Synthesis and Screening of A DNA-Encoded Library of Non-Peptidic Macrocycles

There is considerable interest in the development of libraries of non-peptidic macrocycles as a source of ligands for difficult targets. We report here the solid-phase synthesis of a DNA-encoded library of several hundred thousand thioether-linked macrocycles. The library was designed to be highly diverse with respect to backbone scaffold diversity and to minimize the number of amide N-H bonds, which compromise cell permeability. The utility of the library as a source of protein ligands is demonstrated through the isolation of compounds that bind streptavidin, a model target, with high affinity.

Synthesis and Screening of A DNA-Encoded Library of Non-Peptidic Macrocycles

There is considerable interest in the development of libraries of non-peptidic macrocycles as a source of ligands for difficult targets. We report here the solid-phase synthesis of a DNA-encoded library of several hundred thousand thioether-linked macrocycles. The library was designed to be highly diverse with respect to backbone scaffold diversity and to minimize the number of amide N-H bonds, which compromise cell permeability. The utility of the library as a source of protein ligands is demonstrated through the isolation of compounds that bind streptavidin, a model target, with high affinity.

Scaffold Diversity for Enhanced Activity of Glycosylated Inhibitors of Fungal Adhesion

<div>Candida albicans is one of the most prevalent fungal pathogens involved in</div><div>hospital acquired infections. It uses adhesins to bind to glycans at the cell surface of epithelial</div><div>cells and thus initiate infection. These interactions can be blocked by synthetic carbohydrates</div><div>(such as compound 1) that mimics the structure of cell surface glycans. Herein we report the</div><div>synthesis of a new series of divalent galactosides featuring aromatic (benzene, squaramides)</div><div>and aliphatic (norbornenes) central scaffolds, with the latter being the first examples of their</div><div>kind as small molecule anti-adhesion glycoconjugates. The evaluation of these compounds as</div><div>inhibitors of adhesion of C. albicans o exfoliated buccal epithelial cells (BECs) revealed that</div><div>galactosides 1 and 6, built on an aromatic core, were the most efficient inhibitors of adhesion,</div><div>displacing up to 36% and 48%, respectively, of yeast cells already attached to the BECs at</div><div>0.138 μM. Conformational analysis of compound 1 identified the preference for a folded </div><div>presentation in the lowest energy conformers. Remarkably, cis-endo-norbornene 21 performed</div><div>comparably to the benzene-core derivatives, highlighting the potential of norbornenes as a new</div><div>class of aliphatic scaffolds for the synthesis of anti-adhesion compounds.</div>

Scaffold Diversity for Enhanced Activity of Glycosylated Inhibitors of Fungal Adhesion

<div>Candida albicans is one of the most prevalent fungal pathogens involved in</div><div>hospital acquired infections. It uses adhesins to bind to glycans at the cell surface of epithelial</div><div>cells and thus initiate infection. These interactions can be blocked by synthetic carbohydrates</div><div>(such as compound 1) that mimics the structure of cell surface glycans. Herein we report the</div><div>synthesis of a new series of divalent galactosides featuring aromatic (benzene, squaramides)</div><div>and aliphatic (norbornenes) central scaffolds, with the latter being the first examples of their</div><div>kind as small molecule anti-adhesion glycoconjugates. The evaluation of these compounds as</div><div>inhibitors of adhesion of C. albicans o exfoliated buccal epithelial cells (BECs) revealed that</div><div>galactosides 1 and 6, built on an aromatic core, were the most efficient inhibitors of adhesion,</div><div>displacing up to 36% and 48%, respectively, of yeast cells already attached to the BECs at</div><div>0.138 μM. Conformational analysis of compound 1 identified the preference for a folded </div><div>presentation in the lowest energy conformers. Remarkably, cis-endo-norbornene 21 performed</div><div>comparably to the benzene-core derivatives, highlighting the potential of norbornenes as a new</div><div>class of aliphatic scaffolds for the synthesis of anti-adhesion compounds.</div>

ScaffoldGraph: an open-source library for the generation and analysis of molecular scaffold networks and scaffold trees

Summary ScaffoldGraph (SG) is an open-source Python library and command-line tool for the generation and analysis of molecular scaffold networks and trees, with the capability of processing large sets of input molecules. With the increase in high-throughput screening data, scaffold graphs have proven useful for the navigation and analysis of chemical space, being used for visualization, clustering, scaffold-diversity analysis and active-series identification. Built on RDKit and NetworkX, SG integrates scaffold graph analysis into the growing scientific/cheminformatics Python stack, increasing the flexibility and extendibility of the tool compared to existing software. Availability and implementation SG is freely available and released under the MIT licence at https://github.com/UCLCheminformatics/ScaffoldGraph.

Controllable one-pot synthesis for scaffold diversity via visible-light photoredox-catalyzed Giese reaction and further transformation

This study presents a controllable one-pot synthesis for constructing valuable scaffolds (alcohols, 2,3-dihydrofurans, α-cyano-γ-butyrolactones, and γ-butyrolactones) via a visible-light photoredox-catalyzed Giese reaction and further transformation.