RESUMO
Positive-sense single-stranded RNA (+RNA) viruses have proven to be important pathogens that are able to threaten and deeply damage modern societies, as illustrated by the ongoing COVID-19 pandemic. Therefore, compounds active against most or many +RNA viruses are urgently needed. Here, we present PR673, a helquat-like compound that is able to inhibit the replication of SARS-CoV-2 and tick-borne encephalitis virus in cell culture. Using in vitro polymerase assays, we demonstrate that PR673 inhibits RNA synthesis by viral RNA-dependent RNA polymerases (RdRps). Our results illustrate that the development of broad-spectrum non-nucleoside inhibitors of RdRps is feasible.
Assuntos
COVID-19 , Vírus da Encefalite Transmitidos por Carrapatos , Humanos , Pandemias , RNA Polimerase Dependente de RNA , SARS-CoV-2RESUMO
Diquats with extremely high racemization barriers with ΔG≠theor of 233â kJ mol-1 at 180 °C are described. Reported configurational robustness is due to a combination of two structural features: the rigid o-xylylene tether connecting the nitrogen atoms and the presence of two substituents in the bay region of the bipyridinium scaffold. The straightforward synthesis of diquats, plus facile resolution and derivatization make them attractive for chiral application studies. This is demonstrated by: 1)â synthesis of the first non-racemic diquat dyes with pronounced chiroptical properties, and 2)â capability of diquats to interact stereospecifically with chiral molecules. This suggests potential for diquat derivatives to be used as chiral selectors in separation methods.
RESUMO
A new process for obtaining dibenzo[c,f][1,2,5]thiadiazepines (DBTDs) and their effects on GABA(A) receptors of guinea pig myenteric neurons are described. Synthesis of DBTD derivatives began with two commercial aromatic compounds. An azide group was obtained after two sequential reactions, and the central ring was closed via a nitrene to obtain the tricyclic sulfonamides (DBTDs). Whole-cell recordings showed that DBTDs application did not affect the holding current but inhibited the currents induced by GABA (I(GABA)), which are mediated by GABA(A) receptors. These DBTDs effects reached their maximum 3 min after application and were: (i) reversible, (ii) concentration-dependent (with a rank order of potency of 2c = 2d > 2b), (iii) mediated by a non-competitive antagonism, and (iv) only observed when applied extracellularly. Picrotoxin (which binds in the channel mouth) and DBTDs effects were not modified when both substances were simultaneous applied. Our results indicate that DBTD acted on the extracellular domain of GABA(A) channels but independent of the picrotoxin, benzodiazepine, and GABA binding sites. DBTDs used here could be the initial model for synthesizing new GABA(A) receptor inhibitors with a potential to be used as antidotes for positive modulators of these receptors or to induce experimental epilepsy.
Assuntos
Antagonistas de Receptores de GABA-A/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Tiadiazinas/farmacologia , Animais , Células Cultivadas , Feminino , Antagonistas de Receptores de GABA-A/síntese química , Cobaias , Concentração Inibidora 50 , Masculino , Potenciais da Membrana/efeitos dos fármacos , Plexo Mientérico/citologia , Técnicas de Patch-Clamp , Cultura Primária de Células , Receptores de GABA-A/metabolismo , Tiadiazinas/síntese química , Ácido gama-Aminobutírico/farmacologiaRESUMO
A three-step protocol for the synthesis of 1,2,3,8,9-pentasubstituted-5,6-dihydropyrrolo[2,1-a]isoquinolines is described, using van Leusen's polysubstituted pyrrole construction followed by intramolecular radical-oxidative cyclization of the isoquinoline system. The cytotoxic activities of the dihydropyrroloisoquinolines were tested on six tumor cell lines. Preliminary structure-activity studies revealed the importance of the identity of the aromatic substituent at the C-2 position, particularly a phenyl, m-(amino) phenyl or m-(cyclohexylmethylpiperazinamide) phenyl substituent, for cytotoxic activity.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclização , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoquinolinas/síntese química , Modelos Moleculares , Neoplasias/tratamento farmacológico , Oxirredução , Pirróis/síntese química , Relação Estrutura-AtividadeRESUMO
The formation of a G-quadruplex motif in the promoter region of the c-MYC protooncogene prevents its expression. Accordingly, G-quadruplex stabilization by a suitable ligand may be a viable approach for anticancer therapy. In our study, we used the 4-(4-methylpiperazin-1-yl)aniline molecule, previously identified as a fragment library screen hit, as a template for the SAR-guided design of a new small library of clickable fragments and subjected them to click reactions, including kinetic target-guided synthesis in the presence of a G-quadruplex forming oligonucleotide Pu24. We tested the clickable fragments and products of click reactions for their G-quadruplex stabilizing activity and determined their mode of binding to the c-MYC G-quadruplex by NMR spectroscopy. The enhanced stabilizing potency of click products in biology assays (FRET, Polymerase extension assay) matched the increased yields of inâ situ click reactions. In conclusion, we identified the newly synthesized click products of bis-amino derivatives of 4-(4-methylpiperazin-1-yl)aniline as potent stabilizers of c-MYC G-quadruplex, and their further evolution may lead to the development of an efficient tool for cancer treatment.
Assuntos
Compostos de Anilina/química , Compostos de Anilina/farmacologia , Quadruplex G/efeitos dos fármacos , Compostos de Anilina/síntese química , Técnicas de Química Sintética , Química Click , Genes myc/genética , Cinética , Ligantes , Simulação de Dinâmica MolecularRESUMO
Helquats (HQs) are structurally linked to helicenes and viologens, and they represent an attractive field of research in chemistry and medicinal chemistry. In the present work they were used as catalysts for the synthesis of 1,2,3,4-tetrahydroquinolines in good yields by the Povarov reaction. The substrate scope and the capability of different helquats to promote Povarov reactions are demonstrated. Studies to elucidate mechanistic details revealed that helquats act as single-electron transfer oxidants through a cation-radical mechanism. The screening of the catalytic activity of HQs confirmed that an active HQ must have a LUMO energy below -8.67â eV and the standard redox potential higher (less negative) than -1.2â V vs. the ferrocene/ferrocenium redox couple.
Assuntos
Compostos Policíclicos/química , Quinolinas/síntese química , Viologênios/química , Catálise , Estrutura Molecular , Quinolinas/química , EstereoisomerismoRESUMO
It has been more than 50 years since the discovery of dinucleoside polyphosphates (NpnNs) and yet their roles and mechanisms of action remain unclear. Here, we show that both methylated and non-methylated NpnNs serve as RNA caps in Escherichia coli. NpnNs are excellent substrates for T7 and E. coli RNA polymerases (RNAPs) and efficiently initiate transcription. We demonstrate, that the E. coli enzymes RNA 5'-pyrophosphohydrolase (RppH) and bis(5'-nucleosyl)-tetraphosphatase (ApaH) are able to remove the NpnN-caps from RNA. ApaH is able to cleave all NpnN-caps, while RppH is unable to cleave the methylated forms suggesting that the methylation adds an additional layer to RNA stability regulation. Our work introduces a different perspective on the chemical structure of RNA in prokaryotes and on the role of RNA caps. We bring evidence that small molecules, such as NpnNs are incorporated into RNA and may thus influence the cellular metabolism and RNA turnover.
Assuntos
Hidrolases Anidrido Ácido/metabolismo , Fosfatos de Dinucleosídeos/genética , Proteínas de Escherichia coli/metabolismo , Escherichia coli/genética , Capuzes de RNA/genética , RNA Polimerases Dirigidas por DNA/genética , Metilação , Conformação de Ácido Nucleico , Estabilidade de RNA , RNA Bacteriano/genéticaRESUMO
A two-step protocol for the synthesis of azepino[4,5-b]indolone derivatives featuring a xanthate radical oxidative aromatic substitution on the N-Boc protected tryptamine, using dilauroyl peroxide (DLP) as initiator and oxidant, is described.
Assuntos
Azepinas/síntese química , Indóis/síntese química , Triptaminas/química , Xantenos/química , Azepinas/química , Radicais Livres/química , Indóis/química , Estrutura Molecular , Oxirredução , Peróxidos/química , EstereoisomerismoRESUMO
Noncovalent molecular interactions between helquats, a new class of dicationic helical extended diquats, and several chiral acidic aromatic drugs and catalysts have been investigated using partial-filling affinity capillary electrophoresis (PF-ACE). Helquats dissolved at 1mM concentration in the aqueous background electrolyte (40mM Tris, 20mM acetic acid, pH 8.1) were introduced as ligand zones of variable length (0-130mm) into the hydroxypropylcellulose coated fused silica capillary whereas 0.1mM solutions of negatively charged chiral drugs or catalysts (warfarin, ibuprofen, mandelic acid, etodolac, binaphthyl phosphate and 11 other acidic aromatic compounds) were applied as a short analyte zone at the injection capillary end. After application of electric field, analyte and ligand migrated against each other and in case of their interactions, migration time of the analyte was increasing with increasing length of the ligand zone. From the tested compounds, only isomers of those exhibiting helical chirality and/or possessing conjugated aromatic systems were enantioselectively separated through their differential interactions with helquats. Some compounds with conjugated aromatic groups interacted with helquats moderately strongly but non-enantiospecifically. Small compounds with single benzene ring exhibited no or very weak non-enantiospecific interactions. PF-ACE method allowed to determine binding constants of the analyte-helquat complexes from the changes of migration times of the analytes. Binding constants of the weakest complexes of the analytes with helquats were less than 50L/mol, whereas binding constants of the strongest complexes were in the range 1 000-1 400L/mol.
Assuntos
Eletroforese Capilar/métodos , Hidrocarbonetos Aromáticos/análise , Algoritmos , Celulose/análogos & derivados , Corantes , Indicadores e Reagentes , Ligantes , Preparações Farmacêuticas/análise , EstereoisomerismoRESUMO
Two molecules of mistaken identity are addressed. Uncovering these assignment errors led us to formulate more general guidelines about additional misassignments in cases of published bis-imines derived from 1,2-phenylenediamine and hydroxybenzaldehydes having no substituent in ortho-positions. The main purpose of this article is to highlight this repetitive assignment error in the literature and thus increase the likelihood of correct assignments in future papers.
Assuntos
DNA/química , Quadruplex GRESUMO
Helquat dyes are the first helicene-like cationic styryl dyes obtained as separate enantiomers. Their remarkable chiroptical properties are due to the unique combination of a cationic hemicyanine chromophore and a helicene-like motif. The magnitude of the ECD response and the pH switching along with their positioning in the visible region are unprecedented among helicenoids.