Small molecules, big targets: drug discovery faces the protein-protein interaction challenge.

Protein-protein interactions (PPIs) are of pivotal importance in the regulation of biological systems and are consequently implicated in the development of disease states. Recent work has begun to show that, with the right tools, certain classes of PPI can yield to the efforts of medicinal chemists to develop inhibitors, and the first PPI inhibitors have reached clinical development. In this Review, we describe the research leading to these breakthroughs and highlight the existence of groups of structurally related PPIs within the PPI target class. For each of these groups, we use examples of successful discovery efforts to illustrate the research strategies that have proved most useful.JS, DES and ARB thank the Wellcome Trust for funding.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nrd.2016.2

New pyrrole derivatives with potent tubulin polymerization inhibiting activity as anticancer agents including hedgehog-dependent cancer

We synthesized 3-aroyl-1-arylpyrrole (ARAP) derivatives as potential anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1-phenyl ring and 3-(3,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARAP 22 showed strong inhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog signaling pathway, strongly reducing luciferase activity in SAG treated NIH3T3 Shh-Light II cells, and inhibited the growth of medulloblastoma D283 cells at nanomolar concentrations. ARAPs 22 and 27 represent a new potent class of tubulin polymerization and cancer cell growth inhibitors with the potential to inhibit the Hedgehog signaling pathway

Synthesis of furano-epothilone D

The total synthesis of furano-epothilone D by a convergent route is reported. The key fragments are available on a large scale to provide sufficient material for biological evaluation. The approach involves a palladium-catalyzed coupling that generates a highly functionalized aldehyde which is connected in a stereoselective aldol reaction to yield the framework of furano-epothilone D. Finally, a macrolactonization provides furano-epothilone D

Quantitative structure-activity relationship (5D-QSAR) study of combretastatin-like analogues as inhibitors of tubulin assembly

A molecular modeling study was carried out to develop a predictive model for combretastatin-like analogues populating the colchicine-binding site of Beta-tubulin. A series of compounds built around a framework including two aromatic groups linked by various moieties such as alkenes (stilbenes), enones (chalcones), or ethers was selected for the study. The 5D-QSAR model was developed stepwise. First a model was generated for the chalcone series (19 compounds, 71 conformations), then for the stilbene series (18 compounds, 59 conformations), and finally for the combined dataset (47 ligands, 160 conformers). Although the models for the chalcone and stilbene series appeared slightly different when represented by QSAR colored surfaces, the combined model seems to reconcile the differences without compromise and represents a highly predictive model for compounds that bind to the colchicine-binding site of tubulin

Towards the total synthesis of tangutorine by intramolecular Diels–Alder reaction

The syntheses of 3,5-disubstituted-2-sulfolenes, and their participation in Pictet-Spengler reactions to give precursors of tangutorine, are described

The Microstructure and Mechanical Properties of Cylindrical Elements from Steel 38Mn6 after Continuous Induction Heating

The paper deals with the influence of induction surface hardening on the microstructure and mechanical properties of cylindrical elements made of steel 38Mn6. The first stage was based on computer simulation of the induction hardening process. The second stage - experiments were provided on laboratory stand for induction surface hardening located at the Silesian University of Technology. Microstructure tests were conducted on light and scanning microscopes. The hardness penetration pattern and thickness of hardened layer were marked. It was found that due to properly chosen parameters of the process, the appropriate properties and thickness of hardened layer were achieved

Asymmetric alkylation of diarylmethane derivatives

Deprotonation–alkylation of prochiral diarylmethane substrates using sec-BuLi and (−)-sparteine has been carried out in excellent yields and up to 94% ee. A variety of enantioselective alkylations, silylations and stannylations have been performed on four different diarylmethanes. Surrogates for (+)-sparteine have also been applied in this study including a novel surrogate