RESUMEN
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
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
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
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
Anionic Diels-Alder chemistry of electron-deficient cross-conjugated vinylogous alkenones, providing highly stable sodium dienolate ion pairs as electron-rich dienes in the presence of a weak sodium base in THF, has been newly developed, leading to a single Diels-Alder adduct, in racemic form, in moderate to high yields (up to 97%, 37 examples).
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
Herein, we report the total synthesis of landomycins Q and R as well as the aglycone core, namely anhydrolandomycinone and a related core analogue. The synthesis features an acetate-assisted arylation method for construction of the hindered B-ring in the core component and a one-pot aromatization-deiodination-denbenzylation procedure to streamline the global functional and protecting group manuipulation. Subsequent cytotoxicity and antibacterial studies revealed that the landomycin R is a potential antibacterial agent against methicillin-resistant Staphylococcus aureus.
RESUMEN
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
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
Indoleamine 2,3-dioxygenase (IDO1) inhibitors are speculated to be useful in cancer immunotherapy, but a phase III clinical trial of the most advanced IDO1 inhibitor, epacadostat, did not meet its primary end point and was abandoned. In previous work, we identified the novel IDO1 inhibitor N-(4-chlorophenyl)-2-((5-phenylthiazolo[2,3-c][1,2,4]triazol-3-yl)thio)acetamide 1 through high-throughput screening (HTS). Herein, we report a structure-activity relationship (SAR) study of this compound, which resulted in the potent IDO1 inhibitor 1-(4-cyanophenyl)-3-(3-(cyclopropylethynyl)imidazo[2,1-b]thiazol-5-yl)thiourea 47 (hIDO IC50 = 16.4 nM). X-ray cocrystal structural analysis revealed that the basis for this high potency is a unique sulfur-aromatic interaction network formed by the thiourea moiety of 47 with F163 and F226. This finding is expected to inspire new approaches toward the discovery of potent IDO1 inhibitors in the future.
Asunto(s)
Inhibidores Enzimáticos/química , Imidazoles/química , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Tiazoles/química , Sitios de Unión , Cristalografía por Rayos X , Descubrimiento de Drogas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Humanos , Imidazoles/síntesis química , Imidazoles/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/química , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Estructura Molecular , Unión Proteica , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/metabolismoRESUMEN
We report that compound 13, a novel phosphatidylserine-targeting zinc(II) dipicolylamine drug conjugate, readily triggers a positive feedback therapeutic loop through the in situ generation of phosphatidylserine in the tumor microenvironment. Linker modifications, pharmacokinetics profiling, in vivo antitumor studies, and micro-Western array of treated-tumor tissues were employed to show that this class of conjugates induced regeneration of apoptotic signals, which facilitated subsequent recruitment of the circulating conjugates through the zinc(II) dipicolylamine-phosphatidylserine association and resulted in compounding antitumor efficacy. Compared to the marketed compound 17, compound 13 not only induced regressions in colorectal and pancreatic tumor models, it also exhibited at least 5-fold enhancement in antitumor efficacy with only 40% of the drug employed during treatment, culminating in a >12.5-fold increase in therapeutic potential. Our study discloses a chemically distinct apoptosis-targeting theranostic, with built-in complementary functional moieties between the targeting module and the drug mechanism to expand the arsenal of antitumor therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Complejos de Coordinación/uso terapéutico , Indolizinas/uso terapéutico , Neoplasias/tratamiento farmacológico , Fosfatidilserinas/metabolismo , Picolinas/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Diseño de Fármacos , Humanos , Indolizinas/síntesis química , Indolizinas/química , Masculino , Ratones Endogámicos ICR , Ratones Desnudos , Estructura Molecular , Picolinas/síntesis química , Picolinas/química , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I/síntesis química , Inhibidores de Topoisomerasa I/química , Inhibidores de Topoisomerasa I/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Zinc/químicaRESUMEN
The G protein-coupled receptor (GPCR) CXCR4 is a co-receptor for HIV and is involved in cancers and autoimmune diseases. We characterized five purine or quinazoline core polyamine pharmacophores used for targeting CXCR4 dysregulation in diseases. All were neutral antagonists for wild-type CXCR4 and two were biased antagonists with effects on ß-arrestin-2 only at high concentrations. These compounds displayed various activities for a constitutively active mutant (CAM). We use the IT1t-CXCR4 crystal structure and molecular dynamics (MD) simulations to develop two hypotheses for the activation of the N1193.35A CAM. The N1193.35A mutation facilitates increased coupling of TM helices III and VI. IT1t deactivates the CAM by disrupting the coupling between TM helices III and VI, mediated primarily by residue F872.53. Mutants of F872.53 in N1193.35A CXCR4 precluded constitutive signaling and prevented inverse agonism. This work characterizes CXCR4 ligands and provides a mechanism for N1193.35A constitutive activation.
Asunto(s)
Simulación de Dinámica Molecular , Receptores CXCR4/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/metabolismo , Bencilaminas , Quimiocina CXCL12/farmacología , Ciclamas , Células HEK293 , Infecciones por VIH/metabolismo , Infecciones por VIH/patología , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Compuestos Heterocíclicos/farmacología , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Mutagénesis Sitio-Dirigida , Conformación Proteica en Hélice alfa , Estructura Terciaria de Proteína , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Arrestina beta 2/metabolismoRESUMEN
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
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
Curcumin (Cur), a polyphenolic compound extracted from spice and common food colourant turmeric, contains versatile bio-activities. Monoacetylcurcumin (MAC), a structural analogue of Cur, differs from Cur by acetyl modification, but retains enone groups. Comparative analysis revealed MAC effectively inhibited influenza virus infection (IAV) to a similar extent as, if not superior to, curcumin. Both compounds mildly reduced viral NA activity. Surprisingly, unlike Cur, the MAC inhibition of IAV did not occur through the blocking of HA activity. However, MAC strongly dampened Akt phosphorylation, the prerequisite signalling for efficient IAV propagation. A much stronger inhibition effect on IAV infection was observed when MAC treatment was in combination with Cur. Collectively, MAC demonstrated clear antiviral activity, and likely inhibited IAV via multiple mechanisms that were not identical to Cur. Importantly, Cur and MAC in combination synergistically inhibited IAV infection.
Asunto(s)
Antivirales/farmacología , Curcumina/análogos & derivados , Curcumina/farmacología , Virus de la Influenza A/efectos de los fármacos , Gripe Humana/virología , Animales , Antivirales/química , Curcumina/química , Perros , Sinergismo Farmacológico , Humanos , Virus de la Influenza A/genética , Virus de la Influenza A/fisiología , Gripe Humana/tratamiento farmacológico , Gripe Humana/genética , Gripe Humana/metabolismo , Células de Riñón Canino Madin Darby , Fosforilación , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
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
The function of the CXCR4/CXCL12 axis accounts for many disease indications, including tissue/nerve regeneration, cancer metastasis, and inflammation. Blocking CXCR4 signaling with its antagonists may lead to moving out CXCR4+ cell types from bone marrow to peripheral circulation. We have discovered a novel series of pyrimidine-based CXCR4 antagonists, a representative (i.e., 16) of which was tolerated at a higher dose and showed better HSC-mobilizing ability at the maximal response dose relative to the approved drug 1 (AMD3100), and thus considered a potential drug candidate for PBSCT indication. Docking compound 16 into the X-ray crystal structure of CXCR4 receptor revealed that it adopted a spider-like conformation striding over both major and minor subpockets. This putative binding mode provides a new insight into CXCR4 receptor-ligand interactions for further structural modifications.