da Topoisomerase/síntese química , Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Concentração Inibidora 50 , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Quinoxalinas/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase/farmacologia , Proteína Supressora de Tumor p53/agonistas , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Angucyclinces belong to the class of aromatic polyketides and display a wide variety of structure diversity and pharmaceutical significance. Herein we report the isolation, structure elucidation, and bioactivity evaluation of structure-diversified angucyclinone derivatives and anthracene from the South China Sea-derived Micromonospora echinospora SCSIO 04089, including a thioether, gephysulfuromycin (1), two new benzo[b]phenanthridines, homophenanthroviridone (2) and homophenanthridonamide (3), a new benzo[b]fluorene, homostealthin D (4), a new naphtho[2,3-b]benzofuran, nenesfuran (5), a new naphthoquinone, WS-5995 D (6) and a new anthracene, nenesophanol (7), together with three known compounds (8-10). Their structures were elucidated by extensive spectroscopic analyses. The structures of 1-3 and 5-8 were confirmed by X-ray crystallographic analyses. Gephysulfuromycin (1) featured a rare single S-bridged 3,12a-epithiotetraphene skeleton. Homophenanthroviridone (2) was found to be cytotoxic to SF-268, MCF-7, and HepG2 cell lines with IC50 values of 5.4 ± 0.4, 6.8 ± 0.3, and 1.4 ± 0.1 µM, respectively. Compound 2 was also active against Gram-positive bacteria with MIC (minimal inhibition concentration) values ranging 2-4 µg mL-1.
Assuntos
Antraquinonas/síntese química , Antraquinonas/farmacologia , Micromonospora/química , Antibacterianos/química , Antibacterianos/farmacologia , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Organismos Aquáticos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Fermentação , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Testes de Sensibilidade Microbiana , Difração de Raios XRESUMO
Although anthraquinone derivatives possess significant antitumor activity, most of them also displayed those side effects like cardiotoxicity, mainly owing to their inhibition of topoisomerase II of DNA repair mechanisms. Our raised design strategy by switching therapeutic target from topoisomerase II to histone deacetylase (HDAC) has been applied to the design of anthraquinone derivatives in current study. Consequently, a series of novel HDAC inhibitors with a tricylic diketone of anthraquinone as a cap group have been synthesized. After screening and evaluation, compounds 4b, 4d, 7b and 7d have displayed the comparable inhibition in enzymatic activity and cell proliferation than that of Vorinostat (SAHA). Notably, compound 4b showed certain selectivity of antiproliferative effects on cancer cell lines over non-cancer cell lines.
Assuntos
Antraquinonas/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Antraquinonas/síntese química , Antraquinonas/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Reparo do DNA , Relação Dose-Resposta a Droga , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The emodin anthraquinone derivatives are generally used in traditional Chinese medicine due to their various pharmacological activities. In the present study, a series of emodin anthraquinone derivatives have been designed and synthesized, among which 1,3-dihydroxy-6,8-dimethoxyanthracene-9,10-dione is a natural compound that has been synthesized for the very first time, and 1,3-dimethoxy-5,8-dimethylanthracene-9,10-dione is a compound that has never been reported earlier. Interestingly, while total seven of these compounds showed neuraminidase inhibitory activity in influenza virus with inhibition rate more than 50 %, specific four compounds exhibited significant inhibition of tumor cell proliferation. The further results demonstrate that 1,3-dimethoxy-5,8-dimethylanthracene-9,10-dione showed the best anticancer activity among all the synthesized compounds by inducing highest apoptosis rate to HCT116 cancer cells and arresting their G0/G1â cell cycle phase, through elevation of intracellular level of reactive oxygen species (ROS). Moreover, the binding of 1,3-dimethoxy-5,8-dimethylanthracene-9,10-dione with BSA protein has thoroughly been investigated. Altogether, this study suggests the neuraminidase inhibitory activity and antitumor potential of the new emodin anthraquinone derivatives.
Assuntos
Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Emodina/farmacologia , Simulação de Acoplamento Molecular , Antraquinonas/síntese química , Antraquinonas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Emodina/análogos & derivados , Emodina/química , Humanos , Estrutura Molecular , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
Polypyridyl ruthenium complexes as novel photosensitizers had drawn attention due to its high selectivity towards cancer cells and low toxicity to normal cells. Herein, we synthesized a lysosome-targeted polypyridyl ruthenium complex Rhein-Ru(bpy)3 (bpy = 2,2'-bipyridine, rhein = 4,5-dihydroxy-9,10-dioxoanthracene-2-carboxylic acid), tethering with the Chinese medicine herb rhein. Rhein-Ru(bpy)3 exhibited high phototoxicity with short time of irradiation against tumor cell lines with the IC50 value of 2.4- 8.7 µM, and higher cytotoxicity against cisplatin-resistant A2780 cell lines, suggesting that Rhein-Ru(bpy)3 could overcome the cisplatin resistance. Moreover, Rhein-Ru(bpy)3 displayed low cytotoxicity towards cell lines in dark incubation, which was beneficial to reduce the toxic side effects towards normal cell lines. Besides, the confocal imaging and western blotting assay results suggested that Rhein-Ru(bpy)3 could induce cancer cell death through the autophagy pathway. These results inspired us that lysosome-targeted photosensitizers based on ruthenium complexes showed great potential for photodynamic therapy (PDT) application in cancer treatment.
Assuntos
2,2'-Dipiridil/análogos & derivados , 2,2'-Dipiridil/farmacologia , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Lisossomos/metabolismo , Fármacos Fotossensibilizantes/farmacologia , 2,2'-Dipiridil/efeitos da radiação , Antraquinonas/síntese química , Antraquinonas/farmacologia , Antraquinonas/efeitos da radiação , Antineoplásicos/síntese química , Antineoplásicos/efeitos da radiação , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/efeitos da radiação , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Luz , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/efeitos da radiação , Rutênio/química , Rutênio/efeitos da radiação , Oxigênio Singlete/metabolismoRESUMO
A series of 1,2-, 1,4-disubstituted or 1,2,4-trisubstituted anthraquinone-based compounds was designed, synthesized, characterized and biologically evaluated for anticancer efficacy. 2- or 4-arylated 1-hydroxy-9,10-antraquinones (anthracene-9,10-diones) were prepared by Suzuki-Miyaura cross-coupling reaction of 1-hydroxy-2-bromoanthraquinone, 1-hydroxy-4-iodoanthraquinone or 1-hydroxy-2,4-dibromoanthraquinone with arylboronic acids. The cross-coupling reaction of 2,4-dibromo-9,10-anthraquinone with arylboronic acids provide a convenient approach to 2,4-bis arylated 1-hydroxyanthraquinones with a variety of aryl substituent in the 2 and 4 position. The cytotoxicity of new anthraquinone derivatives was evaluated using the conventional MTT assays. The data revealed that six of the aryl substituted compounds among the entire series 3, 15, 16, 25, 27, 28 were comparable potent with the commercially available reference drug doxorubicin on the human glioblastoma cells SNB-19, prostate cancer DU-145 or breast cancer cells MDA-MB-231 and were relatively safe towards human telomerase (h-TERT)immortalized lung fibroblasts cells. The results suggested that the in vitro antitumor activity of synthesized 2-aryl, 4-aryl- and 2,4-diaryl substituted 1-hydroxyanthraquinones depends on the nature of the substituent within the cyclic backbone. Docking interaction of 2-, 4-substituted and 2,4-disubstituted 1-hydroxyanthraquinones indicates intercalative mode of binding of compounds with DNA topoisomerase. The interaction with the DNA of 4-aryl-13, 15, 16 and 4-(furan-3-yl)-23 1-hydroxyanthraquinones was experimentally confirmed through a change in electroforetic mobility. Further experiments with 1-hydroxy-4-phenyl-anthraquinone 13 demonstrated that the compound induced cell cycle arrest at sub-G1 phase in DU-145 cells in the concentration 1.1 µM, which is probably achieved by inducing apoptosis. 4-Arylsubstituted 1-hydroxyanthraquinones 13 and 16 induced the enhancement of DNA synthesis on SNB19 cell lines.
Assuntos
Antraquinonas/síntese química , Antineoplásicos/farmacologia , Antraquinonas/química , Apoptose , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/química , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Telomerase/metabolismoRESUMO
Heteroarene-fused anthraquinone derivatives represent a class of perspective anticancer drug candidates capable of targeting multiple vital processes including drug resistance. Taking advantage of previously demonstrated potential of amide derivatives of heteroarene-fused anthraquinones, we herein dissected the role of the heterocyclic core in antitumor properties. A new series of naphtho[2,3-f]indole-3- and anthra[2,3-b]thiophene-3-carboxamides was synthesized via coupling the respective acids with cyclic diamines. New compounds demonstrated a submicromolar antiproliferative potency close to doxorubicin (Dox) against five tumor cell lines of various tissue origin. In contrast to Dox, the new compounds were similarly cytotoxic for HCT116 colon carcinoma cells (wild type p53) and their isogenic p53 knockout counterparts. Modification of the heterocyclic core changed the targeting properties: the best-in-series naphtho[2,3-f]indole-3-carboxamide 8 formed more affine complexes with DNA duplex than furan and thiophene analogs, a property that can be translated into a stronger inhibition of topoisomerase 1 mediated DNA unwinding. At tolerable doses the water soluble derivative 8 significantly inhibited tumor growth (up to 79%) and increased the lifespan (153%) of mice bearing P388 lymphoma transplants. Together with better solubility for parenteral administration and well tolerance by animals of the indole derivative 8 indicates prospects for further search of new antitumor drug candidates among the heteroarene-fused anthraquinones.
Assuntos
Amidas/farmacologia , Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Compostos Heterocíclicos/farmacologia , Pirróis/farmacologia , Tiofenos/farmacologia , Amidas/química , Animais , Antraquinonas/síntese química , Antraquinonas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Células K562 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Simulação de Acoplamento Molecular , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Pirróis/química , Relação Estrutura-Atividade , Tiofenos/químicaRESUMO
Cancer, characterized by uncontrolled malignant neoplasm, is a leading cause of death in both advanced and emerging countries. Although, ample drugs are accessible in the market to intervene with tumor progression, none are totally effective and safe. Natural anthraquinone (AQ) equivalents such as emodin, aloe-emodin, alchemix and many synthetic analogs extend their antitumor activity on different targets including telomerase, topoisomerases, kinases, matrix metalloproteinases, DNA and different phases of cell lines. Nano drug delivery strategies are advanced tools which deliver drugs into tumor cells with minimum drug leakage to normal cells. This review delineates the way AQ derivatives are binding on these targets by abolishing tumor cells to produce anticancer activity and purview of nanoformulations related to AQ analogs.