Cristian Ochoa-Puentes

Benzanilide – Biphenyl Replacement: A Bioisosteric Approach to Quinoline Carboxamide-type ABCG2 Modulators

Recently reported compounds such as UR-COP78 (6) are among the most potent and selective ABCG2 modulators known so far but are prone to rapid enzymatic cleavage at the central benzanilide moiety. In search for more stable analogues, according to a bioisosteric approach, a series of N-(biphenyl-3-yl)quinoline carboxamides was prepared by solid phase and solution phase synthesis. The biphenyl moiety was constructed by Suzuki coupling. Inhibition of ABCB1 and ABCG2 was determined in a calcein-AM and a Hoechst 33342 microplate assay, respectively. Most synthesized compounds selectively inhibited the ABCG2 transporter at submicromolar concentrations with a maximal inhibitory effect (I max) over 90% (e.g., UR-COP228 (22a), IC50 591 nM, I max 109%; UR-COP258 (31), IC50 544 nM, I max 112%), though with lower potency and selectivity than 6. The biphenyl analogues are considerably more stable and demonstrate that the benzanilide core is not a crucial structural feature of quinoline carboxamide-type ABCG2 modulators.

Quinoline Carboxamide‐Type ABCG2 Modulators: Indole and Quinoline Moieties as Anilide Replacements

ABC, its 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.

ABCG2/BCRP: Specific and Nonspecific Modulators.

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.

Evaluation of sodium acetate trihydrate–urea DES as a benign reaction media for the Biginelli reaction. Unexpected synthesis of methylenebis(3-hydroxy-5,5-dimethylcyclohex-2-enones), hexahydroxanthene-1,8-diones and hexahydroacridine-1,8-diones

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.

Competitive One-Pot Reactions: Simultaneous Synthesis of Decahydroacridine-1,8-diones and 1,8-Dioxo-octahydroxanthenes and Photophysical Characterization

Abstract A simple and convenient one-pot method for simultaneously obtaining decahydroacridine-1,8-diones and 1,8-dioxo-octahydroxanthene derivatives is described. A high conversion yielding both products was obtained under the reaction conditions. To understand the optical behavior of the model compounds and their potential use as antenna moieties in bichromophoric systems, the photophysical properties of all samples were studied using ultraviolet–visible absorption and steady-state fluorescence spectroscopy in methanol solutions. For the case of the acridinediones, the fluorescence spectra were found to exhibit the typical emission profile of the locally excited state, whereas, contrary to previous published experimental results, reliable fluorescence emission spectra for the xanthenes derivatives could not be obtained. On the other hand, the poor quantum yields of the synthesized decahydroacridine-1,8-diones were explained based on the benzene-like substitution effect, which favors the intersystem crossing relaxation mechanism. [Supplementary materials are available for this article. Go to the publishers online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.] GRAPHICAL ABSTRACT

9-(4-Hydroxybutyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9- hexahydro-1H-xanthene-1,8(2H)-dione

The title compound 9-(4-hydroxybutyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione was synthesized in 72% yield through a simple, convenient and environmentally friendly one-pot reaction between dimedone and 3,4-dihydro-2H-pyran in aqueous citric acid. Additionally, a plausible reaction mechanism for the formation of the target xanthene is proposed.

1,4-Di(2-butoxycarbonyl-trans-vinyl)-2,5-dimethoxybenzene

The title compound 1,4-di(2-butoxycarbonyl-trans-vinyl)-2,5-dimethoxybenzene was synthesized in 94% yield through the Heck reaction between 2,5-diiodo-1,4-dimethoxybenzene and n-butyl acrylate, using bis(dibenzylideneacetone) palladium(0) as homogeneous catalyst.

Tariquidar-Related Chalcones and Ketones as ABCG2 Modulators

ABC transporters, including ABCG2, play a vital role in defending the human body against the vast range of xenobiotics. Even though this is beneficial for human health, these protein transporters have been implicated in the emerging resistance of cancer cells to a variety of structurally and functionally diverse anticancer drugs. In order to investigate their role in resistance, potent and selective ABCG2 modulators have been described in the literature. A leading class of modulators are the tariquidar analogues; however, their susceptibility to hydrolysis limits their applicable use. To overcome this, we synthesized a novel series of chalcone- and ketone-based compounds inspired by reported tariquidar analogues. Compounds were characterized and evaluated for their ABCG2 modulatory activity and ABC transporter selectivity. When compared to transporters ABCB1 and ABCC1, the chalcone-based compounds exhibited selectivity for ABCG2, while the ketone-based compounds showed only a slight preference for ABCG2. From the former series, chalcone 16d (UR-DP48) displayed similar activity to the reference fumitremorgin C, both producing comparable maximal effects. The compound exhibited marked antiproliferative activity, while cytotoxicity was less pronounced for the most active compound 17f from the ketone series. Chalcone-containing tariquidar analogues are promising modulators to aid in functional investigations of ABCG2 transporters.

Micro-composites based on polylactic acid with kaolinite or rice husk particles and their performance on water vapor permeability

ABSTRACT In this work, the effect of addition of kaolinite and rice husk microparticles on the water vapor permeability of polylactic acid (PLA) was evaluated. The PLA-composites materials were characterized by X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and optical microscopy. For the composite preparation, an experimental design was established using two factors: additive type and concentration. When evaluating the water vapor permeability of the composites, it was found that the incorporation of kaolinite at 1% and 5% reduced the permeability coefficient of PLA. Furthermore, the inclusion of 5% kaolinite showed an increase on the tensile strength of the material. By contrast, the addition of rice husk produced an increase on water vapor permeability of the material and a decrease of both the tensile strength and ductility (percent of elongation at fracture). The higher dispersion and more regular morphology of the kaolinite particles could explain the enhancement of the gas barrier. A similar thermal behavior was observed for both PLA and composite materials, confirming that no damage of these properties was caused with the incorporation of the filler particles.

Crystal structure of ethyl (E)-2-cyano-3-(thio­phen-2-yl)acrylate: two conformers forming a discrete disorder

The molecular structure of the title compound is characterized by a planarity that allows the formation of (010) sheets. However, the existence of two different conformations of the ethyl fragment introduces the occurrence of discrete disorder due to a molecular overlay.