RESUMEN
Photoisomerizable peptides are promising drug candidates in photopharmacology. While azobenzene- and diarylethene-containing photoisomerizable peptides have already demonstrated their potential in this regard, reports on the use of spiropyrans to photoregulate bioactive peptides are still scarce. This work focuses on the design and synthesis of a spiropyran-derived amino acid, (S)-2-amino-3-(6'-methoxy-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin-6-yl])propanoic acid, which is suitable for the preparation of photoisomerizable peptides. The utility of this amino acid is demonstrated by incorporating it into the backbone of BP100, a known membrane-active peptide, and by examining the photoregulation of the membrane perturbation by the spiropyran-containing peptides. The toxicity of the peptides (against the plant cell line BY-2), their bacteriotoxicity (E.â coli), and actin-auxin oscillator modulation ability were shown to be significantly dependent on the photoisomeric state of the spiropyran unit.
Asunto(s)
Escherichia coli , Indoles , Nitrocompuestos , Péptidos , Benzopiranos/química , AminoácidosRESUMEN
Over the last decades, the medicinal chemistry of boron-based compounds has been extensively explored, designing valuable small molecule drugs to tackle diseases and conditions, such as cancer, infections, inflammatory and neurological disorders. Notably, boron has proven to also be a valuable element for the development of inhibitors of the metalloenzymes carbonic anhydrases (CAs), a class of drug targets with significant potential in medicinal chemistry. Incorporating boron into carbonic anhydrase inhibitors (CAIs) can modulate the ligand ability to recognize the target and/or influence selectivity towards different CA isoforms, using the tail approach and boron-based tails. The electron-deficient nature of boron and its associated properties have also led to the discovery of novel zinc-binding CAIs, such as boronic acids and the benzoxaboroles, capable of inhibiting the CAs upon a Lewis acid-base mechanism of action. The present manuscript reviews the state-of-the-art of boron-based CAIs. As research in the applications of boron compounds in medicinal chemistry continues, it is anticipated that new boron-based CAIs will soon expand the current array of such compounds. However, further research is imperative to fully unlock the potential of boron-based CAIs and to advance them towards clinical applications.
Asunto(s)
Anhidrasas Carbónicas , Neoplasias , Humanos , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/química , Boro/farmacología , Anhidrasas Carbónicas/metabolismo , Isoformas de Proteínas , Compuestos de Boro , Relación Estructura-ActividadRESUMEN
Thioredoxin reductase is an essential enzyme that plays a crucial role in maintaining cellular redox homeostasis by catalyzing the reduction of thioredoxin, which is involved in several vital cellular processes. The overexpression of TrxR is often associated with cancer development. A series of 1,2-dithiolane-4-carboxylic acid analogs were obtained to verify the selectivity of 1,2-dithiolane moiety toward TrxR. Asparagusic acid analogs and their bioisoters remain inactive toward TrxR, which proves the inability of the 1,2-dithiolane moiety to serve as a pharmacophore during the interaction with TrxR. It was found that the Michael acceptor functionality-containing analogs exhibit higher inhibitory effects against TrxR compared to other compounds of the series. The most potent representatives exhibited micromolar TrxR1 inhibition activity (IC50 varied from 5.3 to 186.0 µM) and were further examined with in vitro cell-based assays to assess the cytotoxic effects on various cancer cell lines and cell death mechanisms.
RESUMEN
The lack of efficacy of current antibacterials to treat multidrug resistant bacteria poses a life-threatening alarm. In order to develop enhancers of the antibacterial activity, we carried out a medicinal chemistry campaign aiming to develop inhibitors of enzymes that synthesise cysteine and belong to the reductive sulphur assimilation pathway, absent in mammals. Previous studies have provided a novel series of inhibitors for O-acetylsulfhydrylase - a key enzyme involved in cysteine biosynthesis. Despite displaying nanomolar affinity, the most active representative of the series was not able to interfere with bacterial growth, likely due to poor permeability. Therefore, we rationally modified the structure of the hit compound with the aim of promoting their passage through the outer cell membrane porins. The new series was evaluated on the recombinant enzyme from Salmonella enterica serovar Typhimurium, with several compounds able to keep nanomolar binding affinity despite the extent of chemical manipulation.
Asunto(s)
Antibacterianos/farmacología , Ácidos Carboxílicos/farmacología , Ciclopropanos/farmacología , Cisteína Sintasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Ciclopropanos/síntesis química , Ciclopropanos/química , Cisteína Sintasa/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Escherichia coli/efectos de los fármacos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Salmonella typhimurium/enzimología , Relación Estructura-ActividadRESUMEN
We aimed to design and synthesize 3-methylenechroman-2-one derivatives and test their potency as TrxR1 inhibitors. A convenient and easy-to-handle synthetic approach to 3-methylenechroman-2-ones was developed. The inâ vitro inhibitory activity towards recombinant TrxR1 was determined for the obtained compounds. The most potent representatives exhibited submicromolar TrxR1 inhibition activity (IC50 varied from 0.29â µM to 10.2â µM). Structure-activity relationship analysis indicates the beneficial role of the substituent at the position C-6 of the core of chroman-2-one, where the derivatives containing halogen are the most active among the scope of compounds obtained. The most potent TrxR1 inhibitor of the series was further examined in inâ vitro cell-based assays to assess cytotoxic effects on various cancer cell lines, and to evaluate their influence on cell apoptosis.
Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Reductasa de Tiorredoxina-Disulfuro , Antineoplásicos/farmacología , Línea Celular , Relación Estructura-ActividadRESUMEN
Lipoic acid (LA) is an essential cofactor in prokaryotic and eukaryotic organisms, required for the function of several multienzyme complexes such as oxoacid dehydrogenases. Prokaryotes either synthesize LA or salvage it from the environment. The salvage pathway in Staphylococcus aureus includes two lipoate-protein ligases, LplA1 and LplA2, as well as the amidotransferase LipL. In this study, we intended to hijack the salvage pathway by LA analogues that are transferred via LplA2 and LipL to the E2 subunits of various dehydrogenases, thereby resulting in nonfunctional enzymes that eventually impair viability of the bacterium. Initially, a virtual screening campaign was carried out to identify potential LA analogues that bind to LplA2. Three selected compounds affected S. aureus USA300 growth in minimal medium at concentrations ranging from 2.5 to 10 µg/mL. Further analysis of the most potent compound (Lpl-004) revealed its transfer to E2 subunits of dehydrogenase complexes and a negative impact on its functionality. Growth impairment caused by Lpl-004 treatment was restored by adding products of the lipoate-dependent enzyme complexes. In addition, Caenorhabditis elegans infected with LpL-004-treated USA300 demonstrated a significantly expanded lifespan compared to worms infected with untreated bacteria. Our results provide evidence that LA analogues exploiting the LA salvage pathway represent an innovative strategy for the development of novel antimicrobial substances.
Asunto(s)
Antibacterianos , Staphylococcus aureus , Ácido Tióctico , Ácido Tióctico/farmacología , Ácido Tióctico/análogos & derivados , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/enzimología , Staphylococcus aureus/genética , Virulencia , Animales , Antibacterianos/farmacología , Antibacterianos/química , Péptido Sintasas/metabolismo , Péptido Sintasas/genética , Caenorhabditis elegans , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/tratamiento farmacológicoRESUMEN
The synthetic approaches towards unique asparagusic acid and its analogues as well as its chemical use, the breadth of its biological properties and their relevant applications have been explored. The significance of the 1,2-dithiolane ring tension in dithiol-mediated uptake and its use for the intracellular transport of molecular cargoes is discussed alongside some of the challenges that arise from the fast thiolate-disulfide interchange. The short overview with the indication of the available literature on natural 1,2-dithiolanes synthesis and biological activities is also included. The general review structure is based on the time-line perspective of the application of asparagusic acid moiety as well as its primitive derivatives (4-amino-1,2-dithiolane-4-carboxylic acid and 4-methyl-1,2-dithiolane-4-carboxilic acid) used in clinics/cosmetics, focusing on the recent research in this area and including international patents applications.