Stimulated Raman scattering (SRS) microscopy represents a powerful method for imaging label-free drug distribution with high resolution. SRS was applied to image label-free ponatinib with high sensitivity and specificity in live human chronic myeloid leukemia (CML) cell lines. This was achieved at biologically relevant, nanomolar concentrations, allowing determination of ponatinib uptake and sequestration into lysosomes during the development of acquired drug resistance and an improved understanding of target engagement.
Modified peptides, such as stapled peptides, which replicate the structure of α-helical protein segments, represent a potential therapeutic advance. However, the 3D solution structure of these stapled peptides is rarely explored beyond the acquisition of circular dichroism (CD) data to quantify bulk peptide helicity; the detailed backbone structure, which underlies this, is typically undefined. Diastereomeric stapled peptides based on helical sections of three proteins (αSyn, Cks1 and CK1α) were generated; their overall helicity was quantified by CD; and the most helical peptide from each series was selected for structural analysis. Solution-phase models for the optimised peptides were generated using NMR-derived restraints and a modified CHARMM22 force field. Comparing these models with PDB structures allowed deviation between the stapled peptides and critical helical regions to be evaluated. These studies demonstrate that CD alone is not sufficient to assess the structural fidelity of a stapled peptide.
Thec atalytic hydrophosphination reaction is one of the most sustainablec hemical transformations today.H ere,t he palladium-catalyzed asymmetric P À Ha ddition of diarylphosphines with N-enoylbenzotriazoles and analogues is described. Chiral phosphinep roductsa re obtained in 100%a tom economy and without cumbersome protection-deprotection manipulations.T he obtained productsc an be subsequently transformedt ob ear various functionalities,i ncluding phosphino-carboxylic esters which play critical roles in catalysisa nd as synthetic aids.A nti-tumour activities of the corresponding gold-phosphine complexes have been explored, contributing to existing chemotherapeuticr esearchi n cancer treatment.
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