RESUMO
The discovery of naturally occurring organohalogen compounds has increased astronomically in the 55 years since they were first discoveredâfrom fewer than 50 in 1968 to a combined 7,958 described examples in three comprehensive reviews. The present survey, which covers the period 2021-2023, brings the number of known natural organohalogens to approximately 8,400. The organization is according to species origin, and coverage includes marine and terrestrial plants, fungi, bacteria, marine sponges, corals, cyanobacteria, tunicates, and other marine organisms.
Assuntos
Cianobactérias , Estrutura Molecular , Animais , Cianobactérias/química , Poríferos/química , Produtos Biológicos/química , Bactérias , Fungos/química , Antozoários/química , Urocordados/química , Plantas/química , Hidrocarbonetos Halogenados/química , Organismos AquáticosRESUMO
The present volume is the third in a trilogy that documents naturally occurring organohalogen compounds, bringing the total number-from fewer than 25 in 1968-to approximately 8000 compounds to date. Nearly all of these natural products contain chlorine or bromine, with a few containing iodine and, fewer still, fluorine. Produced by ubiquitous marine (algae, sponges, corals, bryozoa, nudibranchs, fungi, bacteria) and terrestrial organisms (plants, fungi, bacteria, insects, higher animals) and universal abiotic processes (volcanos, forest fires, geothermal events), organohalogens pervade the global ecosystem. Newly identified extraterrestrial sources are also documented. In addition to chemical structures, biological activity, biohalogenation, biodegradation, natural function, and future outlook are presented.
Assuntos
Antozoários , Produtos Biológicos , Animais , Ecossistema , Biodegradação Ambiental , BromoRESUMO
A novel generation of indole-2,3-quinodimethanes via the deamination of 1,2,3,4-tetrahydropyrrolo[s3,4-b]indoles is reported.
Assuntos
Indóis/química , Pirróis/química , Desaminação , Indóis/síntese química , Nitritos/química , Pirróis/síntese químicaRESUMO
In the title compound, C14H11ClN2O2S, the dihedral angle between the pyrrolo-[1,2-c]pyrimidine ring system (r.m.s. deviation = 0.008â Å) and the benzene ring is 80.2â (9)°. In the crystal, inversion dimers linked by pairs of C-Hâ¯O inter-actions generate R 2 2(16) loops. Several aromatic π-π stacking inter-actions between the pyrrolo-[1,2-c]pyrimidine rings, as well as separately between the pyrrolo and pyrimidine groups [shortest centroid-centroid separation = 3.5758â (14)â Å], help to consolidate the packing.
RESUMO
Genetic activation of the bacterial two-component signal transduction system, CpxRA, abolishes the virulence of a number of pathogens in human and murine infection models. Recently, 2,3,4,9-tetrahydro-1H-carbazol-1-amines were shown to activate the CpxRA system by inhibiting the phosphatase activity of CpxA. Herein we report the initial structure-activity relationships of this scaffold by focusing on three approaches 1) A-ring substitution, 2) B-ring deconstruction to provide N-arylated amino acid derivatives, and 3) C-ring elimination to give 2-ethylamino substituted indoles. These studies demonstrate that the A-ring is amenable to functionalization and provides a promising avenue for continued optimization of this chemotype. Further investigations revealed that the C-ring is not necessary for activity, although it likely provides conformational constraint that is beneficial to potency, and that the (R) stereochemistry is required at the primary amine. Simplification of the scaffold through deconstruction of the B-ring led to inactive compounds, highlighting the importance of the indole core. A new lead compound 26 was identified, which manifests a â¼30-fold improvement in CpxA phosphatase inhibition over the initial hit. Comparison of amino and des-amino derivatives in bacterial strains differing in membrane permeability and efflux capabilities demonstrate that the amine is required not only for target engagement but also for permeation and accumulation in Escherichia coli.
Assuntos
Carbazóis/uso terapêutico , Animais , Carbazóis/farmacologia , Humanos , Camundongos , Relação Estrutura-AtividadeRESUMO
We have previously designed and synthesized small-molecule inhibitors that reduce Vibrio cholerae virulence in vitro by targeting the transcription factor ToxT. Here we report the synthesis and biological activity of derivatives of our previous bicyclic, fatty acid-like inhibitors. All of the synthesized derivatives show antivirulence activity in vitro. For the most potent compounds, a concentration of 5 µM completely inhibited ToxT-mediated tcpA expression as measured in the ß-galactosidase assay. One indole compound, 3-(1-butyl-1 H-indol-7-yl)propanoic acid (8), was also effective at inhibiting intestinal colonization in the infant mouse. These modified compounds may serve as good candidates for further anti-cholera drug development.
Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Cólera/tratamento farmacológico , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Fatores de Transcrição/antagonistas & inibidores , Vibrio cholerae/efeitos dos fármacos , Virulência/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Cólera/microbiologia , Mucosa Intestinal/microbiologia , Camundongos , Vibrio cholerae/patogenicidadeRESUMO
We report the synthesis and biological activity of C-24 demethyl CDDO-Me 2 and the C-28 amide derivatives 3 and 4, which are analogues of the anti-inflammatory synthetic triterpenoid bardoxolone methyl (CDDO-Me) 1. Demethylation of the C-24 methyl group was accomplished via "abnormal Beckmann" rearrangement and subsequent ring A reformation. Amides 3 and 4 were found to be potent inhibitors of the production of the inflammatory mediator NO in vitro.
Assuntos
Anti-Inflamatórios/farmacologia , Desenho de Fármacos , Inflamação/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Feminino , Inflamação/metabolismo , Camundongos , Conformação Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Ácido Oleanólico/síntese química , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Células RAW 264.7RESUMO
Vibrio cholerae is responsible for the diarrheal disease cholera that infects millions of people worldwide. While vaccines protecting against cholera exist, and oral rehydration therapy is an effective treatment method, the disease will remain a global health threat until long-term solutions such as improved sanitation and access to clean water become widely available. Because of this, there is a pressing need for potent therapeutics that can either mitigate cholera symptoms, or act prophylactically to prevent the virulent effects of a cholera infection. Here we report the design, synthesis, and characterization of a set of compounds that bind and inhibit ToxT, the transcription factor that directly regulates the two primary V. cholerae virulence factors. Using the folded structure of the monounsaturated fatty acid observed in the X-ray structure of ToxT as a template, we designed ten novel compounds that inhibit the virulence cascade to a greater degree than any known inhibitor. Our findings provide a structural and functional basis for the development of viable antivirulence therapeutics that combat cholera and, potentially, other forms of bacterial pathogenic disease.
Assuntos
Antibacterianos/química , Proteínas de Bactérias/química , Citarabina/química , Fatores de Transcrição/química , Vibrio cholerae , Antibacterianos/síntese química , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Sítios de Ligação , Citarabina/análogos & derivados , Citarabina/síntese química , Citarabina/farmacologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Desenho de Fármacos , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Ligação Proteica , Fatores de Transcrição/antagonistas & inibidores , Vibrio cholerae/efeitos dos fármacos , Vibrio cholerae/metabolismo , Fatores de Virulência/antagonistas & inibidoresRESUMO
The US military is developing insensitive munitions (IM) that are less sensitive to shock and high temperatures to minimize unintentional detonations. DNAN (2,4-dinitroanisole) is one of the main ingredients of these IM formulations. During live-fire training, chunks of IM formulations are scattered by partial detonations and, once on the soil, they weather and dissolve. DNAN changes color when exposed to sunlight suggesting that it photodegrades into other compounds. We investigated the photo-degradation of DNAN both as a pure solid and as part of solid IM formulations, IMX101, IMX104 and PAX21. The concentrations of degradation products found were small, <1%, relative to DNAN concentrations. We saw transient peaks in the chromatograms indicating intermediate, unstable products but we consistently found methoxy nitrophenols and methoxy nitroanilines. We also found one unknown in most of the samples and other unknowns less frequently.
Assuntos
Anisóis/química , Substâncias Explosivas/química , Nitrocompostos/química , Processos Fotoquímicos , Luz Solar , Cor , CinéticaRESUMO
A three-step synthesis of masked 2,3-diaminoindole 1 from 2-iodo-3-nitro-1-(phenylsulfonyl)indole (2) has been developed. Treatment of 1 with trifluoroacetic acid generates the unstable 2,3-diamino-1-(phenylsulfonyl)indole (3), which can be trapped with α-dicarbonyl compounds to afford 5H-pyrazino[2,3-b]indoles 7-10.
RESUMO
Lactols II, obtained by DIBAL reduction of their corresponding lactones I, in equilibrium with their hydroxyaldehyde tautomers III were used in a three-component reductive alkylation with 2-hydroxy-1,4-naphthoquinone to give a series of 3-alkylated 2-hydroxy-1,4-naphthoquinone derivatives IV.
RESUMO
A new synthesis of dibenzo[a,c]anthracene (4) is described that features the generation, from tetrabromo-bis-triflate 1 and phenyllithium, of a 1,3,6-naphthotriyne (2) synthetic equivalent that is trapped with 3 equiv of furan to form Diels-Alder tris-adduct 3. A subsequent two-step deoxygenation of 3 represents the first synthesis of dibenz[a,c]anthracene (4) that involves a tandem aryne Diels-Alder cycloaddition-deoxygenation strategy.
RESUMO
Two new analogues of CDDO-Imidazolide (CDDO-Im), namely 1-[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4(-pyridin-2-yl)-1H-imidazole ("CDDO-2P-Im") and 1-[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4(-pyridin-3-yl)-1H-imidazole ("CDDO-3P-Im") have been synthesized and tested for their potential use as chemopreventive drugs. At nanomolar concentrations, they were equipotent to CDDO-Im for inducing differentiation and apoptosis in U937 leukemia cells. As inflammation and oxidative stress contribute to carcinogenesis, we also assessed their cytoprotective potential. The new compounds suppressed inducible nitric oxide synthase (iNOS) expression in RAW264.7 macrophage-like cells and significantly elevated heme oxygenase-1 (HO-1) and quinone reductase (NQO1) mRNA and protein levels in various mouse tissues in vivo. Most importantly, pharmacokinetic studies performed in vitro in human plasma and in vivo showed that each new analogue was more stable than CDDO-Im. Much higher concentrations of the new derivatives were found in mouse liver, lung, pancreas and kidney after gavage in contrast to CDDO-Im. Because of their better bioavailability and their excellent anti-inflammatory profile in vitro, CDDO-2P-Im and CDDO-3P-Im were tested for prevention in a highly relevant mouse lung cancer model, in which A/J mice develop lung carcinomas after injection of vinyl carbamate, a potent carcinogen. CDDO-2P-Im and CDDO-3P-Im were as effective as CDDO-Im for reducing the size and the severity of the lung tumors.
Assuntos
Anticarcinógenos/farmacologia , Antineoplásicos/farmacologia , Imidazóis/farmacologia , Neoplasias/prevenção & controle , Ácido Oleanólico/análogos & derivados , Animais , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Heme Oxigenase-1/metabolismo , Humanos , Camundongos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Neoplasias/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ácido Oleanólico/farmacologia , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/metabolismo , Células U937RESUMO
This review presents the biological activity-antibacterial, antifungal, anti-parasitic, antiviral, antitumor, antiinflammatory, antioxidant, and enzymatic activity-of halogenated marine natural products discovered in the past five years. Newly discovered examples that do not report biological activity are not included.
Assuntos
Organismos Aquáticos/química , Produtos Biológicos/farmacologia , Descoberta de Drogas , Hidrocarbonetos Halogenados/farmacologia , Animais , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Antiparasitários/farmacologia , Antivirais/farmacologia , HumanosRESUMO
The Diels-Alder reaction between 2-methylfuran and 3-bromobenzyne (3), which was generated under mild conditions from 1,3-dibromobenzene and lithium diisopropylamide (LDA), gives a mixture of regioisomeric 1,4-dihydro-1,4-epoxynaphthalenes 4 and 5. A subsequent two-step deoxygenation affords the corresponding 1-bromo-8-methylnaphthalene (1) and 1-bromo-5-methylnaphthalene (2) in high yields.
RESUMO
An efficient synthesis of methyl 2-cyano-3,12-dioxoursol-1,9-dien-28-oate (CDDU-methyl ester) from commercially available ursolic acid, which features an oxidative ozonolysis-mediated C-ring enone formation, and provides the first access to ursolic acid-derived cyano enone analogues with C-ring activation. These new ursolic acid analogues show potent biological activities, with potency of approximately five-fold less than the corresponding oleanolic acid derivatives.
Assuntos
Anti-Infecciosos/síntese química , Ácido Oleanólico/química , Triterpenos Pentacíclicos/síntese química , Triterpenos/química , Animais , Anti-Infecciosos/farmacologia , Linhagem Celular , Ésteres , Concentração Inibidora 50 , Interferon gama/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Ácido Oleanólico/farmacologia , Triterpenos Pentacíclicos/farmacologia , Triterpenos/farmacologia , Ácido UrsólicoRESUMO
In the title compound, C26H23NO2, the dihedral angles between the pyrrole ring and the two phenyl rings are 58.1â (6) and 71.5â (5)°. The mean planes of the 5-methyl-benzene ring and the carboxyl group are twisted by 89.5â (3) and 22.1â (9)°, respectively, from the pyrrole ring. In the crystal, weak C-Hâ¯O inter-actions lead to supra-molecular layers in the ab plane.
RESUMO
2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO, 2) was condensed with various amino acid methyl esters at the C-28 carboxylic acid. The new amide conjugates were evaluated for their inhibition of nitric oxide (NO) production in RAW264.7 cells stimulated with interferon-γ (IFNγ). Of these new compounds, CDDO conjugates with alanine, valine, and serine are nearly equipotent to CDDO-ethyl amide (4), a triterpenoid with promising biological activity in numerous disease models. Some of these conjugates also induce the in vitro expression of heme oxygenase-1, and inhibit the proliferation of Panc-1343 pancreatic cells.
Assuntos
Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Ácido Oleanólico/análogos & derivados , Aminoácidos/química , Aminoácidos/farmacologia , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Camundongos , Ácido Oleanólico/química , Ácido Oleanólico/farmacologiaRESUMO
The synthesis of dicyano abietane 11, a potential precursor to the biologically active tricyclic bis-cyano enone 6 (TBE-31), was accomplished in eight steps from epoxide 13. The synthesis features a Lewis acid promoted stereoselective cyclization of epoxide 13 to generate the tricyclic ring system 12 in one step.