ABCG2/BCRP: Specific and Nonspecific Modulators Peña‐Solórzano, Diana; Stark, Simone Alexandra; König, Burkhard ...
Medicinal research reviews,
September 2017, Letnik:
37, Številka:
5
Journal Article
Recenzirano
Multidrug resistance (MDR) in cancer cells is the development of resistance to a variety of structurally and functionally nonrelated anticancer drugs. This phenomenon has become a major obstacle to ...cancer chemotherapy seriously affecting the clinical outcome. MDR is associated with increased drug efflux from cells mediated by an energy‐dependent mechanism involving the ATP‐binding cassette (ABC) transporters, mainly P‐glycoprotein (ABCB1), the MDR‐associated protein‐1 (ABCC1), and the breast cancer resistance protein (ABCG2). The first two transporters have been widely studied already and reviews summarized the results. The ABCG2 protein has been a subject of intense study since its discovery as its overexpression has been detected in resistant cell lines in numerous types of human cancers. To date, a long list of modulators of ABCG2 exists and continues to increase. However, little is known about the clinical consequences of ABCG2 modulation. This makes the design of novel, potent, and nontoxic inhibitors of this efflux protein a major challenge to reverse MDR and thereby increase the success of chemotherapy. The aim of the present review is to describe and highlight specific and nonspecific modulators of ABCG2 reported to date based on the selectivity of the compounds, as many of them are effective against one or more ABC transport proteins.
Se describió la intervención del mineral magnetita como catalizador o como soporte catalítico, un material inorgánico con una estructura de espinela inversa (FeFe2O4), en el desarrollo de un número ...importante de reacciones químicas de interés científico, tecnológico y ambiental. Debido a la necesidad actual de generar procesos químicos eficientes y favorables ambientalmente, la magnetita se ha convertido en un material promisorio en los contextos de la química verde, la química fina y la catálisis heterogénea. Este óxido de hierro se ha estudiado en diversas reacciones: catalizador másico, soporte catalítico de metales y de óxidos metálicos, núcleo de catalizadores tipo core-shell, o modificado mediante el anclaje de organocatalizadores y complejos metálicos. Se discute el desempeño catalítico de estos sistemas basados en magnetita, en reacciones de catálisis asimétrica, ambiental, ácido-base, de óxido-reducción, de síntesis multicomponente y de acoplamiento C-C. Particularmente, dichos catalizadores han mostrado enorme importancia en ciertas reacciones de tipo Sonogashira, Sonogashira–Hagihara, Mannich, Ullman, Knoevenagel, Suzuki-Miyaura y Fenton heterogénea, entre otras. Finalmente, se detallaron algunos usos tecnológicos de la magnetita en el contexto nacional (Colombia) y se intentó localizar geográficamente los depósitos importantes.
New advances in preparation of homoallylamines are discussed. Novel syntheses of saturated nitrogen‐containing heterocycles from N‐substituted homoallylic amines are reviewed.
ABC, it's easy as 1 2 3! Bioisosteric replacement of the anilide core by an indole moiety considerably increased stability and gave potent and selective ABCG2 (BCRP) inhibitors. Some compounds are ...superior to the reference substances fumitremorgin C and Ko143 in terms of potency and efficacy and are the most potent ABCG2 modulators reported so far.
In this contribution, we report on the electronic energy transfer dynamics of bichromophoric systems incorporating two pyrene chromophores tethered by variable-length flexible alkyloxy chains to ...p-phenylenevinylene oligomers. These were studied using UV–vis absorption and both steady state and time-resolved fluorescence spectroscopy. Time-resolved emission measurements showed an efficient photoinduced energy transfer process in all the multichromophoric systems, which occurs on the time scale of tens of picoseconds after excitation at 265 nm. The energy transfer process is especially efficient in systems where the linker is formed by eight atoms (up to k ET ≈ 2.7 × 1010 s–1), which, despite not being the shortest bridge studied, allows the approach of the donor and acceptor chromophores due to an appropriate number of flexible single bonds. Using Förster theory, we calculated the donor–acceptor distance in each triad from the experimental energy transfer rate, finding them to be in the range 8.8–10 Å.
Aiming at structural optimization of potent and selective ABCG2 inhibitors, such as UR-ME22-1, from our laboratory, an efficient solid phase synthesis was developed to get convenient access to this ...class of compounds. 7-Carboxyisatoic anhydride was attached to Wang resin to give resin bound 2-aminoterephthalic acid. Acylation with quinoline-2- or -6-carbonyl chlorides, coupling with tetrahydroisoquinolinylethylphenylamine derivatives, cleavage of the carboxylic acids from solid support and treatment with trimethylsilydiazomethane gave the corresponding methyl esters. Among these esters highly potent and selective ABCG2 modulators were identified (inhibition of ABCB1 and ABCG2 determined in the calcein-AM and the Hoechst 33342 microplate assay, respectively). Interestingly, compounds bearing triethyleneglycol ether groups at the tetrahydroisoquinoline moiety (UR-COP77, UR-COP78) were comparable to UR-ME22-1 in potency but considerably more efficient (max inhibition 83% and 88% vs 60%, rel. to fumitremorgin c, 100%) These results support the hypothesis that solubility of the new ABCG2 modulators and of the reference compounds tariquidar and elacridar in aqueous media is the efficacy-limiting factor.
Atom‐based bilinear indices and linear discriminant analysis are used to discover novel trypanosomicidal compounds. The obtained linear discriminant analysis‐based quantitative structure–activity ...relationship models, using non‐stochastic and stochastic indices, provide accuracies of 89.02% (85.11%) and 89.60% (88.30%) of the chemicals in the training (test) sets, respectively. Later, both models were applied to the virtual screening of 18 in‐house synthesized compounds to find new pro‐lead antitrypanosomal agents. The in vitro antitrypanosomal activity of this set against epimastigote forms of Trypanosoma cruzi is assayed. Predictions agree with experimental results to a great extent (16/18) of the chemicals. Sixteen compounds show more than 70% of epimastigote inhibition at a concentration 100 μg/mL. In addition, three compounds (CRIS 112, CRIS 140 and CRIS 147) present more than 70% of epimastigote inhibition at a concentration of 10 μg/mL (79.95%, 73.97% and 78.13%, respectively) with low values of cytotoxicity (19.7%, 7.44% and 20.63%, correspondingly).Taking into account all these results, we could say that these three compounds could be optimized in forthcoming works. Even though none of them resulted more active than nifurtimox, the current results constitute a step forward in the search for efficient ways to discover new lead antitrypanosomals.
Two LDA‐based QSAR models were developed and validated. A pool of approximately 200 compounds was screened to identify potential antitrypanosomal activity. Eighteen compounds were identifies as antitrypanosomal agents by our models. Sixteen of them shown more than 70% of epimastigote inhibition at a concentration of 100 μg/mL
Cycloadditions in combination with multicomponent reactions are among the most valuable synthetic tools used by organic chemists to construct cyclic and heterocyclic compounds in a straightforward ...way. Although cycloadditions, such as the Diels–Alder reaction, are mainly covered in basic and advanced organic courses for undergraduate students, few experiments are reported in the literature for undergraduate organic chemistry laboratories. Here we describe a new experiment to illustrate the multicomponent imino-Diels–Alder cycloaddition to obtain a tetrahydroquinoline derivative under green chemistry conditions. Different synthesis procedures, including solvent-free reactions, microwave assisted reactions, use of a deep eutectic solvent, and star anise oil as starting material, were evaluated by students. The structure of the synthesized compound was confirmed by NMR spectroscopy (1H, APT, COSY, HSQC), IR spectroscopy, mass spectrometry, and melting point analysis. In addition, the stereochemistry was also proposed by students based on the NMR data.
In this work, the low melting mixture sodium acetate trihydrate–urea was synthesized and the eutectic composition was determined and characterized using differential scanning calorimetry (DSC) and ...thermogravimetric analysis (TGA). The physical properties of the deep eutectic solvent (DES) such as viscosity, electrical conductivity, density, pH and refractive index were measured and analyzed as a function of temperature. To explore the use of this DES as a reaction media, the Biginelli one-pot reaction for the preparation of polyhydroquinoxaline derivatives was studied and unexpectedly methylenebis(3-hydroxy-5,5-dimethylcyclohex-2-enones) and hexahydroxanthene-1,8-diones were obtained when the reaction was performed at 60 °C, and hexahydroacridine-1,8-diones when the reaction was conducted at 100 °C. Our results showed that the nature of the obtained products can be tuned by increasing the temperature of the reaction.
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