RESUMO
OBJECTIVE: Targeting bacterial translocation in cirrhosis is limited to antibiotics with risk of antimicrobial resistance. This study explored the therapeutic potential of a non-absorbable, gut-restricted, engineered carbon bead adsorbent, Yaq-001 in models of cirrhosis and acute-on-chronic liver failure (ACLF) and, its safety and tolerability in a clinical trial in cirrhosis. DESIGN: Performance of Yaq-001 was evaluated in vitro. Two-rat models of cirrhosis and ACLF, (4 weeks, bile duct ligation with or without lipopolysaccharide), receiving Yaq-001 for 2 weeks; and two-mouse models of cirrhosis (6-week and 12-week carbon tetrachloride (CCl4)) receiving Yaq-001 for 6 weeks were studied. Organ and immune function, gut permeability, transcriptomics, microbiome composition and metabolomics were analysed. The effect of faecal water on gut permeability from animal models was evaluated on intestinal organoids. A multicentre, double-blind, randomised, placebo-controlled clinical trial in 28 patients with cirrhosis, administered 4 gr/day Yaq-001 for 3 months was performed. RESULTS: Yaq-001 exhibited rapid adsorption kinetics for endotoxin. In vivo, Yaq-001 reduced liver injury, progression of fibrosis, portal hypertension, renal dysfunction and mortality of ACLF animals significantly. Significant impact on severity of endotoxaemia, hyperammonaemia, liver cell death, systemic inflammation and organ transcriptomics with variable modulation of inflammation, cell death and senescence in the liver, kidneys, brain and colon was observed. Yaq-001 reduced gut permeability in the organoids and impacted positively on the microbiome composition and metabolism. Yaq-001 regulated as a device met its primary endpoint of safety and tolerability in the clinical trial. CONCLUSIONS: This study provides strong preclinical rationale and safety in patients with cirrhosis to allow clinical translation. TRIAL REGISTRATION NUMBER: NCT03202498.
Assuntos
Insuficiência Hepática Crônica Agudizada , Microbioma Gastrointestinal , Cirrose Hepática , Humanos , Animais , Cirrose Hepática/complicações , Camundongos , Masculino , Microbioma Gastrointestinal/efeitos dos fármacos , Método Duplo-Cego , Ratos , Modelos Animais de Doenças , Feminino , Pessoa de Meia-Idade , Translocação Bacteriana/efeitos dos fármacos , Carbono/uso terapêutico , Carbono/farmacologiaRESUMO
While cancer survivorship has increased due to advances in treatments, chemotherapy often carries long-lived neurotoxic side effects which reduce quality of life. Commonly affected domains include memory, executive function, attention, processing speed and sensorimotor function, colloquially known as chemotherapy-induced cognitive impairment (CICI) or "chemobrain". Oxidative stress and neuroimmune signaling in the brain have been mechanistically linked to the deleterious effects of chemotherapy on cognition and sensorimotor function. With this in mind, we tested if activation of the master regulator of antioxidant response nuclear factor E2-related factor 2 (Nrf2) alleviates cognitive and sensorimotor impairments induced by doxorubicin. The FDA-approved systemic Nrf2 activator, diroximel fumarate (DRF) was used, along with our recently developed prodrug 1c which has the advantage of specifically releasing monomethyl fumarate at sites of oxidative stress. DRF and 1c both reversed doxorubicin-induced deficits in executive function, spatial and working memory, as well as decrements in fine motor coordination and grip strength, across both male and female mice. Both treatments reversed doxorubicin-induced loss of synaptic proteins and microglia phenotypic transition in the hippocampus. Doxorubicin-induced myelin damage in the corpus callosum was reversed by both Nrf2 activators. These results demonstrate the therapeutic potential of Nrf2 activators to reverse doxorubicin-induced cognitive impairments, motor incoordination, and associated structural and phenotypic changes in the brain. The localized release of monomethyl fumarate by 1c has the potential to diminish unwanted effects of fumarates while retaining efficacy.
RESUMO
Encoded by PTPN11, the Src-homology 2 domain-containing phosphatase 2 (SHP2) integrates signals from various membrane-bound receptors such as receptor tyrosine kinases (RTKs), cytokine and integrin receptors and thereby promotes cell survival and proliferation. Activating mutations in the PTPN11 gene may trigger signaling pathways leading to the development of hematological malignancies, but are rarely found in solid tumors. Yet, aberrant SHP2 expression or activation has implications in the development, progression and metastasis of many solid tumor entities. SHP2 is involved in multiple signaling cascades, including the RAS-RAF-MEK-ERK-, PI3K-AKT-, JAK-STAT- and PD-L1/PD-1- pathways. Although not mutated, activation or functional requirement of SHP2 appears to play a relevant and context-dependent dichotomous role. This mostly tumor-promoting and infrequently tumor-suppressive role exists in many cancers such as gastrointestinal tumors, pancreatic, liver and lung cancer, gynecological entities, head and neck cancers, prostate cancer, glioblastoma and melanoma. Recent studies have identified SHP2 as a potential biomarker for the prognosis of some solid tumors. Based on promising preclinical work and the advent of orally available allosteric SHP2-inhibitors early clinical trials are currently investigating SHP2-directed approaches in various solid tumors, either as a single agent or in combination regimes. We here provide a brief overview of the molecular functions of SHP2 and collate current knowledge with regard to the significance of SHP2 expression and function in different solid tumor entities, including cells in their microenvironment, immune escape and therapy resistance. In the context of the present landscape of clinical trials with allosteric SHP2-inhibitors we discuss the multitude of opportunities but also limitations of a strategy targeting this non-receptor protein tyrosine phosphatase for treatment of solid tumors.
Assuntos
Neoplasias Pulmonares , Fosfatidilinositol 3-Quinases , Masculino , Humanos , Transdução de Sinais , Mutação com Ganho de Função , Tirosina , Microambiente Tumoral , Proteína Tirosina Fosfatase não Receptora Tipo 11/genéticaRESUMO
Hyperactivation of the RAS-RAF-MEK-ERK cascade - a mitogen-activated protein kinase pathway - has a well-known association with oncogenesis of leading tumor entities, including non-small cell lung cancer, colorectal carcinoma, pancreatic ductal adenocarcinoma, and malignant melanoma. Increasing evidence shows that genetic alterations leading to RAS-RAF-MEK-ERK pathway hyperactivation mediate contact- and soluble-dependent crosstalk between tumor, tumor microenvironment (TME) and the immune system resulting in immune escape mechanisms and establishment of a tumor-sustaining environment. Consequently, pharmacological interruption of this pathway not only leads to tumor-cell intrinsic disruptive effects but also modification of the TME and anti-tumor immunomodulation. At the same time, the importance of ERK signaling in immune cell physiology and potentiation of anti-tumor immune responses through ERK signaling inhibition within immune cell subsets has received growing appreciation. Specifically, a strong case was made for targeted MEK inhibition due to promising associated immune cell intrinsic modulatory effects. However, the successful transition of therapeutic agents interrupting RAS-RAF-MEK-ERK hyperactivation is still being hampered by significant limitations regarding durable efficacy, therapy resistance and toxicity. We here collate and summarize the multifaceted role of RAS-RAF-MEK-ERK signaling in physiology and oncoimmunology and outline the rationale and concepts for exploitation of immunomodulatory properties of RAS-RAF-MEK-ERK inhibition while accentuating the role of MEK inhibition in combinatorial and intermittent anticancer therapy. Furthermore, we point out the extensive scientific efforts dedicated to overcoming the challenges encountered during the clinical transition of various therapeutic agents in the search for the most effective and safe patient- and tumor-tailored treatment approach.
RESUMO
Fumarates are successfully used for the treatment of psoriasis and multiple sclerosis. Their antioxidative, immunomodulatory, and neuroprotective properties make fumarates attractive therapeutic candidates for other pathologies. The exact working mechanisms of fumarates are, however, not fully understood. Further elucidation of the mechanisms is required if these drugs are to be successfully repurposed for other diseases. Towards this, administration route, dosage, and treatment timing, frequency, and duration are important parameters to consider and optimize with clinical paradigms in mind. Here, we summarize the rapidly expanding literature on the pharmacokinetics and pharmacodynamics of fumarates, including a discussion on two recently FDA-approved fumarates VumerityTM and BafiertamTM. We review emerging applications of fumarates, focusing on neurological and cardiovascular diseases.
Assuntos
Fumaratos , Esclerose Múltipla , Humanos , Fatores Imunológicos , Esclerose Múltipla/tratamento farmacológicoRESUMO
Mycobacterium tuberculosis dethiobiotin synthase (MtDTBS) is a crucial enzyme involved in the biosynthesis of biotin in the causative agent of tuberculosis, M. tuberculosis. Here, we report a binder of MtDTBS, cyclopentylacetic acid 2 (KD = 3.4 ± 0.4 mM), identified via in silico screening. X-ray crystallography showed that 2 binds in the 7,8-diaminopelargonic acid (DAPA) pocket of MtDTBS. Appending an acidic group to the para-position of the aromatic ring of the scaffold revealed compounds 4c and 4d as more potent binders, with KD = 19 ± 5 and 17 ± 1 µM, respectively. Further optimization identified tetrazole 7a as a particularly potent binder (KD = 57 ± 5 nM) and inhibitor (Ki = 5 ± 1 µM) of MtDTBS. Our findings highlight the first reported inhibitors of MtDTBS and serve as a platform for the further development of potent inhibitors and novel therapeutics for the treatment of tuberculosis.
Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Carbono-Nitrogênio Ligases/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/enzimologia , Antituberculosos/metabolismo , Carbono-Nitrogênio Ligases/metabolismo , Cristalografia por Raios X , Desenvolvimento de Medicamentos , Inibidores Enzimáticos/metabolismo , Estrutura Molecular , Ligação ProteicaRESUMO
Herein we report examples of the insertion of a carbenoid into a peroxide linkage. This study reveals that intramolecular insertion of carbenes into the peroxide linkage of 3,6-dihydro-1,2-dioxines is preferred over olefin insertion. The initial scope of the reaction and mechanistic considerations, have been probed. This methodology also generates unusual bicyclic hemiacetals (2) and tricyclic peroxides (3).
RESUMO
As part of the vital search towards improved therapeutic agents for the treatment of neuropathic pain, the central nervous system glutamate receptors have become a major focus of research. Outlined herein are the syntheses of two new biologically active 3'-cycloalkyl-substituted carboxycyclopropylglycines, utilizing novel synthetic chemistry. The reaction between substituted 1,2-dioxines and an aminophosphonate furnished the cyclopropane core in a single step with all required stereochemistry of pendant groups. In vitro binding assays at metabotropic glutamate receptors revealed selective activity. In vivo testing in a rodent model of neuropathic pain indicated one amino acid significantly and dose-dependently decreased mechanical allodynia.
Assuntos
Analgésicos/química , Analgésicos/uso terapêutico , Ciclopropanos/química , Ciclopropanos/uso terapêutico , Glicina/análogos & derivados , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Receptores de Glutamato Metabotrópico/agonistas , Analgésicos/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Ciclopropanos/farmacologia , Glicina/química , Glicina/farmacologia , Glicina/uso terapêutico , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismoRESUMO
1,4-Disubstituted 2,3-dioxabicyclo[2.2.2]oct-5-enes were dihydroxylated with osmium tetroxide to yield diols anti to the peroxide linkage in a highly selective manner. Reduction of the peroxide bond furnished cyclohexane-1,2,3,4-tetraols with toxocarol relative stereochemistry in excellent yield. This new methodology was employed to synthesize the natural product (1S,2R,3S,4R,5R)-2-methyl-5-(propan-2-yl)cyclohexane-1,2,3,4-tetrol (1) in a short sequence from (R)-alpha-phellandrene. Moreover, during the study of the chemistry of 2,3-dioxabicyclo[2.2.2]octane-5,6-diols a hitherto unknown rearrangement was discovered which has wide applicability for the synthesis of 1,4-dicarbonyls, including optically enriched synthons. A broad range of mechanistic investigations applicable to this rearrangement are also reported.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Octanóis/química , Octanóis/síntese química , Estrutura Molecular , EstereoisomerismoRESUMO
Positive allosteric modulators (PAMs) of α7 nAChRs can have different properties with respect to their effects on channel kinetics. Type I PAMs amplify peak channel response to acetylcholine but do not appear to influence channel desensitization kinetics, whereas Type II PAMs both increase channel response and delay receptor desensitization. Both Type I and Type II PAMs are reported in literature, but there are limited reports describing their structure-kinetic profile relationships. Here, we report a novel class of compounds with either Type I or Type II behavior that can be tuned by the relative stereochemistry around the central cyclopropyl ring: for example, (R,R)-13 (BNC375) and its analogues with RR stereochemistry around the central cyclopropyl ring are Type I PAMs, whereas compounds in the same series with SS stereochemistry (e.g., (S,S)-13) are Type II PAMs as measured using patch-clamp electrophysiology. Further fine control over the kinetics has been achieved by changing the substitutions on the aniline ring: generally the substitution of aniline with strong electron withdrawing groups reduces the Type II character of these compounds. Our structure-activity optimization efforts have led to the discovery of BNC375, a small molecule with good CNS-drug like properties and clinical candidate potential.
RESUMO
We report the synthesis of a series of novel epoxy endoperoxide compounds that can be prepared in high yields in one to three steps from simple starting materials. Some of these compounds inhibit the growth of Plasmodium falciparum in vitro. Structure-activity studies indicate that an endoperoxide ring bisubstituted with saturated cyclic moieties is the pharmacophore. To study the molecular basis of the action of these novel antimalarial compounds, we examined their ability to interact with oxidized and reduced forms of heme. Some of the compounds interact with oxidized heme in a fashion similar to chloroquine and other 4-aminoquinolines, while some of the compounds interact with reduced heme. However, the level of antimalarial potency is not well correlated with these activities, suggesting that some of the endoperoxides may exert their antimalarial activities by a novel mechanism of action.
Assuntos
Antimaláricos/síntese química , Heme/química , Peróxidos/síntese química , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Cristalografia por Raios X , Eritrócitos/efeitos dos fármacos , Eritrócitos/parasitologia , Humanos , Técnicas In Vitro , Peróxidos/química , Peróxidos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
[reaction: see text] 1,3-Dipolar cycloaddition of propargyl bromide with the carbonyl ylide derived from 6-diazoheptane-2,5-dione is the key step in concise syntheses of cis-nemorensic acid and 4-hydroxy-cis-nemorensic acid.
Assuntos
Antineoplásicos Fitogênicos/síntese química , Furanos/síntese química , Pargilina/síntese química , Alcaloides de Pirrolizidina/síntese química , Senécio/química , Catálise , Cristalografia por Raios X , Ciclização , Furanos/farmacologia , Modelos Moleculares , Pargilina/análogos & derivados , Pargilina/farmacologia , Alcaloides de Pirrolizidina/farmacologia , EstereoisomerismoRESUMO
The combination of chiral cobalt beta-ketoiminato or cobalt salen complexes and meso 1,2-dioxines leads to catalytic asymmetric ring-opening affording enantio-enriched cis gamma-hydroxy enones; subsequent capture by an ylide affords enantio-enriched cyclopropanes.
RESUMO
For the diagnosis of systemic autoimmune rheumatic diseases (SARD), patients are screened for anti-nuclear antibodies (ANA). ANA, as assessed by indirect immunofluorescence (IIF), have a poor specificity. This hampers interpretation of positive results in clinical settings with low pretest probability of SARD. We hypothesized that the utility of positive ANA IIF results increases from primary to tertiary care. We retrospectively determined ANA, anti-ENA, and anti-dsDNA antibody prevalence in patient cohorts from primary (n = 1453), secondary (n = 1621), and tertiary (n = 1168) care settings. Results reveal that from primary care to tertiary care, ANA prevalence increases (6.2, 10.8, and 16.0%, resp.). Moreover, in primary care low titres (70% versus 51% and 52% in secondary and tertiary care, resp.) are more frequent and anti-ENA/dsDNA reactivities are less prevalent (21% versus 39% in secondary care). Typically, in tertiary care the prevalence of anti-ENA/dsDNA reactivities (21%) is lower than expected. From this descriptive study we conclude that positive ANA IIF results are more prone to false interpretation in clinical settings with low pretest probabilities for SARD, as in primary care. Whether alternative approaches, that is, immunoadsorption of anti-DFS70 antibodies or implementation of anti-ENA screen assays, perform better, needs to be determined.
Assuntos
Anticorpos Antinucleares/sangue , Doenças Autoimunes/epidemiologia , Atenção Primária à Saúde/estatística & dados numéricos , Doenças Reumáticas/epidemiologia , Atenção Secundária à Saúde/estatística & dados numéricos , Atenção Terciária à Saúde/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/diagnóstico , Feminino , Imunofluorescência/métodos , Técnica Indireta de Fluorescência para Anticorpo/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Vigilância da População , Doenças Reumáticas/diagnóstico , Estudos Soroepidemiológicos , Adulto JovemRESUMO
1,2-Dioxines react with glycine-derived phosphonate nucleophiles via a multistep cascade reaction to give beta-cyclopropyl amino acid derivatives in good yield with excellent control of the cyclopropane stereocentres. The cyclopropyl ketones were oxidized to the corresponding carboxylic esters using Baeyer-Villiger conditions. Standard deprotection protocols produced a series of known beta-cyclopropyl amino acids that are selective and potent agonists or antagonists of the metabotropic glutamate receptors in excellent yields.
Assuntos
Aminoácidos/síntese química , Ciclopropanos/síntese química , Dioxanos/química , Compostos Organofosforados/química , Aminoácidos/química , Ciclopropanos/química , Conformação Molecular , EstereoisomerismoRESUMO
Artermisinin and its derivatives are now the mainstays of antimalarial treatment; however, their mechanism of action is only poorly understood. We report on the synthesis of a novel series of epoxy-endoperoxides that can be prepared in high yields from simple starting materials. Endoperoxides that are disubstituted with alkyl or benzyl side chains show efficient inhibition of the growth of both chloroquine-sensitive and -resistant strains of Plasmodium falciparum. A trans-epoxide with respect to the peroxide linkage increases the activity compared to that of its cis-epoxy counterpart or the parent endoperoxide. The novel endoperoxides do not show a strong interaction with artemisinin. We have compared the mechanism of action of the novel endoperoxides with that of artemisinin. Electron microscopy reveals that the novel endoperoxides cause the early accumulation of endocytic vesicles, while artemisinin causes the disruption of the digestive vacuole membrane. At longer incubation times artemisinin causes extensive loss of organellar structures, while the novel endoperoxides cause myelin body formation as well as the accumulation of endocytic vesicles. An early event following endoperoxide treatment is the redistribution of the pH-sensitive probe LysoSensor Blue from the digestive vacuole to punctate structures. By contrast, neither artemisinin nor the novel endoperoxides caused alterations in the morphology of the endoplasmic reticulum nor showed antagonistic antimalarial activity when they were used with thapsigargin. Analysis of rhodamine 123 uptake by P. falciparum suggests that disruption of the mitochondrial membrane potential occurs as a downstream effect rather than as an initiator of parasite killing. The data suggest that the digestive vacuole is an important initial site of endoperoxide antimalarial activity.
Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Peróxidos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Vacúolos/efeitos dos fármacos , Vacúolos/ultraestrutura , Animais , Antimaláricos/química , Interações Medicamentosas , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/ultraestrutura , Humanos , Concentração Inibidora 50 , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Testes de Sensibilidade Parasitária , Peróxidos/síntese química , Peróxidos/química , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium falciparum/ultraestrutura , Fatores de TempoRESUMO
Broad antifungal structure-activity relationships governing epoxy-endoperoxides 2 and 3 and their parent endoperoxides 1 are reported. Their inhibitory activity against Candida albicans in conjunction with hemolytic activity and/or growth inhibition of cultured mammalian cells are reported. This information provided guidance for the further development of endoperoxide and epoxy-endoperoxides as topical antifungal agents.
Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Desenho de Fármacos , Peróxidos/síntese química , Peróxidos/farmacologia , Animais , Antifúngicos/química , Células CHO , Proliferação de Células/efeitos dos fármacos , Cricetinae , Eritrócitos/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Conformação Molecular , Peróxidos/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A concise, high yielding route to the naturally occurring enantiomer of grenadamide utilizing a 3,6-disubstituted 1,2-dioxine starting material is presented. The route allows for ease in synthesizing grenadamide derivatives varying at cyclopropyl carbons 2 and 3, with access to both enantiomers. Evidence for phosphorus-assisted deprotonation of 1,2-dioxines is also discussed.
Assuntos
Amidas/síntese química , Ciclopropanos/síntese química , Fósforo , EstereoisomerismoRESUMO
Fifteen new endoperoxides have been synthesised and tested for activity against pathogenic Candida species. These endoperoxides can be prepared in high yields, in one to three steps, from inexpensive starting materials. Despite chemical and structural similarities, their inhibitory activity against Candida growth varied greatly from one endoperoxide to another, and one species to another. This study of susceptibility to endoperoxide compounds presented here may lead to the development of potent new antifungal agents.
Assuntos
Candida/classificação , Candida/efeitos dos fármacos , Peróxidos/síntese química , Peróxidos/farmacologia , Candida/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Conformação Molecular , Peróxidos/química , Especificidade da Espécie , EstereoisomerismoRESUMO
A new method for the construction of tetrahydropyrans derived from readily available 1,2-dioxines containing a tethered hydroxyl moiety is described. The reaction proceeds via a base-catalyzed rearrangement of the 1,2-dioxines to either the isomeric cis or trans gamma-hydroxy enones followed by intramolecular oxa-Michael addition of the tethered hydroxyl group.