RESUMEN
The CXC chemokine receptor type 4 (CXCR4) receptor and its ligand, CXCL12, are overexpressed in various cancers and mediate tumor progression and hypoxia-mediated resistance to cancer therapy. While CXCR4 antagonists have potential anticancer effects when combined with conventional anticancer drugs, their poor potency against CXCL12/CXCR4 downstream signaling pathways and systemic toxicity had precluded clinical application. Herein, BPRCX807, known as a safe, selective, and potent CXCR4 antagonist, has been designed and experimentally realized. In in vitro and in vivo hepatocellular carcinoma mouse models it can significantly suppress primary tumor growth, prevent distant metastasis/cell migration, reduce angiogenesis, and normalize the immunosuppressive tumor microenvironment by reducing tumor-associated macrophages (TAMs) infiltration, reprogramming TAMs toward an immunostimulatory phenotype and promoting cytotoxic T cell infiltration into tumor. Although BPRCX807 treatment alone prolongs overall survival as effectively as both marketed sorafenib and anti-PD-1, it could synergize with either of them in combination therapy to further extend life expectancy and suppress distant metastasis more significantly.
Asunto(s)
Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Receptores CXCR4/antagonistas & inhibidores , Animales , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Dietilnitrosamina/administración & dosificación , Dietilnitrosamina/toxicidad , Sinergismo Farmacológico , Humanos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/inmunología , Neoplasias Hepáticas Experimentales/patología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Ratones , Simulación del Acoplamiento Molecular , Ratas , Receptores CXCR4/metabolismo , Transducción de Señal/efectos de los fármacos , Sorafenib/farmacología , Sorafenib/uso terapéutico , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Macrófagos Asociados a Tumores/efectos de los fármacos , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cannabinoid receptor 1 (CB1) is a G protein-coupled receptor and a therapeutic target for metabolic disorders. Numerous CB1 antagonists have been developed, but their functional selectivities and bias towards G protein or ß-arrestin signaling have not been systemically characterized. In this study, we analyzed the binding affinities and downstream signaling of two series of pyrazole derivatives bearing 1-aminopiperidine (Series I) or 4-aminothiomorpholine 1,1-dioxide (Series II) moieties, as well as the well-known CB1 antagonists rimonabant and taranabant. Analyses of the results for the Series I and II derivatives showed that minor structure modifications to their functional groups and especially the incorporation of 1-aminopiperidine or 4-aminothiomorpholine 1,1-dioxide motifs can profoundly affect their bias toward G protein or ß-arrestin signaling, and that their binding affinity and functional activity can be disassociated. Docking and molecular dynamics simulations revealed that the binding modes of Series I and II antagonists differed primarily in that Series I antagonists formed an additional hydrogen bond with the receptor, whereas those in Series II formed a water bridge.
Asunto(s)
Antagonistas de Receptores de Cannabinoides , Proteínas de Unión al GTP , Antagonistas de Receptores de Cannabinoides/farmacología , Antagonistas de Receptores de Cannabinoides/metabolismo , Rimonabant , beta-Arrestinas/metabolismo , Proteínas de Unión al GTP/metabolismo , Receptores de Cannabinoides/metabolismoRESUMEN
Making use of a Diels-Alder approach based on various α,ß-unsaturated 2-carbomethoxy-4,4-dimethyl-1-tetralones as novel dienophiles, the corresponding polycyclic adducts could be efficiently synthesized in good to high yields (74~99%) in the presence of Lewis acid (e.g., SnCl4). Accordingly, a synthetically useful platform is established to provide a focused aromatic polyketide-like library for screening of potential natural and non-natural antimicrobial agents.
Asunto(s)
Antibacterianos , Tetralonas , Estructura Molecular , Antibacterianos/farmacología , Estereoisomerismo , Biblioteca de GenesRESUMEN
CXCR4 antagonists have been claimed to reduce mortality after myocardial infarction in myocardial infarction (MI) animals, presumably due to suppressing inflammatory responses caused by myocardial ischemia-reperfusion injury, thus, subsequently facilitating tissue repair and cardiac function recovery. This study aims to determine whether a newly designed CXCR4 antagonist DBPR807 could exert better vascular-protective effects than other clinical counterparts (e.g., AMD3100) to alleviate cardiac damage further exacerbated by reperfusion. Consequently, we find that instead of traditional continuous treatment or multiple-dose treatment at different intervals of time, a single-dose treatment of DBPR807 before reperfusion in MI animals could attenuate inflammation via protecting oxidative stress damage and preserve vascular/capillary density and integrity via mobilizing endothelial progenitor cells, leading to a desirable fibrosis reduction and recovery of cardiac function, as evaluated with the LVEF (left ventricular ejection fraction) in infarcted hearts in rats and mini-pigs, respectively. Thus, it is highly suggested that CXCR4 antagonists should be given at a single high dose prior to reperfusion to provide the maximal cardiac functional improvement. Based on its favorable efficacy and safety profiles indicated in tested animals, DBPR807 has a great potential to serve as an adjunctive medicine for percutaneous coronary intervention (PCI) therapies in acute MI patients.
Asunto(s)
Infarto del Miocardio , Daño por Reperfusión Miocárdica , Intervención Coronaria Percutánea , Receptores CXCR4 , Animales , Infarto del Miocardio/terapia , Daño por Reperfusión Miocárdica/etiología , Ratas , Receptores CXCR4/antagonistas & inhibidores , Volumen Sistólico , Porcinos , Porcinos Enanos , Función Ventricular IzquierdaRESUMEN
Using an established CRISPR-Cas mediated genome editing technique for streptomycetes, we explored the combinatorial biosynthesis potential of the auroramycin biosynthetic gene cluster in Streptomyces roseosporous. Auroramycin is a potent anti-MRSA polyene macrolactam. In addition, auroramycin has antifungal activities, which is unique among structurally similar polyene macrolactams, such as incednine and silvalactam. In this work, we employed different engineering strategies to target glycosylation and acylation biosynthetic machineries within its recently elucidated biosynthetic pathway. Auroramycin analogs with variations in C-, N- methylation, hydroxylation and extender units incorporation were produced and characterized. By comparing the bioactivity profiles of five of these analogs, we determined that unique disaccharide motif of auroramycin is essential for its antimicrobial bioactivity. We further demonstrated that C-methylation of the 3, 5-epi-lemonose unit, which is unique among structurally similar polyene macrolactams, is key to its antifungal activity.
Asunto(s)
Antibacterianos/biosíntesis , Antifúngicos/química , Vías Biosintéticas/genética , Ingeniería Metabólica/métodos , Streptomyces/genética , Antibacterianos/química , Antibacterianos/farmacología , Antifúngicos/farmacología , Sistemas CRISPR-Cas , Edición Génica/métodos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Polienos/química , Streptomyces/metabolismoRESUMEN
Intracerebral hemorrhage (ICH) is a major cause of stroke, with high mortality and morbidity. There is no effective pharmacological therapy for ICH. Previous studies have indicated that CXCR4 antagonists reduced microglia activation, attenuated infiltration of T cells, and improved functional recovery in ischemic stroke animals. The interaction of CXCR4 antagonists and ICH has not been characterized. The purpose of this study is to examine the neuroprotective action of a novel CXCR4 antagonist CX807 against ICH. In primary cortical neuronal and BV2 microglia co-culture, CX807 reduced glutamate-mediated neuronal loss and microglia activation. Adult rats were locally administered with collagenase VII to induce ICH. CX807 was given systemically after the ICH. Early post-treatment with CX807 improved locomotor activity in ICH rats. Brain tissues were collected for qRTPCR and histological staining. ICH upregulated the expression of CXCR4, CD8, TNFα, IL6, and TLR4. The immunoreactivity of IBA1 and CD8, as well as TUNEL labeling, were enhanced in the perilesioned area. CX807 significantly mitigated these responses. In conclusion, our data suggest that CX807 is neuroprotective and anti-inflammatory against ICH. CX807 may have clinical implications for the treatment of hemorrhagic stroke.
Asunto(s)
Antiinflamatorios/uso terapéutico , Hemorragia Cerebral/tratamiento farmacológico , Locomoción/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Receptores CXCR4/antagonistas & inhibidores , Accidente Cerebrovascular/tratamiento farmacológico , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Células Cultivadas , Hemorragia Cerebral/inducido químicamente , Células HEK293 , Humanos , Masculino , Colagenasa Microbiana , Microglía/efectos de los fármacos , Microglía/patología , Ratas Sprague-DawleyRESUMEN
The cross-conjugated vinylogous [4+2] anionic annulation has been newly developed, the cascade process of which has a high preference for regiochemical control and chemoselectivity, giving rise to exclusively Michael-type adducts in moderate to high yields (up to 94 %, 35 examples). By making use of this approach as a key operation, the first total synthesis of natural antibiotic ABX, in racemic form, has been successfully achieved in a concise 7-step sequence with an overall yield of about 20 %.
Asunto(s)
Antibacterianos/síntesis química , Productos Biológicos/química , Aniones/química , Antibacterianos/química , Productos Biológicos/síntesis química , Reacción de Cicloadición , EstereoisomerismoRESUMEN
The [18F] isotope-labelled CB1 inverse agonist 3 was elaborated and synthesized for positron emission tomography scanning studies. After immediate purification and calibration with its unlabeled counterpart, compound 3 was intravenously injected in mice and revealed that its distribution percentage in brain over 90-min scans among five region of interests, including brain, liver, heart, thigh muscle and kidney was lower than 1%, thus providing direct evidence to justify itself as a peripherally restricted CB1 antagonist.
Asunto(s)
Agonistas de Receptores de Cannabinoides/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/agonistas , Sulfonamidas/farmacología , Tiofenos/farmacología , Animales , Agonistas de Receptores de Cannabinoides/síntesis química , Agonistas de Receptores de Cannabinoides/química , Agonistas de Receptores de Cannabinoides/farmacocinética , Agonismo Inverso de Drogas , Radioisótopos de Flúor , Marcaje Isotópico , Masculino , Ratones Endogámicos C57BL , Tomografía de Emisión de Positrones/métodos , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacocinética , Receptor Cannabinoide CB1/antagonistas & inhibidores , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacocinética , Tiofenos/química , Tiofenos/farmacocinética , Distribución TisularRESUMEN
CXCR4 antagonists (e.g., PlerixaforTM ) have been successfully validated as stem cell mobilizers for peripheral blood stem cell transplantation. Applications of the CXCR4 antagonists have heralded the era of cell-based therapy and opened a potential therapeutic horizon for many unmet medical needs such as kidney injury, ischemic stroke, cancer, and myocardial infarction. In this review, we first introduce the central role of CXCR4 in diverse cellular signaling pathways and discuss its involvement in several disease progressions. We then highlight the molecular design and optimization strategies for targeting CXCR4 from a large number of case studies, concluding that polyamines are the preferred CXCR4-binding ligands compared to other structural options, presumably by mimicking the highly positively charged natural ligand CXCL12. These results could be further justified with computer-aided docking into the CXCR4 crystal structure wherein both major and minor subpockets of the binding cavity are considered functionally important. Finally, from the clinical point of view, CXCR4 antagonists could mobilize hematopoietic stem/progenitor cells with long-term repopulating capacity to the peripheral blood, promising to replace surgically obtained bone marrow cells as a preferred source for stem cell transplantation.
Asunto(s)
Quimiocina CXCL12/química , Infecciones por VIH/tratamiento farmacológico , Movilización de Célula Madre Hematopoyética , Células Madre Hematopoyéticas/citología , Receptores CXCR4/antagonistas & inhibidores , Animales , Enfermedades Autoinmunes/tratamiento farmacológico , Ensayos Clínicos como Asunto , Cristalografía por Rayos X , Humanos , Inmunoterapia , Ligandos , Isquemia Miocárdica/tratamiento farmacológico , Metástasis de la Neoplasia , Neutrófilos/citología , Péptidos/química , Regeneración , Transducción de Señal , Trasplante de Células MadreRESUMEN
Silent biosynthetic gene clusters represent a potentially rich source of new bioactive compounds. We report the discovery, characterization, and biosynthesis of a novel doubly glycosylated 24-membered polyene macrolactam from a silent biosynthetic gene cluster in Streptomyces roseosporus by using the CRISPR-Cas9 gene cluster activation strategy. Structural characterization of this polyketide, named auroramycin, revealed a rare isobutyrylmalonyl extender unit and a unique pair of amino sugars. Relative and absolute stereochemistry were determined by using a combination of spectroscopic analyses, chemical derivatization, and computational analysis. The activated gene cluster for auroramycin production was also verified by transcriptional analyses and gene deletions. Finally, auroramycin exhibited potent anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity towards clinical drug-resistant isolates.
RESUMEN
Making use of a reductive olefin coupling reaction and Michael-Dieckmann condensation as two key operations, we have completed a concise total synthesis of tetarimycin A, (±)-naphthacemycin A9, and (±)-fasamycin A in a highly convergent and practical protocol. Synthetic procedures thus developed have also been applied to provide related analogues for structure-activity relationship studies, thereby coming to the conclusion that the free hydroxyl group at C-10 is essential for exerting inhibitory activities against a panel of Gram-positive bacteria, including drug-resistant strains VRE and MRSA.
Asunto(s)
Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacología , Farmacorresistencia Microbiana/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Naftacenos/síntesis química , Naftacenos/farmacología , Hidrocarburos Policíclicos Aromáticos/síntesis química , Hidrocarburos Policíclicos Aromáticos/farmacología , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/farmacología , Relación Estructura-ActividadRESUMEN
Making use of temperature-controlled thiation as a key operation, a simple route to 2-aminothiophenes or thieno[2,3- c]isothiazoles has been newly developed wherein the 2-aminothiophene nucleus was formed through an initial formation of thioamide followed by a 5-exo-dig addition to the tethered alkyne; however, under harsher thermal conditions, excess sulfur-transferring reagents enabled further oxidative thiation to generate the corresponding thieno[2,3- c]isothiazoles.
RESUMEN
A series of zinc(II) dipicolylamine (ZnDPA)-based drug conjugates have been synthesized to probe the potential of phosphatidylserine (PS) as a new antigen for small molecule drug conjugate (SMDC) development. Using in vitro cytotoxicity and plasma stability studies, PS-binding assay, in vivo pharmacokinetic studies, and maximum tolerated dose profiles, we provided a roadmap and the key parameters required for the development of the ZnDPA based drug conjugate. In particular, conjugate 24 induced tumor regression in the COLO 205 xenograft model and exhibited a more potent antitumor effect with a 70% reduction of cytotoxic payload compared to that of the marketed irinotecan when dosed at the same regimen. In addition to the validation of PS as an effective pharmacodelivery target for SMDC, our work also provided the foundation that, if applicable, a variety of therapeutic agents could be conjugated in the same manner to treat other PS-associated diseases.
Asunto(s)
Antineoplásicos/farmacocinética , Inmunoconjugados/uso terapéutico , Terapia Molecular Dirigida/métodos , Compuestos Organometálicos/inmunología , Fosfatidilserinas/inmunología , Ácidos Picolínicos/inmunología , Animales , Antineoplásicos/síntesis química , Línea Celular Tumoral , Humanos , Inmunoconjugados/química , Inmunoconjugados/farmacocinética , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/farmacología , Fosfatidilserinas/metabolismo , Ácidos Picolínicos/síntesis química , Ácidos Picolínicos/farmacología , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A new N-hydroxyphthalimide (NHPI)/Co(II)-catalyzed protocol, mechanistically involving a sequence of α-hydrogen abstraction, 5-exo-dig cyclization, oxygen capture, hydrogen transfer, and 1,4-dehydration, has been developed to facilitate aerobic oxidation of aryl-, silyl-, and alkyl-capped alkynyl α-cyano alkanone systems to the corresponding highly functionalized products in an effective manner, thus turning this novel chain reaction, originally occurring spontaneously in low yields, into a practical methodology.
RESUMEN
Tandem reactions use consecutive reaction steps to efficiently synthesize compounds of high molecular complexity. This paper presents a tandem Pd-catalyzed Heck and alkoxycarbonylation reaction for the stereoselective synthesis of (E)-oxindolylidene acetates. The mechanism underlying the Pd-catalyzed tandem reaction involves the syn-carbopalladation of ynamides followed by alkoxycarbonylation with CO and alcohol. This method makes it possible to obtain the desired (E)-configuration of oxindolylidene acetates exclusively. We evaluated the scope of the reaction by applying optimal reaction conditions to the facile synthesis of a library of (E)-oxindolylidene acetates. The resulting (E)-oxindolylidene acetates exhibited potent anticancer activities against a variety of human cancer cell lines. The anticancer activities of some (E)-oxindolylidene acetates were even superior to those of known CDK inhibitors indirubin-3'-oxime and roscovitine.
Asunto(s)
Antineoplásicos/farmacología , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Indoles/farmacología , Compuestos Organometálicos/química , Paladio/química , Inhibidores de Proteínas Quinasas/farmacología , Alcoholes/química , Amidas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Monóxido de Carbono/química , Catálisis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Indoles/síntesis química , Indoles/química , Estructura Molecular , Oxindoles , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-ActividadRESUMEN
Making use of a tandem free radical cyclization process mediated by Mn(OAc)3 as a key operation, the total synthesis of retrojusticidin B, justicidin E, and helioxanthin has been concisely achieved in four or five steps in an overall yield of 45, 33 and 44%, respectively, from a common starting material 5.
Asunto(s)
Dioxolanos/síntesis química , Lignanos/síntesis química , Naftalenos/síntesis química , Catálisis , Ciclización , Dioxolanos/química , Lignanos/química , Estructura Molecular , Naftalenos/químicaRESUMEN
A highly efficient annulative approach towards the construction of the structurally attractive methylenecyclohexane ring was developed through a convenient 1,4-addition of 4-pentenylmagnesium bromide to 2-cyano-2-cycloalkenones followed by a Pd(II)-mediated oxidative cyclization of the resulting ω-unsaturated α-cyano ketones. Based on this newly developed protocol, polycyclic adducts bearing various ring sizes and substitutions can be prepared in moderate to high yields.
Asunto(s)
Acetatos/química , Cianocetona/química , Ciclohexanos/química , Compuestos Organometálicos/química , Ciclización , Metilación , Estructura Molecular , Oxidación-ReducciónRESUMEN
Upon treatment with phenyl dichlorophosphate (PhOP=OCl(2)) in acetonitrile at ambient temperature, a variety of ketoximes underwent a Beckmann rearrangement in an effective manner to afford the corresponding amides in moderate to high yields.
Asunto(s)
Compuestos Organofosforados/química , Oximas/química , Acetonitrilos/química , Acetofenonas/química , Amidas/síntesis química , Modelos Químicos , Solventes/química , TemperaturaRESUMEN
Chemotherapy-induced neurotoxicity is a common adverse effect of cancer treatment. No medication has been shown to be effective in the prevention or treatment of chemotherapy-induced neurotoxicity. Using minoxidil as an initial template for structural modifications in conjunction with an in vitro neurite outgrowth assay, an image-based high-content screening platform, and mouse behavior models, an effective neuroprotective agent CN016 was discovered. Our results showed that CN016 could inhibit paclitaxel-induced inflammatory responses and infiltration of immune cells into sensory neurons significantly. Thus, the suppression of proinflammatory factors elucidates, in part, the mechanism of action of CN016 on alleviating paclitaxel-induced peripheral neuropathy. Based on excellent efficacy in improving behavioral functions, high safety profiles (MTD > 500 mg/kg), and a large therapeutic window (MTD/MED > 50) in mice, CN016 might have great potential to become a peripherally neuroprotective agent to prevent neurotoxicity caused by chemotherapeutics as typified by paclitaxel.
Asunto(s)
Antineoplásicos Fitogénicos , Antineoplásicos , Fármacos Neuroprotectores , Enfermedades del Sistema Nervioso Periférico , Animales , Antineoplásicos/farmacología , Antineoplásicos Fitogénicos/toxicidad , Ganglios Espinales , Ratones , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Paclitaxel/toxicidad , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/prevención & controlRESUMEN
Under catalysis with ZnI(2), an effective annulation process of ω-silylacetylenic α-cyano ketones, leading to the formation of various bicyclic frameworks characterized with a TMS-containing methylenecyclopentane ring, has been developed.