Isosteric Approach Research Articles

Targeting hPKM2 in cancer: A bio isosteric approach for ligand design

The term cancer refers to a plethora of diseases characterized by the development of abnormal cells that divide uncontrollably and can infiltrate further proximal or distal body tissues. Each type of cancer can be defined by aggressiveness, localization, metabolism, and response to available treatments. Among the most common hallmarks of cancer is a more acidic intracellular microenvironment. Offset pH values are due to an excess of lactate and an increased hypoxia-inducible factor (HIF) expression, which leads to a hypoxic state and a metabolic shift towards glycolysis to produce adenosine-5′-triphosphate (ATP) necessary for cellular metabolism. Warburg's hypothesis underpins this concept, making glycolysis and its central enzyme pyruvate kinase (hPKM2), an ideal target for drug development. Using molecular docking and extensive molecular dynamics (MD) simulations we investigated the binding mode of phosphoenolpyruvate (PEP) inside the hPKM2 active site, and then evaluated a set of known bio-isosteric inhibitors to understand the differences caused by their substitutions on their binding mode. Ultimately, we propose a new molecular entity to hamper hPKM2, unbalance cellular energy, and possibly trigger autophagic mechanisms.

N‐pyridinylbenzamides: an isosteric approach towards new antimycobacterial compounds

A series of N-pyridinylbenzamides was designed and prepared to investigate the influence of isosterism and positional isomerism on antimycobacterial activity. Comparison to previously published isosteric N-pyrazinylbenzamides was made as an attempt to draw structure-activity relationships in such type of compounds. In total, we prepared 44 different compounds, out of which fourteen had minimum inhibitory concentration (MIC) values against Mycobacterium tuberculosis H37Ra below 31.25µg/ml, most promising being N-(5-chloropyridin-2-yl)-3-(trifluoromethyl)benzamide (23) and N-(6-chloropyridin-2-yl)-3-(trifluoromethyl)benzamide (24) with MIC=7.81µg/ml (26µm). Five compounds showed broad-spectrum antimycobacterial activity against M. tuberculosis H37Ra, M. smegmatis and M. aurum. N-(pyridin-2-yl)benzamides were generally more active than N-(pyridin-3-yl)benzamides, indicating that N-1 in the parental structure of N-pyrazinylbenzamides might be more important for antimycobacterial activity than N-4. Marginal antibacterial and antifungal activity was observed for title compounds. The hepatotoxicity of title compounds was assessed in vitro on hepatocellular carcinoma cell line HepG2, and they may be considered non-toxic (22 compounds with IC50 over 200µm).

P.524 Decreased medial prefrontal connectivity and lack of age-related gains in mentalizing in adolescents at clinical high risk transitioning to psychosis

Proline-based N,N′-dioxide ligands were designed on the basis of isosteric approach, and were successfully applied in enantioselective nucleophilic addition to aldehydes. In the presence of 10 mol% of chiral ligand 1b, enantioselective addition of diethylzinc to aldehydes provided the corresponding secondary alcohols in up to 90% isolated yield and up to 99% ee. Similarly, using 3e as chiral ligand, enantioselective arylation and alkynylation of aldehydes also proceeded readily, leading to the desired chiral alcohols in up to 92% isolated yield at 99% ee and 80% isolated yields and up to 84% ee, respectively. The current work would shed light on expanding the structure diversity in the design of chiral ligands and chiral catalysts.

Isosterically designed chiral catalysts: Rationale, optimization and their application in enantioselective nucleophilic addition to aldehydes

Abstract Proline-based N,N′-dioxide ligands were designed on the basis of isosteric approach, and were successfully applied in enantioselective nucleophilic addition to aldehydes. In the presence of 10 mol% of chiral ligand 1b, enantioselective addition of diethylzinc to aldehydes provided the corresponding secondary alcohols in up to 90% isolated yield and up to 99% ee. Similarly, using 3e as chiral ligand, enantioselective arylation and alkynylation of aldehydes also proceeded readily, leading to the desired chiral alcohols in up to 92% isolated yield at 99% ee and 80% isolated yields and up to 84% ee, respectively. The current work would shed light on expanding the structure diversity in the design of chiral ligands and chiral catalysts.

Comparative analysis of calculation method of adsorption isosteric heat: Case study of CO2 capture using MOFs

The isosteric heat of adsorption ( q st ) is a critical parameter to describe the CO 2 adsorption separation system for the determination of energy consumption of regeneration. The q st could be easily determined using the ensemble fluctuation approach as well as indirect approaches, including the isosteric and analytic ones; however the obtained q st values could be affected by the method used to determine them. To date, only a few studies compared these approaches using the same criteria, leading to challenges in identifying the proper approach for calculating q st . In this study, detailed comparisons of the indirect approaches and ensemble fluctuation approach were performed. The adsorption isotherms and q st values of Cu-BTC, MIL-47(V), MIL-100(Cr), and MIL-101(Cr), were obtained using the grand canonical Monte Carlo simulation. Then, q st was calculated using indirect approaches and the effect of the fitting equation was discussed. The results indicated that the ensemble fluctuation approach significantly depended on the force field. The simulated q st values of MIL-100(Cr) and MIL-101(Cr) were consistent with the calorimetric data; however, the simulated q st values of Cu-BTC and MIL-47(V) were not. For the indirect approaches, the Padè equation, combined with the isosteric approach, provided the most accurate q st values, and the relative deviation was approximately 1% under most conditions. This indicated the Padè equation could emerge as a universal fitting equation. Moreover, for the pressure or temperature swing adsorption processes, using excess variables to directly determine q st was not recommended, because the “isoexcess heat” could deviate from the isosteric heat by up to 10%. • Detailed overview of theory on isosteric heat. • Comprehensive comparison of various approaches for determination of isosteric heat. • GCMC simulation study of CO 2 gas adsorption on Cu-BTC, MIL-47(V), MIL-100(Cr), and MIL-101(Cr). • Effect of fitting formula on calculation of isosteric heat. • Effect of use of excess amounts on calculated isosteric heat of TSA and PSA.

Isosteric expansion of the structural diversity of chiral ligands: Design and application of proline-based N,N′-dioxide ligands for copper-catalyzed enantioselective Henry reactions

Chiral N,N′-dioxide catalysts were designed based on isosteric approach. Using l-Proline as the starting material, a variety of chiral N,N′-dioxide ligands were obtained via conventional functional group transformations and were utilized in asymmetric Henry reactions between nitromethane and aromatic aldehydes. Using the N,N′-dioxide-copper(II) complexes as the catalysts, asymmetric Henry reaction produced the corresponding β-nitroalcohols in up to 66% yields and up to 83% ee's under mild conditions. The reactions were easy to carry out, and special care such as air or moisture-free conditions was not required.

Moisture adsorption thermodynamics of wood from fractal-geometry approach

Abstract The fractal-geometry approach was used to calculate the thermodynamic properties of moisture sorption by wood from the adsorption isotherms in this study. The results were compared with those from an isosteric approach and a calorimetric approach. The adsorption isotherms of Southern yellow pine (Pinus spp.) were measured at 4, 15, 30, and 40°C to provide source data for the calculation of both fractal-geometry and isosteric approaches. The results show that the fractal dimensions of the internal surfaces of wood vary between 2.4 and 2.5. The curves of the differential heat of adsorption −∆H against moisture content from the fractal-geometry approach are similar to those from calorimetric measurements in previous research. The −∆H values from the isosteric approach increased with moisture content within a moisture content range up to 3%. And, at moisture contents higher than 3%, the −∆H values from this method are much higher than those from the fractal-geometry approach and calorimetric approach. As a result, the fractal-geometry approach is applicable to calculate the differential thermodynamic properties of moisture sorption by wood in future research.

Adsorption of normal hexane in silicalite-1: an isosteric approach

An isosteric method has been used to determine the adsorption equilibrium of hexane in silicalite-1 from 333 K to 423 K, and loadings of 2.8 to 5.5 molecules per unit cell. The isosteric heats of adsorption, q st, and the differential molar entropies of adsorption, ΔS∘, have been calculated from the isosteres. Isotherms were also obtained from the isosteres. All isotherms show an inflection at a coverage of ~4 molecules per unit cell.