ABSTRACT
Dynamic covalent chemistry has become an invaluable tool for the design and preparation of adaptable yet robust molecular systems. Herein we explore the scope of a largely overlooked dynamic covalent reaction - amidinium exchange - and report on conditions that allow formal amidinium metathesis reactions.
Subject(s)
Anions , AmidinesABSTRACT
Advances in supramolecular chemistry are often underpinned by the development of fundamental building blocks and methods enabling their interconversion. In this work, we report the use of an underexplored dynamic covalent reaction for the synthesis of stimuli-responsive [2]rotaxanes. The formamidinium moiety lies at the heart of these mechanically interlocked architectures, because it enables both dynamic covalent exchange and the binding of simple crown ethers. We demonstrated that the rotaxane self-assembly follows a unique reaction pathway and that the complex interplay between crown ether and thread can be controlled in a transient fashion by addition of base and fuel acid. Dynamic combinatorial libraries, when exposed to diverse nucleophiles, revealed a profound stabilizing effect of the mechanical bond as well as intriguing reactivity differences between seemingly similar [2]rotaxanes.
Subject(s)
RotaxanesABSTRACT
A dual Bcl-XL / Bcl-2 inhibitor was discovered from DNA-encoded libraries using a two steps process. In the first step, DNA was used to pair PNA-encoded fragments exploring > 250 000 combinations. In the second step, a focused library combining the selected fragments with linkers of different lengths and geometries led to the identification of tight binding adducts that were further investigated for their selective target engagement in pull-down assays, for their affinity by SPR, and their selectivity in a cytotoxicity assay. The best compound showed comparable cellular activity to venetoclax, the first-in-class therapeutic targeting Bcl-2.
Subject(s)
Antineoplastic Agents/pharmacology , DNA/chemistry , Drug Discovery , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Small Molecule Libraries/pharmacology , bcl-X Protein/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , K562 Cells , Molecular Structure , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Structure-Activity RelationshipABSTRACT
A concise and asymmetric synthesis of the enantiomeric pyrrolidines 2 and ent-2 are herein reported. Both enantiomers were assessed as ß-GCase inhibitors. While compound ent-2 acted as a poor competitive inhibitor, its enantiomer 2 proved to be a potent non-competitive inhibitor. Docking studies were carried out to substantiate their respective protein binding mode. Both pyrrolidines were also able to enhance lysosomal ß-GCase residual activity in N370S homozygous Gaucher fibroblasts. Notably, the non-competitive inhibitor 2 displayed an enzyme activity enhancement comparable to that of reference compounds IFG and NN-DNJ. This work highlights the impact of inhibitors chirality on their protein binding mode and shows that, beyond competitive inhibitors, the study of non-competitive ones can lead to the identification of new relevant parmacological chaperones.
