ABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Receptors, CXCR4/antagonists & inhibitors , Animals , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Hepatocellular/immunology , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Diethylnitrosamine/administration & dosage , Diethylnitrosamine/toxicity , Drug Synergism , Humans , Liver Neoplasms/immunology , Liver Neoplasms/pathology , Liver Neoplasms, Experimental/chemically induced , Liver Neoplasms, Experimental/drug therapy , Liver Neoplasms, Experimental/immunology , Liver Neoplasms, Experimental/pathology , Lymphocytes, Tumor-Infiltrating/drug effects , Lymphocytes, Tumor-Infiltrating/immunology , Male , Mice , Molecular Docking Simulation , Rats , Receptors, CXCR4/metabolism , Signal Transduction/drug effects , Sorafenib/pharmacology , Sorafenib/therapeutic use , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/immunology , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Tumor-Associated Macrophages/drug effects , Tumor-Associated Macrophages/immunology , Tumor-Associated Macrophages/metabolism , Xenograft Model Antitumor AssaysABSTRACT
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.
Subject(s)
Cannabinoid Receptor Antagonists , GTP-Binding Proteins , Cannabinoid Receptor Antagonists/pharmacology , Cannabinoid Receptor Antagonists/metabolism , Rimonabant , beta-Arrestins/metabolism , GTP-Binding Proteins/metabolism , Receptors, Cannabinoid/metabolismABSTRACT
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.
Subject(s)
Anti-Bacterial Agents , Tetralones , Molecular Structure , Anti-Bacterial Agents/pharmacology , Stereoisomerism , Gene LibraryABSTRACT
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.
Subject(s)
Myocardial Infarction , Myocardial Reperfusion Injury , Percutaneous Coronary Intervention , Receptors, CXCR4 , Animals , Myocardial Infarction/therapy , Myocardial Reperfusion Injury/etiology , Rats , Receptors, CXCR4/antagonists & inhibitors , Stroke Volume , Swine , Swine, Miniature , Ventricular Function, LeftABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/biosynthesis , Antifungal Agents/chemistry , Biosynthetic Pathways/genetics , Metabolic Engineering/methods , Streptomyces/genetics , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , CRISPR-Cas Systems , Gene Editing/methods , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Polyenes/chemistry , Streptomyces/metabolismABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Cerebral Hemorrhage/drug therapy , Locomotion/drug effects , Neuroprotective Agents/therapeutic use , Receptors, CXCR4/antagonists & inhibitors , Stroke/drug therapy , Animals , Brain/drug effects , Brain/pathology , Cells, Cultured , Cerebral Hemorrhage/chemically induced , HEK293 Cells , Humans , Male , Microbial Collagenase , Microglia/drug effects , Microglia/pathology , Rats, Sprague-DawleyABSTRACT
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 %.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Biological Products/chemistry , Anions/chemistry , Anti-Bacterial Agents/chemistry , Biological Products/chemical synthesis , Cycloaddition Reaction , StereoisomerismABSTRACT
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.
Subject(s)
Cannabinoid Receptor Agonists/pharmacology , Pyrazoles/pharmacology , Receptor, Cannabinoid, CB1/agonists , Sulfonamides/pharmacology , Thiophenes/pharmacology , Animals , Cannabinoid Receptor Agonists/chemical synthesis , Cannabinoid Receptor Agonists/chemistry , Cannabinoid Receptor Agonists/pharmacokinetics , Drug Inverse Agonism , Fluorine Radioisotopes , Isotope Labeling , Male , Mice, Inbred C57BL , Positron-Emission Tomography/methods , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Thiophenes/chemistry , Thiophenes/pharmacokinetics , Tissue DistributionABSTRACT
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.
Subject(s)
Chemokine CXCL12/chemistry , HIV Infections/drug therapy , Hematopoietic Stem Cell Mobilization , Hematopoietic Stem Cells/cytology , Receptors, CXCR4/antagonists & inhibitors , Animals , Autoimmune Diseases/drug therapy , Clinical Trials as Topic , Crystallography, X-Ray , Humans , Immunotherapy , Ligands , Myocardial Ischemia/drug therapy , Neoplasm Metastasis , Neutrophils/cytology , Peptides/chemistry , Regeneration , Signal Transduction , Stem Cell TransplantationABSTRACT
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.
ABSTRACT
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.
Subject(s)
Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/pharmacology , Drug Resistance, Microbial/drug effects , Gram-Positive Bacteria/drug effects , Naphthacenes/chemical synthesis , Naphthacenes/pharmacology , Polycyclic Aromatic Hydrocarbons/chemical synthesis , Polycyclic Aromatic Hydrocarbons/pharmacology , Polycyclic Compounds/chemical synthesis , Polycyclic Compounds/pharmacology , Structure-Activity RelationshipABSTRACT
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.
ABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Immunoconjugates/therapeutic use , Molecular Targeted Therapy/methods , Organometallic Compounds/immunology , Phosphatidylserines/immunology , Picolinic Acids/immunology , Animals , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Humans , Immunoconjugates/chemistry , Immunoconjugates/pharmacokinetics , Organometallic Compounds/chemical synthesis , Organometallic Compounds/pharmacology , Phosphatidylserines/metabolism , Picolinic Acids/chemical synthesis , Picolinic Acids/pharmacology , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
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.
ABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Cyclin-Dependent Kinases/antagonists & inhibitors , Indoles/pharmacology , Organometallic Compounds/chemistry , Palladium/chemistry , Protein Kinase Inhibitors/pharmacology , Alcohols/chemistry , Amides/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Carbon Monoxide/chemistry , Catalysis , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Indoles/chemical synthesis , Indoles/chemistry , Molecular Structure , Oxindoles , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Dioxolanes/chemical synthesis , Lignans/chemical synthesis , Naphthalenes/chemical synthesis , Catalysis , Cyclization , Dioxolanes/chemistry , Lignans/chemistry , Molecular Structure , Naphthalenes/chemistryABSTRACT
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.
Subject(s)
Acetates/chemistry , Cyanoketone/chemistry , Cyclohexanes/chemistry , Organometallic Compounds/chemistry , Cyclization , Methylation , Molecular Structure , Oxidation-ReductionABSTRACT
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.
Subject(s)
Organophosphorus Compounds/chemistry , Oximes/chemistry , Acetonitriles/chemistry , Acetophenones/chemistry , Amides/chemical synthesis , Models, Chemical , Solvents/chemistry , TemperatureABSTRACT
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.
Subject(s)
Antineoplastic Agents, Phytogenic , Antineoplastic Agents , Neuroprotective Agents , Peripheral Nervous System Diseases , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents, Phytogenic/toxicity , Ganglia, Spinal , Mice , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Paclitaxel/toxicity , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/drug therapy , Peripheral Nervous System Diseases/prevention & controlABSTRACT
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.