Photoswitchable basicity through the use of azoheteroarenes

We report an azoheteroarene photoswitchable base, where proton stabilisation in Z isomer is facilitated by neighbouring imidazole rings. A 1.3 unit difference in pKa is observed between the E and Z isomers, which leads to the ability to reversibly control solution pH.</p

Facile Protocol for Water-Tolerant “Frustrated Lewis Pair”-Catalyzed Hydrogenation

Despite rapid advances in the field of metal-free, “frustrated Lewis pair” (FLP)-catalyzed hydrogenation, the need for strictly anhydrous reaction conditions has hampered wide-scale uptake of this methodology. Herein, we report that, despite the generally perceived moisture sensitivity of FLPs, 1,4-dioxane solutions of B(C6F5)3 actually show appreciable moisture tolerance and can catalyze hydrogenation of a range of weakly basic substrates without the need for rigorously inert conditions. In particular, reactions can be performed directly in commercially available nonanhydrous solvents without subsequent drying or use of internal desiccants

Chiroptical studies on brevianamide B : vibrational and electronic circular dichroism confronted

Chiroptical spectroscopy, such as electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) are highly sensitive techniques to probe molecular conformation, configuration, solvation and aggregation. Here we report the application of these techniques to study the fungal metabolite brevianamide B. Comparison of the experimental ECD and VCD spectra with the density functional theory (DFT) simulated counterparts establishes that VCD is the more reliable technique to assign absolute configuration due to the larger functional and dispersion dependence of computed ECD spectra. Despite a low amount of available material, and a relatively unusual example of using VCD carbonyl multiplets, the absolute configuration could be reliably predicted, strengthening the case for application of VCD in the study of complex natural products. Spectral and crystallographic evidence for or against the formation of a dimeric aggregate is discussed; in solution the VCD spectra strongly suggest only monomeric species are present

Thermodynamics of ligand binding to histone deacetylase like amidohydrolase from Bordetella/Alcaligenes

Thermodynamic studies on ligand–protein binding have become increasingly important in the process of drug design. In combination with structural data and molecular dynamics simulations, thermodynamic studies provide relevant information about the mode of interaction between compounds and their target proteins and therefore build a sound basis for further drug optimization. Using the example of histone deacetylases (HDACs), particularly the histone deacetylase like amidohydrolase (HDAH) from Bordetella/Alcaligenes, a novel sensitive competitive fluorescence resonance energy transfer-based binding assay was developed and the thermodynamics of interaction of both fluorescent ligands and inhibitors to histone deacetylase like amidohydrolase were investigated. The assay consumes only small amounts of valuable target proteins and is suitable for fast kinetic and mechanistic studies as well as high throughput screening applications. Binding affinity increased with increasing length of aliphatic spacers (n?=?4–7) between the hydroxamate moiety and the dansyl head group of ligand probes. Van't Hoff plots revealed an optimum in enthalpy contribution to the free energy of binding for the dansyl-ligand with hexyl spacer. The selectivity in the series of dansyl-ligands against human class I HDAC1 but not class II HDACs 4 and 6 increased with the ratio of deltaH0/deltaG0. The data clearly emphasize the importance of thermodynamic signatures as useful general guidance for the optimization of ligands or rational drug design

On the promise of photopharmacology using photoswitches: a medicinal chemist's perspective.

Photopharmacology is a growing area of endeavor that employs photoswitchable ligands to allow for light-dependent pharmacological activity. By coupling light to therapeutic action, improved spatial and temporal selectivity can be achieved and subsequently harnessed for new concepts in therapy. Tremendous progress has already been made, with photopharmacological agents now reported against a wide array of target classes, and light-dependent results demonstrated in a range of live cell and animal models. Several challenges remain however, especially in order for photopharmacology to truly impact the clinical management of disease. This perspective aims to summarize these challenges, particularly with attention to the medicinal chemistry that will be unavoidably required for the further translation of these agents/approaches. By clearly defining challenges for drug hunters, it is hoped that further research into the medicinal chemistry of photopharmacological agents will be stimulated; ultimately enabling full realization of the huge potential for this exciting field

Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells

Background: Many cancers show aberrant silencing of gene expression and overexpression of histone methyltransferases. The histone methyltransferases (HKMT) EZH2 and EHMT2 maintain the repressive chromatin histone methylation marks H3K27me and H3K9me, respectively, which are associated with transcriptional silencing. Although selective HKMT inhibitors reduce levels of individual repressive marks, removal of H3K27me3 by specific EZH2 inhibitors, for instance, may not be sufficient for inducing the expression of genes with multiple repressive marks. Results: We report that gene expression and inhibition of triple negative breast cancer cell growth (MDA-MB-231) are markedly increased when targeting both EZH2 and EHMT2, either by siRNA knockdown or pharmacological inhibition, rather than either enzyme independently. Indeed, expression of certain genes is only induced upon dual inhibition. We sought to identify compounds which showed evidence of dual EZH2 and EHMT2 inhibition. Using a cell-based assay, based on the substrate competitive EHMT2 inhibitor BIX01294, we have identified proof-of-concept compounds that induce re-expression of a subset of genes consistent with dual HKMT inhibition. Chromatin immunoprecipitation verified a decrease in silencing marks and an increase in permissive marks at the promoter and transcription start site of re-expressed genes, while Western analysis showed reduction in global levels of H3K27me3 and H3K9me3. The compounds inhibit growth in a panel of breast cancer and lymphoma cell lines with low to sub-micromolar IC50s. Biochemically, the compounds are substrate competitive inhibitors against both EZH2 and EHMT1/2. Conclusions: We have demonstrated that dual inhibition of EZH2 and EHMT2 is more effective at eliciting biological responses of gene transcription and cancer cell growth inhibition compared to inhibition of single HKMTs, and we report the first dual EZH2-EHMT1/2 substrate competitive inhibitors that are functional in cells

The 3D coarse-graining formulation of interacting elastohydrodynamic filaments and multi-body microhydrodynamics

Elastic filaments are vital to biological, physical and engineering systems, from cilia driving fluid in the lungs to artificial swimmers and micro-robotics. Simulating slender structures requires intricate balance of elastic, body, active, and hydrodynamic moments, all in three-dimensions. Here, we present a generalised 3D coarse-graining formulation that is efficient, simple-to-implement, readily extendable and usable for a wide array of applications. Our method allows for simulation of collections of 3D elastic filaments, capable of full flexural and torsional deformations, coupled non-locally via hydrodynamic interactions, and including multi-body microhydrodynamics of structures with arbitrary geometry. The method exploits the exponential mapping of quaternions for tracking three-dimensional rotations of each interacting element in the system, allowing for computation times up to 150 times faster than a direct quaternion implementation. Spheres are used as a `building block' of both filaments and solid micro-structures for straightforward and intuitive construction of arbitrary three-dimensional geometries present in the environment. We highlight the strengths of the method in a series of non-trivial applications including bi-flagellated swimming, sperm-egg scattering, and particle transport by cilia arrays. Applications to lab-on-a-chip devices, multi-filaments, mono-to-multi flagellated microorganisms, Brownian polymers, and micro-robotics are straightforward. A Matlab code is provided for further customization and generalizations.Comment: 16 pages, 6 figure