RESUMEN
Liver fibrosis is a critical wound healing response to chronic liver injury such as hepatitis C virus (HCV) infection. If persistent, liver fibrosis can lead to cirrhosis and hepatocellular carcinoma (HCC). The development of new therapies for preventing liver fibrosis and its progression to cancer associated with HCV infection remains a critical challenge. Identification of novel anti-fibrotic compounds will provide opportunities for innovative therapeutic intervention of HCV-mediated liver fibrosis. We designed and synthesized a focused set of 5-arylthio-5H-chromenopyridines as a new class of anti-fibrotic agents. Liver fibrosis assays demonstrated that the compounds 3a and 3c show inhibitory activity towards human hepatic stellate cells (LX2) activation at 10µM. The HCV NS3 and NS5A proteins in HCV subgenome-expressing cells were also significantly reduced in cells treated with 3a and 3c, suggesting the possible inhibitory role of the compounds in HCV translation/replication activities. We have also examined the reactivity of these compounds with medicinally-relevant metal compounds such as platinum and gold. The reactivity of these complexes with metals and during Mass Spectrometry suggests that CS bond cleavage is relatively facile.
Asunto(s)
Hepatitis C/complicaciones , Cirrosis Hepática/prevención & control , Pirimidinas/farmacología , Hepacivirus/metabolismo , Humanos , Cirrosis Hepática/etiología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismoRESUMEN
The vacuolar (Hâº)-ATPases (V-ATPases) are a family of ATP-driven proton pumps and they have been associated with cancer invasion, metastasis, and drug resistance. Despite the clear involvement of V-ATPases in cancer, the therapeutic use of V-ATPase-targeting small molecules has not reached human clinical trials to date. Thus, V-ATPases are emerging as important targets for the identification of potential novel therapeutic agents. We identified a bisbenzimidazole derivative (V) as an initial hit from a similarity search using four known V-ATPase inhibitors (I-IV). Based on the initial hit (V), we designed and synthesized a focused set of novel bisbenzimidazole analogs (2a-e). All newly prepared compounds have been screened for selected human breast cancer (MDA-MB-468, MDA-MB-231, and MCF7) and ovarian cancer (A2780, Cis-A2780, and PA-1) cell lines, along with the normal breast epithelial cell line, MCF10A. The bisbenzimidazole derivative (2e) is active against all cell lines tested. Remarkably, it demonstrated high cytotoxicity against the triple-negative breast cancer (TNBC) cell line, MDA-MB-468 (IC50 = 0.04 ± 0.02 µM). Additionally, it has been shown to inhibit the V-ATPase pump that is mainly responsible for acidification. To the best of our knowledge the bisbenzimidazole pharmacophore has been identified as the first V-ATPase inhibitor in its class. These results strongly suggest that the compound 2e could be further developed as a potential anticancer V-ATPase inhibitor for breast cancer treatment.
Asunto(s)
Antineoplásicos/química , Bisbenzimidazol/análogos & derivados , Bisbenzimidazol/química , ATPasas de Translocación de Protón Vacuolares/antagonistas & inhibidores , Antineoplásicos/farmacología , Bisbenzimidazol/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
Lysophosphatidic acid (LPA) is a pleiotropic lipid signaling molecule associated with asthma pathobiology. LPA elicits its effects by binding to at least six known cell surface G protein-coupled receptors (LPA1-6) that are expressed in the lung in a cell type-specific manner. LPA2 in particular has emerged as an attractive therapeutic target in asthma because it appears to transduce inhibitory or cell-protective signals. We studied a novel and specific small molecule LPA2 agonist (2-[4-(1,3-dioxo-1H,3H-benzoisoquinolin-2-yl)butylsulfamoyl] benzoic acid [DBIBB]) in a mouse model of house dust mite-induced allergic airway inflammation. Mice injected with DBIBB developed significantly less airway and lung inflammation compared with vehicle-treated controls. Levels of lung Th2 cytokines were also significantly attenuated by DBIBB. We conclude that pharmacologic activation of LPA2 attenuates Th2-driven allergic airway inflammation in a mouse model of asthma. Targeting LPA receptor signaling holds therapeutic promise in allergic asthma.
Asunto(s)
Antiasmáticos/farmacología , Antiinflamatorios/farmacología , Asma/prevención & control , Pulmón/efectos de los fármacos , Naftalimidas/farmacología , Neumonía/prevención & control , Receptores del Ácido Lisofosfatídico/agonistas , Sulfonamidas/farmacología , Alérgenos , Animales , Antígenos Dermatofagoides , Proteínas de Artrópodos , Asma/inmunología , Asma/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Femenino , Mediadores de Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Ratones Endogámicos BALB C , Hidrolasas Diéster Fosfóricas/metabolismo , Neumonía/inmunología , Neumonía/metabolismo , Receptores del Ácido Lisofosfatídico/inmunología , Receptores del Ácido Lisofosfatídico/metabolismo , Transducción de Señal/efectos de los fármacos , Células Th2/efectos de los fármacos , Células Th2/inmunología , Células Th2/metabolismo , Factores de TiempoRESUMEN
Autotaxin (ATX), through its lysophospholipase D activity controls physiological levels of lysophosphatidic acid (LPA) in blood. ATX is overexpressed in multiple types of cancers, and together with LPA generated during platelet activation promotes skeletal metastasis of breast cancer. However, the pathophysiological sequelae of regulated interactions between circulating LPA, ATX, and platelets remain undefined in cancer. In this study, we show that ATX is stored in α-granules of resting human platelets and released upon tumor cell-induced platelet aggregation, leading to the production of LPA. Our in vitro and in vivo experiments using human breast cancer cells that do not express ATX (MDA-MB-231 and MDA-B02) demonstrate that nontumoral ATX controls the early stage of bone colonization by tumor cells. Moreover, expression of a dominant negative integrin αvß3-Δ744 or treatment with the anti-human αvß3 monoclonal antibody LM609, completely abolished binding of ATX to tumor cells, demonstrating the requirement of a fully active integrin αvß3 in this process. The present results establish a new mechanism for platelet contribution to LPA-dependent metastasis of breast cancer cells, and demonstrate the therapeutic potential of disrupting the binding of nontumor-derived ATX with the tumor cells for the prevention of metastasis.
Asunto(s)
Plaquetas/inmunología , Neoplasias Óseas/secundario , Neoplasias de la Mama/patología , Integrina alfaVbeta3/inmunología , Hidrolasas Diéster Fosfóricas/inmunología , Animales , Plaquetas/patología , Neoplasias Óseas/sangre , Neoplasias Óseas/inmunología , Neoplasias Óseas/patología , Huesos/inmunología , Huesos/patología , Mama/inmunología , Mama/patología , Neoplasias de la Mama/sangre , Neoplasias de la Mama/inmunología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Femenino , Humanos , Lisofosfolípidos/inmunología , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica/inmunología , Invasividad Neoplásica/patología , Activación PlaquetariaRESUMEN
Lysophosphatidic acid (LPA) has been implicated as a mediator of several cardiovascular functions, but its potential involvement in the control of vascular tone is obscure. Here, we show that both LPA (18:1) and VPC31143 (a synthetic agonist of LPA1-3 receptors) relax intact mouse thoracic aorta with similar Emax values (53.9 and 51.9% of phenylephrine-induced precontraction), although the EC50 of LPA- and VPC31143-induced vasorelaxations were different (400 vs. 15 nM, respectively). Mechanical removal of the endothelium or genetic deletion of endothelial nitric oxide synthase (eNOS) not only diminished vasorelaxation by LPA or VPC31143 but converted it to vasoconstriction. Freshly isolated mouse aortic endothelial cells expressed LPA1, LPA2, LPA4 and LPA5 transcripts. The LPA1,3 antagonist Ki16425, the LPA1 antagonist AM095, and the genetic deletion of LPA1, but not that of LPA2, abolished LPA-induced vasorelaxation. Inhibition of the phosphoinositide 3 kinase-protein kinase B/Akt pathway by wortmannin or MK-2206 failed to influence the effect of LPA. However, pharmacological inhibition of phospholipase C (PLC) by U73122 or edelfosine, but not genetic deletion of PLCε, abolished LPA-induced vasorelaxation and indicated that a PLC enzyme, other than PLCε, mediates the response. In summary, the present study identifies LPA as an endothelium-dependent vasodilator substance acting via LPA1, PLC, and eNOS.
Asunto(s)
Lisofosfolípidos/farmacología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Receptores del Ácido Lisofosfatídico/metabolismo , Fosfolipasas de Tipo C/metabolismo , Vasodilatación/efectos de los fármacos , Animales , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Técnicas In Vitro , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo III/genética , Vasodilatación/genéticaRESUMEN
PURPOSE: Our objective was to synthesize LHRH-conjugated amphiphilic copolymer for micellar delivery of CBDIV17, a novel antiandrogen for treating prostate cancer. METHODS: LHRH-PEG-b-p(CB-co-LA) was synthesized by opening polymerization of carbonate (CB), lactide (LA), and HOOC-PEG-OH followed by conjugation with LHRH analogue. Bicalutamide analogue CBIDV17 loaded micelles were formulated by film hydration method, and characterized for critical micelle concentration (CMC), drug loading and in vitro drug release. Formulations were tested on LNCaP and C4-2 cells for cellular uptake, induction of apoptosis, viability and dowregulation of androgen receptor (AR). In vivo studies were performed in ectopic tumor bearing athymic nude mice after tail vein injection at a dose of 10 mg/kg. Tumor volume and body weight were measured for 25 days followed by immunohistochemistry (IHC) of tumor samples for Ki-67, caspase-3, and prostate specific antigen (PSA). RESULTS: HOOC-PEG-b-p(CB-co-LA) and LHRH-PEG-b-p(CB-co-LA) were characterized by (1)HNMR and used for preparing micelles, which had a mean particle size of 75.60 ± 2.25 and 72.64 ± 1.15 nm, respectively and CBDIV17 loading of 4.6% w/w. LHRH conjugated micelles showed higher cellular uptake, cytotoxicity, and apoptosis in LNCaP and C4-2 cells compared to non-targeted micelles. CBDIV17 loaded LHRH micelles more efficiently inhibited the proliferation and induced apoptosis of tumor cells according to Ki-67, caspase-3, and PSA expression. There was significant inhibition of tumor growth with the treatment of CBDIV17 loaded LHRH-conjugated micelles. CONCLUSION: These results demonstrated that LHRH-b-PEG-p(CB-co-LA) micelles have the potential for targeted delivery of CBDIV17 to treat advanced prostate cancer.
Asunto(s)
Antagonistas de Andrógenos/administración & dosificación , Anilidas/administración & dosificación , Portadores de Fármacos/química , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/química , Hidroxibutiratos/administración & dosificación , Neoplasias de la Próstata/tratamiento farmacológico , Antagonistas de Andrógenos/uso terapéutico , Anilidas/uso terapéutico , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Portadores de Fármacos/síntesis química , Composición de Medicamentos , Liberación de Fármacos , Humanos , Hidroxibutiratos/uso terapéutico , Masculino , Ratones Desnudos , Micelas , Terapia Molecular Dirigida , Invasividad Neoplásica , Tamaño de la Partícula , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Autotaxin (ATX), a lysophospholipase D, plays an important role in cancer invasion, metastasis, tumor progression, tumorigenesis, neuropathic pain, fibrotic diseases, cholestatic pruritus, lymphocyte homing, and thrombotic diseases by producing the lipid mediator lysophosphatidic acid (LPA). A high-throughput screen of ATX inhibition using the lysophosphatidylcholine-like substrate fluorogenic substrate 3 (FS-3) and â¼10,000 compounds from the University of Cincinnati Drug Discovery Center identified several small-molecule inhibitors with IC50 vales ranging from nanomolar to low micromolar. The pharmacology of the three most potent compounds: 918013 (1; 2,4-dichloro-N-(3-fluorophenyl)-5-(4-morpholinylsulfonyl) benzamide), 931126 (2; 4-oxo-4-{2-[(5-phenoxy-1H-indol-2-yl)carbonyl]hydrazino}-N-(4-phenylbutan-2-yl)butanamide), and 966791 (3; N-(2,6-dimethylphenyl)-2-[N-(2-furylmethyl)(4-(1,2,3,4-tetraazolyl)phenyl)carbonylamino]-2-(4-hydroxy-3-methoxyphenyl) acetamide), were further characterized in enzyme, cellular, and whole animal models. Compounds 1 and 2 were competitive inhibitors of ATX-mediated hydrolysis of the lysophospholipase substrate FS-3. In contrast, compound 3 was a competitive inhibitor of both FS-3 and the phosphodiesterase substrate p-nitrophenyl thymidine 5'-monophosphate. Computational docking and mutagenesis suggested that compounds 1 and 2 target the hydrophobic pocket, thereby blocking access to the active site of ATX. The potencies of compounds 1-3 were comparable to each other in each of the assays. All of these compounds significantly reduced invasion of A2058 human melanoma cells in vitro and the colonization of lung metastases by B16-F10 murine melanoma cells in C57BL/6 mice. The compounds had no agonist or antagonist effects on select LPA or sphingosine 1-phosphate receptors, nor did they inhibit nucleotide pyrophosphatase/phosphodiesterase (NPP) enzymes NPP6 and NPP7. These results identify the molecular surface of the hydrophobic pocket of ATX as a target-binding site for inhibitors of enzymatic activity.
Asunto(s)
Antineoplásicos/química , Benzamidas/química , Bencenoacetamidas/química , Hidrazinas/química , Indoles/química , Inhibidores de Fosfodiesterasa/química , Hidrolasas Diéster Fosfóricas/química , Sulfonamidas/química , Tetrazoles/química , Animales , Antineoplásicos/farmacología , Benzamidas/farmacología , Bencenoacetamidas/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Ensayos Analíticos de Alto Rendimiento , Humanos , Hidrazinas/farmacología , Interacciones Hidrofóbicas e Hidrofílicas , Indoles/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/secundario , Ratones , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Mutación , Invasividad Neoplásica , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/metabolismo , Relación Estructura-Actividad , Sulfonamidas/farmacología , Tetrazoles/farmacologíaRESUMEN
LPA (lysophosphatidic acid, 1-acyl-2-hydroxy-sn-glycero-3-phosphate), is a growth factor-like lipid mediator that regulates many cellular functions, many of which are unique to malignantly transformed cells. The simple chemical structure of LPA and its profound effects in cancer cells has attracted the attention of the cancer therapeutics field and drives the development of therapeutics based on the LPA scaffold. In biological fluids, LPA is generated by ATX (autotaxin), a lysophospholipase D that cleaves the choline/serine headgroup from lysophosphatidylcholine and lysophosphatidylserine to generate LPA. In the present article, we review some of the key findings that make the ATX-LPA signalling axis an emerging target for cancer therapy.
Asunto(s)
Neoplasias/metabolismo , Hidrolasas Diéster Fosfóricas/metabolismo , Receptores del Ácido Lisofosfatídico/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Humanos , Lisofosfolípidos/metabolismo , Terapia Molecular Dirigida , Invasividad Neoplásica , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Organofosfonatos/farmacología , Organofosfonatos/uso terapéutico , Inhibidores de Fosfodiesterasa/farmacología , Inhibidores de Fosfodiesterasa/uso terapéutico , Hidrolasas Diéster Fosfóricas/genética , Transducción de Señal , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
To investigate the effectiveness of EDL-291, a 6,7-dimethoxy-1-[4-(4-methoxypyridin-3-yl)benzyl]-1,2,3,4-tetrahydroisoquinoline dihydrochloride compound, in inhibiting the survival of glioblastoma in vitro and in vivo. Dose-response curves were generated to determine the EC50 in rat and human glioblastoma cell lines by treatment with different dilutions of EDL-291. To evaluate the architecture of the glioblastoma cells after treatment with EDL-291, the rat and human glioblastoma cells were stained with Mito Tracker Green FM. To determine whether autophagy was induced in EDL-291-treated glioblastoma cells, both rat and human glioblastoma cell lines were stained with acridine orange and light chain-3 immunoblots were performed. The efficacy of EDL-291 was monitored in vivo using a rat glioblastoma model. Rat glioblastoma cells were transplanted into an intracranial rat model, followed by infusions of saline, a low dose of EDL-291 (20 mg/kg for the first half hour, followed by 40 mg/kg EDL-291 in saline for 4 h), or a high dose of EDL-291 (60 mg/kg for the first half hour, followed by 90 mg/kg EDL-291 for 4 h). EDL-291 inhibits glioblastoma in vitro by destroying the mitochondria as shown with Mito Tracker Green FM. Acridine orange staining and light chain-3 immunoblots suggest that autophagy is induced when glioblastoma cells are treated with EDL-291. In vivo, a low dosage of EDL-291 is sufficient and effective in reducing glioblastoma tumor size. EDL-291 selectively induces cell death in rat and human glioblastoma cell lines by the induction of autophagy. EDL-291 exhibits antiglioblastoma effects both in vitro and in vivo.
Asunto(s)
Antineoplásicos/farmacología , Glioblastoma/tratamiento farmacológico , Isoquinolinas/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Astrocitos/efectos de los fármacos , Astrocitos/patología , Autofagia/efectos de los fármacos , Western Blotting , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Glioblastoma/patología , Humanos , Isoquinolinas/química , Isoquinolinas/uso terapéutico , Masculino , Microscopía Confocal , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Overexpression of the androgen receptor (AR) and anti-apoptotic genes including X-linked inhibitor of apoptosis protein (XIAP) provide tumors with a proliferative advantage. Therefore, our objective was to determine whether novel antiandrogen (CBDIV17) and XIAP inhibitor based combination therapy can treat advanced prostate cancer. METHODS: CBDIV17 and embelin-6g were synthesized and their effect on cell proliferation, apoptosis, cell cycle and AR and XIAP gene silencing determined. RESULTS: CBDIV17 was more potent than bicalutamide and inhibited proliferation of C4-2 and LNCaP cells, IC(50) for CBDIV17 was ≈ 12 µM and ≈ 21 µM in LNCaP and C4-2 cells, respectively, whereas bicalutamide had IC(50) of ≈ 46 µM in LNCaP cells and minimal effect in C4-2 cells. CBDIV17 induced apoptosis more effectively compared to bicalutamide and significantly inhibited DNA replication. Combination of CBDIV17 and embelin resulted in supra-additive antiproliferative and apoptotic effects. Embelin downregulated AR expression and decreased androgen-mediated AR phosphorylation at Ser(81). These hydrophobic drugs were solubilized using micelles prepared with polyethylene glycol-b-poly (carbonate-co-lactide) (PEG-b-p(CB-co-LA)) copolymer. Combination therapy inhibited prostate tumor growth more effectively compared to control or monotherapy in vivo. CONCLUSIONS: Our results demonstrated that CBDIV17 in combination with embelin can potentially treat advanced prostate cancer.
Asunto(s)
Antagonistas de Andrógenos/uso terapéutico , Anilidas/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzoquinonas/uso terapéutico , Hidroxibutiratos/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Proteína Inhibidora de la Apoptosis Ligada a X/antagonistas & inhibidores , Antagonistas de Andrógenos/administración & dosificación , Antagonistas de Andrógenos/farmacología , Anilidas/administración & dosificación , Anilidas/farmacología , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Benzoquinonas/administración & dosificación , Benzoquinonas/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Hidroxibutiratos/administración & dosificación , Hidroxibutiratos/farmacología , Masculino , Ratones , Micelas , Nitrilos/farmacología , Próstata/efectos de los fármacos , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Compuestos de Tosilo/farmacología , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismoRESUMEN
As a continuation of our efforts to discover and develop small molecules as anticancer agents, we identified GRI-394837 as an initial hit from similarity search on RGD and its analogs. Based on GRI-394837, we designed and synthesized a focused set of novel chromenes (4a-e) in a single step using microwave method. All five compounds showed activity in the nanomolar range (IC(50): 7.4-640 nM) in two melanoma, three prostate and four glioma cancer cell lines. The chromene 4e is active against all the cell lines and particularly against the A172 human glioma cell line (IC(50): 7.4 nM). Interestingly, in vitro tubulin polymerization assay shows 4e to be a weak tubulin polymerization inhibitor but it shows very strong cytotoxicity in cellular assays, therefore there must be additional unknown mechanism(s) for the anticancer activity. Additionally, the strong antiproliferative activity was verified by one of the selected chromene (4a) by the NCI 60 cell line screen. These results strongly suggest that the novel chromenes could be further developed as a potential therapeutic agent for a variety of aggressive cancers.
Asunto(s)
Antineoplásicos/química , Benzopiranos/química , Antineoplásicos/síntesis química , Antineoplásicos/toxicidad , Astrocitos/efectos de los fármacos , Benzopiranos/síntesis química , Benzopiranos/toxicidad , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Simulación por Computador , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Oligopéptidos/química , Estructura Terciaria de Proteína , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/química , Moduladores de Tubulina/toxicidadRESUMEN
BACKGROUND: Search for new antiviral and anticancer agents are essential because of the emergence of drug resistance in recent years. In continuation of our efforts in identifying the new small molecule antiviral and anticancer agents, we identified chalcones as potent antiviral and anticancer agents. OBJECTIVE: With the aim of identifying the broad acting antiviral and anticancer agents, we discovered substituted aryl/heteroaryl derived thienyl chalcones as antiviral and anticancer agents. METHOD: A focused set of thienyl chalcone derivaties II-VI was screened for selected viruses Hepatitis B virus (HBV), Herpes simplex virus 1 (HSV-1), Human cytomegalovirus (HCMV), Dengue virus 2 (DENV2), Influenza A (H1N1) virus, MERS coronavirus, Poliovirus 1 (PV 1), Rift Valley fever (RVF), Tacaribe virus (TCRV), Venezuelan equine encephalitis virus (VEE) and Zika virus (ZIKV) using the National Institute of Allergy and Infectious Diseases (NIAID)'s Division of Microbiology and Infectious Diseases (DMID) antiviral screening program. Additionally, a cyclopropylquinoline derivative IV has been screened for 60 human cancer cell lines using the Development Therapeutics Program (DTP) of NCI. RESULTS: All thienyl chalcone derivatives II-VI displayed moderate to excellent antiviral activity towards several viruses tested. Compounds V and VI were turned out be active compounds towards human cytomegalovirus for both normal strain (AD169) as well as resistant isolate (GDGr K17). Particularly, cyano derivative V showed very high potency (EC50: <0.05 µM) towards AD169 strain of HCMV compared to standard drug Ganciclovir (EC50: 0.12 µM). Additionally, it showed moderate activity in the secondary assay (AD169; EC50: 2.30 µM). The cyclopropylquinoline derivative IV displayed high potency towards Rift Valley fever virus (RVFV) and Tacaribe virus (TCRV) towards Rift Valley fever virus (RVFV). The cyclopropylquinoline derivative IV is nearly 28 times more potent in our initial in vitro visual assay (EC50: 0.39 µg/ml) and nearly 17 times more potent in neutral red assay (EC50: 0.71 µg/ml) compared to the standard drug Ribavirin (EC50: 11 µg/ml; visual assay and EC50: 12 µg/ml; neutral red assay). It is nearly 12 times more potent in our initial in vitro visual assay (EC50: >1 µg/ml) and nearly 8 times more potent in neutral red assay (EC50: >1.3 µg/ml) compared to the standard drug Ribavirin (EC50: 12 µg/ml; visual assay and EC50: 9.9 µg/ml; neutral red assay) towards Tacaribe virus (TCRV). Additionally, cyclopropylquinoline derivative IV has shown strong growth inhibitory activity towards three major cancers (colon, breast, and leukemia) cell lines and moderate growth inhibition shown towards other cancer cell lines screened. CONCLUSION: Compounds V and VI were demonstrated viral inhibition towards Human cytomegalovirus, whereas cyclopropylquinoline derivative IV towards Rift Valley fever virus and Tacaribe virus. Additionally, cyclopropylquinoline derivative IV has displayed very good cytotoxicity against colon, breast and leukemia cell lines in vitro.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Antivirales/química , Antivirales/farmacología , Chalconas/química , Chalconas/farmacología , Virus/efectos de los fármacos , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , HumanosRESUMEN
PURPOSE: Tetrahydroisoquinolines (THIs) have demonstrated anti-cancer activity in rodent models of glioma, a form of brain cancer refractory to therapeutic intervention. In this study, peripheral and cerebrospinal fluid (CSF) pharmacokinetics in rats were determined to assess the drug developability of the novel THI EDL-155 for the treatment of glioma. METHODS: Serial blood and CSF samples were collected from rats following intravenous bolus administration of EDL-155 (10-20 mg/kg). Samples were analyzed by LC/MS/MS. Pharmacokinetic analyses using compartmental and noncompartmental methods were performed using the computer program WinNonlin. Plasma protein binding was measured using the charcoal adsorption method. The in vivo efficacy of EDL-155 (i.p. 20 mg/kg twice daily for 7 days) was assessed in rats with stereotactically implanted C6 glioma cells into the caudate. RESULTS: EDL-155 plasma concentration data were described by a one-compartment model. EDL-155 demonstrated rapid clearance (342.5+/-49.9 ml/min/kg), high volume of distribution (13.0+/-1.2 l/kg) and a terminal half-life of 23.7+/-1.5 min. Dose-normalized CSF area under the curve (AUC(CSF)) as a percentage of peripheral exposure (AUC(Plasma)) was 1.4%. EDL-155 was highly bound to plasma proteins (>93%). Intracranial tumor volume at 7 days post-implantation was approximately 30% smaller in animals treated with EDL-155 when compared to vehicle control animals (13.2+/-5.3 mm(3) vs. 18.7+/-6.3 mm(3); P=0.04). CONCLUSION: High clearance and extensive protein binding limit the brain availability of EDL-155 following systemic administration. EDL-155 treatment resulted in reduced tumor size despite limited blood brain barrier penetrability, which suggests that analogs with increased metabolic stability and brain penetrability may provide a therapeutic option for primary central nervous system tumors such as glioma. On-going studies are focused on the design, synthesis, and testing of novel analogs based upon these findings.
Asunto(s)
Antineoplásicos/farmacocinética , Tetrahidroisoquinolinas/farmacocinética , Animales , Antineoplásicos/sangre , Antineoplásicos/líquido cefalorraquídeo , Disponibilidad Biológica , Neoplasias Encefálicas/metabolismo , Cromatografía Liquida , Glioma/metabolismo , Semivida , Humanos , Inyecciones Intravenosas , Masculino , Espectrometría de Masas , Trasplante de Neoplasias , Ratas , Ratas Sprague-Dawley , Tetrahidroisoquinolinas/sangre , Tetrahidroisoquinolinas/líquido cefalorraquídeoRESUMEN
Indanone is one of the privileged structures in medicinal chemistry and it's commonly associated with various pharmacologically active compounds. The indanone moiety is found in several natural compounds and also, it can be used as intermediate in the synthesis of many different types of medicinally important molecules. Among the medicinally important indanones, the most significant drug probably is donepezil (IV), an acetylcholinesterase (AChE) inhibitor, which has been approved by the US Food and Drug Administration for the treatment of Alzheimer's disease (AD). Along with donepezil, the indanone moiety can be seen in a number of other pre-clinical and clinical candidates which belong to different categories with diverse therapeutic activities. In summary, the present review article encompasses the recent biological applications such as antialzheimer, anticancer, antimicrobial and antiviral activity of various indanone derivatives.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Antiinfecciosos/farmacología , Antineoplásicos/farmacología , Antivirales/farmacología , Inhibidores de la Colinesterasa/farmacología , Indanos/farmacología , Acetilcolinesterasa/metabolismo , Antiinfecciosos/química , Antineoplásicos/química , Antivirales/química , Bacterias/efectos de los fármacos , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Hongos/efectos de los fármacos , Humanos , Indanos/química , Estructura Molecular , Relación Estructura-Actividad , Virus/efectos de los fármacosRESUMEN
Macrocyclic chemistry is one of the emerging research areas in the chemical science. Macrocyclic compounds continue to attract significant attention due to their numerous possible applications particularly in the areas like biology, catalysis and industry. This review article summarizes the developments and advances in synthesis and medicinal applications of macrocyclic compounds derived from (benz)imidazole- and indole-based heterocycles. Important medicinal applications of (benz)imidazole- and indole-based macrocycles include antimicrobial and anticancer activities. The representative lead compounds in each series of macromolecules have been discussed. All these initial lead breakthroughs help validate the great potential of (benz)imidazole- and indole-based macrocyclic compounds as a class of effective medicinal agents.
Asunto(s)
Bencimidazoles/química , Indoles/química , Compuestos Macrocíclicos/química , Antiinfecciosos/farmacología , Antineoplásicos/farmacología , Bencimidazoles/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Indoles/farmacología , Compuestos Macrocíclicos/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
BACKGROUND: Discovery of novel antiviral agents is essential because viral infection continues to threaten human life globally. Various heterocyclic small molecules have been developed as antiviral agents. The 5,6-dimethoxyindan-1-on nucleus is of considerable interest as this ring is the key constituent in a range of bioactive compounds, both naturally occurring and synthetic, and often of considerable complexity. OBJECTIVE: The main purpose of this research was to discover and develop small molecule heterocycles as broad-spectrum of antiviral agents. METHOD: A focused small set of 5,6-dimethoxyindan-1-one analogs (6-8) along with a thiopene derivative (9) was screened for selected viruses (Vaccinia virus - VACA, Human papillomavirus - HPV, Zika virus - ZIKV, Dengue virus - DENV, Measles virus - MV, Poliovirus 3 - PV, Rift Valley fever virus - RVFV, Tacaribe virus - TCRV, Venezuelan equine encephalitis virus - VEEV, Herpes simplex virus 1 -HSV-1 and Human cytomegalovirus - HCMV) using the National Institute of Allergy and Infectious Diseases (NIAID)'s Division of Microbiology and Infectious Diseases (DMID) antiviral screening program. RESULTS: These molecules demonstrated moderate to excellent antiviral activity towards variety of viruses. The 5,6-dimethoxyindan-1-one analog (7) demonstrated high efficacy towards vaccinia virus (EC50: <0.05 µM) and was nearly 232 times more potent than the standard drug Cidofovir (EC50: 11.59 µM) in primary assay whereas it demonstrated moderate activity (EC50: >30.00 µM) in secondary plaque reduction assay. The thiophene analog (9) has shown very good viral inhibition towards several viruses such as Human papillomavirus, Measles virus, Rift Valley fever virus, Tacaribe virus and Herpes simplex virus 1. CONCLUSION: Our research identified a novel 5,6-dimethoxyindan-1-one analog (compound 7), as a potent antiviral agent for vaccinia virus, and heterocyclic chalcone analog (compound 9) as a broad spectrum antiviral agent.
Asunto(s)
Antivirales/farmacología , Indanos/farmacología , Virus/efectos de los fármacos , Antivirales/síntesis química , Antivirales/química , Relación Dosis-Respuesta a Droga , Indanos/síntesis química , Indanos/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
In ovarian cancer (OVCA), treatment failure due to chemo-resistance is a serious challenge. It is therefore critical to identify new therapies that are effective against resistant tumors and have reduced side effects. We recently identified 4-H-chromenes as tubulin depolymerizing agents that bind to colchicine site of beta-tubulin. Here, we screened a chemical library of substituted 4-H-chromenes and identified SP-6-27 to exhibit most potent anti-proliferative activity towards a panel of human cisplatin sensitive and resistant OVCA cell lines with 50% inhibitory concentration (IC50; mean ± SD) ranging from 0.10 ± 0.01 to 0.84 ± 0.20 µM. SP-6-27 exhibited minimum cytotoxicity to normal ovarian epithelia. A pronounced decrease in microtubule density as well as G2/M cell cycle arrest was observed in SP-6-27 treated cisplatin sensitive/resistant OVCA cells. The molecular mechanism of SP-6-27 induced cell death revealed modulation in cell-cycle regulation by upregulation of growth arrest and DNA damage inducible alpha transcripts (GADD45). An enhanced intrinsic apoptosis was observed in OVCA cells through upregulation of Bax, Apaf-1, caspase-6, -9, and caspase-3. In vitro wound healing assay revealed reduced OVCA cell migration upon SP-6-27 treatment. Additionally, SP-6-27 and cisplatin combinatorial treatment showed enhanced cytotoxicity in chemo-sensitive/resistant OVCA cells. Besides effect on cancer cells, SP-6-27 further restrained angiogenesis by inhibiting capillary tube formation by human umbilical vein endothelial cells (HUVEC). Together, these findings show that the chromene analog SP-6-27 is a novel chemotherapeutic agent that offers important advantages for the treatment of ovarian cancer.
RESUMEN
Cultured rat astrocytes and C6 rat glioma were used as a differential screen for a variety of 1,2,3,4-tetrahydroisoquinoline (THI) derivatives. Compound 1 [1-(biphenyl-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6,7-diol hydrochloride] selectively blocked the growth of C6 glioma leaving normal astrocytes relatively unaffected. The potential for clinical utility of 1 was further substantiated in human gliomas and other tumor cell lines. Preliminary SAR of this activity was characterized by synthesis and testing of several THI and conformationally flexible variants.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos de Bifenilo/síntesis química , Isoquinolinas/síntesis química , Tetrahidroisoquinolinas/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Astrocitos/efectos de los fármacos , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Línea Celular Tumoral , Células Cultivadas , Ensayos de Selección de Medicamentos Antitumorales , Glioma , Humanos , Isoquinolinas/química , Isoquinolinas/farmacología , Conformación Molecular , Ratas , Relación Estructura-Actividad , Tetrahidroisoquinolinas/química , Tetrahidroisoquinolinas/farmacologíaRESUMEN
A novel 1,4-N-->O migration of a disubstituted phenyl ring was observed during N-methylation of a bicalutamide derivative, (2S)-2-(tert-butyldimethylsilanyloxy)-N-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenoxy)-2-methylpropionamide, in the presence of CsF-Celite/acetonitrile and desilylation of (2S)-2-(tert-butyldimethylsilanyloxy)-N-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenoxy)-2,N-dimethylpropionamide in tetra-n-butylammonium fluoride/THF. Both NMR and X-ray analysis confirmed the structure of the 1,4-N-->O disubstituted phenyl ring migrated product.
RESUMEN
Cancer remains one of the unsolved diseases of today's advanced drug discovery world even though it is known to humans for centuries. There is continued effort to discover new chemotherapeutic agents to improve the outcome of cancer patients. Small-molecule agonists at tolllike receptor 7 and 8 (TLR7/8) have recently generated renewed interest in cancer research owing to their profound antitumoral activity. TLR-7/8 agonist imidazoquinolines (Imiquimod, and Resiquimod) and dual inhibitor of phosphoinositide 3-kinase and mammalian target of rapamycin (NVP-BEZ235) have emerged as clinically important candidates for treating cancers. This article reviews briefly the synthesis, structure-activity relationship (SAR) and biological activities of clinically studied imidazoquinolines along with novel emerging preclinical imidazoquinolines for the anticancer activity.