RESUMEN
The inhibition of kynurenine production is considered a promising target for cancer immunotherapy. In this study, an amino acid derivative, compound 1 was discovered using a cell-based assay with our screening library. Compound 1 suppressed kynurenine production without inhibiting indoleamine 2,3-dioxygenase 1 (IDO1) activity. The activity of 1 was derived from the inhibition of IDO1 by a metabolite of 1, O-benzylhydroxylamine (OBHA, 2a). A series of N-substituted 2a derivatives that exhibit potent activity in cell-based assays may represent effective prodrugs. Therefore, we synthesized and evaluated novel N,O-substituted hydroxylamine derivatives. The structure-activity relationships revealed that N,O-substituted hydroxylamine 2c inhibits kynurenine production in a cell-based assay. We conducted an in vivo experiment with 2c, although the effectiveness of O-substituted hydroxylamine derivatives in vivo has not been previously reported. The results indicate that N,O-substituted hydroxylamine derivatives are promising IDO1 inhibitors.
Asunto(s)
Hidroxilamina , Indolamina-Pirrol 2,3,-Dioxigenasa , Quinurenina , Quinurenina/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Relación Estructura-Actividad , Humanos , Hidroxilamina/química , Hidroxilamina/farmacología , Hidroxilaminas/química , Hidroxilaminas/farmacología , Estructura Molecular , Animales , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Ratones , Relación Dosis-Respuesta a DrogaRESUMEN
The androgen receptor (AR) is a critical target in all the clinical stages of prostate cancer. To identify a new AR inhibitor, we constructed a new screening system using the androgen-dependent growth of prostate cancer cell lines as a screening indicator. We screened 50,000 culture broths of microorganisms using this screening system and found that the fermentation broth produced by a fungus inhibited androgen-dependent growth of human prostate cancer LNCaP cells without cytotoxicity. Purification of this culture medium was performed, and this resulted in deoxynortryptoquivaline (DNT) being identified as a novel inhibitor of AR function. DNT showed potent inhibition of androgen-dependent growth of human prostate cancer LNCaP cells. The AR competitor assay was performed, and DNT did not act as an AR antagonist. However, DNT inhibited AR-dependent transcriptional activity and AR nuclear translocation, it suggested that the suppression of AR function leads to inhibition activity against androgen-dependent growth.
Asunto(s)
Andrógenos , Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Línea CelularRESUMEN
Point-mutations of MEK1, a central component of ERK signaling, are present in cancer and RASopathies, but their precise biological effects remain obscure. Here, we report a mutant MEK1 structure that uncovers the mechanisms underlying abnormal activities of cancer- and RASopathy-associated MEK1 mutants. These two classes of MEK1 mutations differentially impact on spatiotemporal dynamics of ERK signaling, cellular transcriptional programs, gene expression profiles, and consequent biological outcomes. By making use of such distinct characteristics of the MEK1 mutants, we identified cancer- and RASopathy-signature genes that may serve as diagnostic markers or therapeutic targets for these diseases. In particular, two AKT-inhibitor molecules, PHLDA1 and 2, are simultaneously upregulated by oncogenic ERK signaling, and mediate cancer-specific ERK-AKT crosstalk. The combined expression of PHLDA1/2 is critical to confer resistance to ERK pathway-targeted therapeutics on cancer cells. Finally, we propose a therapeutic strategy to overcome this drug resistance. Our data provide vital insights into the etiology, diagnosis, and therapeutic strategy of cancers and RASopathies.
Asunto(s)
Neoplasias , Proteínas Proto-Oncogénicas c-akt , Humanos , MAP Quinasa Quinasa 1/genética , Sistema de Señalización de MAP Quinasas/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/genéticaRESUMEN
The first medicine containing the boron element, bortezomib, was approved for clinical use just 18 years ago. The boronic acid substructure in bortezomib serves as an electrophilic functionality with high affinity for hydroxy groups, which are frequently found in catalytic sites of proteolytic enzymes, to create reversible covalent bonds with a slow dissociation rate. Today, boronic acid is considered an important molecule in the medicinal chemistry toolbox, which was promoted by the success of bortezomib and pioneering approaches to use boronic acid in the molecular design of serine protease inhibitors in the 1980s. In this review article, we first provide an overview of the development of bortezomib, and then summarize our achievements to construct boronic acid analogs of tyropeptin A, a naturally occurring proteasome inhibitor, with potent in vivo efficacy. Representative stereoselective synthetic methods of α-aminoboronic acid are also showcased.
Asunto(s)
Antineoplásicos/síntesis química , Ácidos Borónicos/química , Bortezomib/síntesis química , Desarrollo de Medicamentos/métodos , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Inhibidores de Serina Proteinasa/síntesis química , Bortezomib/química , Catálisis , Dipéptidos/síntesis química , Dipéptidos/química , Diseño de Fármacos , Inhibidores de Serina Proteinasa/química , EstereoisomerismoRESUMEN
The androgen receptor (AR) is an important therapeutic target for all clinical states of prostate cancer. We screened cultured broths of microorganisms for their ability to suppress androgen-dependent growth of human prostate cancer LNCaP and VCaP cells without cytotoxicity. We have already identified androprostamine A (APA) from a Streptomyces culture broth as a functional inhibitor of AR. APA repressed R1881 (the synthetic androgen methyltrienolone)-induced androgen-regulated gene expression and dramatically inhibited R1881-induced prostate-specific antigen levels. However, APA did not act as an AR antagonist and did not inhibit AR transcriptional activity. Moreover, AS2405, an APA derivative, significantly inhibited the growth of VCaP cells in SCID mice upon oral administration.
Asunto(s)
Antineoplásicos/uso terapéutico , Cinamatos/uso terapéutico , Oligopéptidos/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Antineoplásicos/química , Antineoplásicos/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cinamatos/química , Cinamatos/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Estructura Molecular , Oligopéptidos/química , Oligopéptidos/metabolismo , Streptomyces/metabolismoRESUMEN
Four new quinofuracins F - I were isolated from the culture broth of Staphylotrichum boninense PF1444. The structures of quinofuracins F - I were elucidated by extensive spectroscopic analysis. These quinofuracins induced tumor suppressor protein p53-dependent cell death in human glioblastoma LNZTA3 cells.
Asunto(s)
Antineoplásicos/farmacología , Ascomicetos/química , Nitrofurazona/análogos & derivados , Nitrofurazona/química , Antineoplásicos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma , Humanos , Estructura Molecular , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Gold compounds have been employed throughout history to treat various types of disease, from ancient times to the present day. In the year 1985, auranofin, a gold-containing compound, was approved by U.S. Food and Drug Administration (FDA) as a therapeutic agent to target rheumatoid arthritis that would facilitate easy oral drug administration as opposed to conventional intramuscular injection used in treatments. Furthermore, auranofin demonstrates promising results for the treatment of various diseases beyond rheumatoid arthritis, including cancer, neurodegenerative diseases, acquired immune deficiency syndrome, and bacterial and parasitic infections. Various potential novel applications for auranofin have been proposed for treating human diseases. Auranofin has previously been demonstrated to inhibit thioredoxin reductase (TrxR) involved within the thioredoxin (Trx) system that comprises one of the critical cellular redox systems within the body. TrxR comprises the sole known enzyme that catalyzes Trx reduction. With cancers in particular, TrxR inhibition facilitates an increase in cellular oxidative stress and suppresses tumor growth. In this review, we describe the potential of auranofin to serve as an anticancer agent and further drug repurposing to utilize this as a strategy for further appropriate drug developments.
Asunto(s)
Antineoplásicos , Artritis Reumatoide/tratamiento farmacológico , Auranofina/administración & dosificación , Auranofina/farmacología , Reposicionamiento de Medicamentos , Desarrollo de Medicamentos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Estrés Oxidativo , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidoresRESUMEN
Large regions in tumor tissues, particularly pancreatic cancer, are hypoxic and nutrient-deprived because of unregulated cell growth and insufficient vascular supply. Certain cancer cells, such as those inside a tumor, can tolerate these severe conditions and survive for prolonged periods. We hypothesized that small molecular agents, which can preferentially reduce cancer cell survival under nutrient-deprived conditions, could function as anticancer drugs. In this study, we constructed a high-throughput screening system to identify such small molecules and screened chemical libraries and microbial culture extracts. We were able to determine that some small molecular compounds, such as penicillic acid, papyracillic acid, and auranofin, exhibit preferential cytotoxicity to human pancreatic cancer cells under nutrient-deprived compared with nutrient-sufficient conditions. Further analysis revealed that these compounds target to redox systems such as GSH and thioredoxin and induce accumulation of reactive oxygen species in nutrient-deprived cancer cells, potentially contributing to apoptosis under nutrient-deprived conditions. Nutrient-deficient cancer cells are often deficient in GSH; thus, they are susceptible to redox system inhibitors. Targeting redox systems might be an attractive therapeutic strategy under nutrient-deprived conditions of the tumor microenvironment.
Asunto(s)
Alquenos/química , Auranofina/química , Glutatión/química , Ácido Penicílico/química , Compuestos de Espiro/química , Tiorredoxinas/química , Alquenos/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Auranofina/farmacología , Auranofina/uso terapéutico , Caspasa 3/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Glutatión/metabolismo , Humanos , Metaboloma/efectos de los fármacos , Ratones , Ratones Desnudos , Nutrientes/química , Nutrientes/deficiencia , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Ácido Penicílico/farmacología , Especies Reactivas de Oxígeno/metabolismo , Compuestos de Espiro/farmacología , Tiorredoxinas/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Leucinostatin Y, a new peptaibiotic, was isolated from the culture broth of the entomoparasitic fungus Purpureocillium lilacinum 40-H-28. The planar structure was elucidated by detailed analysis of its NMR and MS/MS data. The absolute configurations of the amino acids were partially determined by an advanced Marfey's method. The biological activities of leucinostatin Y were assessed using human pancreatic cancer cells, revealing the importance of the C-terminus of leucinostatins for preferential cytotoxicity to cancer cells under glucose-deprived conditions and inhibition of mitochondrial function.
Asunto(s)
Antineoplásicos/aislamiento & purificación , Paecilomyces/química , Peptaiboles/aislamiento & purificación , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Humanos , Espectroscopía de Resonancia Magnética , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Peptaiboles/química , Peptaiboles/farmacologíaRESUMEN
Gold compounds have a long history of use in medicine. Auranofin was developed more than 30 years ago as an oral therapy for rheumatoid arthritis. Now, however, auranofin is rarely used in clinical practice despite its efficacy for treating rheumatoid arthritis because more novel antirheumatic medications are available. Although its use in clinical practice has decreased, studies on auranofin have continued and it shows promise for the treatment of several different diseases, including cancer and bacterial and parasitic infections. Several potential novel applications of auranofin for treating human disease have been proposed. Auranofin inhibits the activity of thioredoxin reductase (TrxR), an enzyme of the thioredoxin (Trx) system that is important for maintaining the intracellular redox state. Particularly in cancers, TrxR inhibition leads to an increase in cellular oxidative stress and induces apoptosis. TrxR overexpression is associated with aggressive tumor progression and poor survival in patients with breast, ovarian, and lung cancers. The Trx system may represent an attractive target for the development of new cancer treatments. Therefore, the TrxR inhibitor auranofin may be a potent anticancer agent. This review summarizes the current understanding of auranofin for cancer therapy.
Asunto(s)
Antineoplásicos/farmacología , Auranofina/farmacología , Animales , Apoptosis/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Neoplasias/enzimología , Neoplasias/metabolismo , Neoplasias/patología , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Tiorredoxinas/metabolismoRESUMEN
Mitogen-activated protein kinase (MAPK) pathways that direct cellular responses are involved in various biological processes; the RAS-RAF-MEK-ERK pathway is one of the most important MAPK pathways. It is frequently activated in human malignant tumors such as melanomas, thyroid tumors and colorectal carcinomas. Therefore, targeting this pathway has been considered an attractive strategy for new anticancer drugs. In particular, MEK is a promising target because it is a kinase that directly phosphorylates ERK. We performed a screening to discover new MEK inhibitors, and found a guanine derivative produced by Streptomyces sp. MK63-43F2. This guanine derivative was identified to be 2-amino-4-methoxy-5-cyanopyrrolo[2,3-d]pyrimidine (1) through spectroscopic analysis. Compound 1 inhibited MEK1 kinase activity in an ATP-dependent manner and suppressed the phosphorylation of ERK in cancer cells and cell proliferation. Therefore, 1 might be a potent lead compound for new MEK inhibitors.The Journal of Antibiotics advance online publication, 6 September 2017; doi:10.1038/ja.2017.100.
RESUMEN
Tyropeptins are new proteasome inhibitors isolated from the culture broth of Kitasatospora sp. MK993-dF2. Tyropeptins permeate cell membranes, inhibit intracellular proteasomes and reduce the degradation of ubiquitinated proteins in mammalian cells. We performed structure-based drug design and structure-activity relationship studies on tyropeptin derivatives to obtain valuable information of derivatives. Among the synthesized tyropeptin derivatives, some boronic acid derivatives exhibited potent antitumor effects against human multiple myeloma. In this review, we summarize the discovery of tyropeptins and the development of tyropeptin derivatives.
Asunto(s)
Dipéptidos/aislamiento & purificación , Diseño de Fármacos , Streptomycetaceae/metabolismo , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Dipéptidos/química , Dipéptidos/farmacología , Humanos , Complejo de la Endopetidasa Proteasomal , Inhibidores de Proteasoma/química , Inhibidores de Proteasoma/aislamiento & purificación , Inhibidores de Proteasoma/farmacología , Relación Estructura-ActividadRESUMEN
Syntheses of androprostamine A (1), and resormycin (3), anti-prostate cancer peptidyl natural products produced by microorganisms, were completed. The characteristic enamide structures of these compounds were installed using the Horner-Wadsworth-Emmons reaction from the corresponding phosphonates in reasonable Z-selectivity.
Asunto(s)
Cinamatos/síntesis química , Oligopéptidos/síntesis química , Propionatos/síntesis química , Cinamatos/química , Estructura Molecular , Oligopéptidos/química , Propionatos/química , EstereoisomerismoRESUMEN
Four unique isoflavone aglycones (barpisoflavone A (1), 2'-hydroxygenistein (2), 5-methylgenistein (3), and gerontoisoflavone A (4)) whose structures were related to genistein were prepared from the tuber of Apios americana Medik. We examined the estrogen receptor and androgen receptor binding activities, estrogen agonistic activities, antioxidant activities, and α-glucosidase inhibitory activities of 1-4. The results obtained showed that 2 possessed potent and 1, 3, and 4 possessed moderate estrogen partial agonistic activities, 1 and 2 possessed moderate antioxidant activities, and 2 and 3 possessed moderate α-glucosidase inhibitory activities.
Asunto(s)
Fabaceae/química , Isoflavonas/farmacologíaRESUMEN
The proteasome influences cellular homeostasis through the degradation of regulatory proteins, many of which are also involved in disease pathogenesis. In particular, numerous regulatory proteins associated with tumor growth, such as cyclins, cyclin-dependent kinase inhibitors, tumor suppressors, and NF-κB inhibitors are degraded by the proteasome. Proteasome inhibitors can stabilize these regulatory proteins, resulting in the suppression of tumor development and the regulation of immune responses. Thus, proteasome inhibitors are promising candidate antitumor agents and immune-regulatory agents. Bortezomib is the first-in-class proteasome inhibitor approved for the treatment of multiple myeloma. Despite its high efficiency, however, a large proportion of patients do not attain sufficient clinical response due to toxicity and drug resistance. Therefore, the development of new proteasome inhibitors with improved pharmacological properties is needed. Natural products produced by microorganisms are a promising source of such compounds. This review provides an overview of proteasome inhibitors produced by microorganisms, with special focus on inhibitors isolated from actinomycetes.
Asunto(s)
Actinobacteria/química , Antineoplásicos/uso terapéutico , Productos Biológicos/uso terapéutico , Bortezomib/uso terapéutico , Factores Inmunológicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Inhibidores de Proteasoma/uso terapéutico , Actinobacteria/metabolismo , Antineoplásicos/farmacología , Productos Biológicos/farmacología , Bortezomib/química , Bortezomib/farmacología , Burkholderiaceae/química , Burkholderiaceae/metabolismo , Descubrimiento de Drogas/métodos , Humanos , Factores Inmunológicos/farmacología , Terapia Molecular Dirigida/métodos , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/síntesis química , Inhibidores de Proteasoma/farmacología , Xylariales/química , Xylariales/metabolismoAsunto(s)
Antraquinonas/farmacología , Antineoplásicos/farmacología , Ascomicetos/metabolismo , Antraquinonas/química , Antineoplásicos/química , Ascomicetos/clasificación , Ascomicetos/aislamiento & purificación , Línea Celular Tumoral/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Glioblastoma/patología , Humanos , Espectroscopía de Resonancia Magnética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Quinofuracins A-E, novel anthraquinone derivatives containing ß-D-galactofuranose that were isolated from the fungus Staphylotrichum boninense PF1444, induced p53-dependent cell death in human tumor cells. The structures of quinofuracins A-E, including absolute configurations, were elucidated by extensive spectroscopic analysis and chemical transformation studies. Quinofuracins were classified into three groups according to the aglycone moieties. 5'-Oxoaverantin was present in quinofuracins A-C, whereas averantin and versicolorin B were identified in quinofuracins D and E, respectively. These quinofuracins induced p53-dependent growth suppression in human glioblastoma LNZTA3 cells.
Asunto(s)
Antraquinonas/aislamiento & purificación , Antraquinonas/farmacología , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Ascomicetos/química , Proteína p53 Supresora de Tumor/metabolismo , Antraquinonas/química , Antineoplásicos/química , Muerte Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Glioblastoma/tratamiento farmacológico , Humanos , Japón , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Proteína p53 Supresora de Tumor/efectos de los fármacosRESUMEN
Androgen receptor (AR) is a validated target in all clinical states of prostate cancer. Androprostamines A and B, the new inhibitors of androgen receptor, were isolated from Streptomyces sp. MK932-CF8. Their structures were determined by the spectroscopic analysis, degradation studies and synthesis. Androprostamines showed potent inhibitory effect against androgen-dependent growth of human prostate cancer cells without cytotoxicity and repressed the androgen-induced expression of AR-regulated genes.