Evaluation of the Topology Space of DNA-Encoded Libraries.

DNA-encoded libraries (DELs) are widely used in the discovery of drug candidates, and understanding their design principles is critical for accessing better libraries. Most DELs are combinatorial in nature and are synthesized by assembling sets of building blocks in specific topologies. In this study, different aspects of library topology were explored and their effect on DEL properties and chemical diversity was analyzed. We introduce a descriptor for DEL topological assignment (DELTA) and use it to examine the landscape of possible DEL topologies and their coverage in the literature. A generative topographic mapping analysis revealed that the impact of library topology on chemical space coverage is secondary to building block selection. Furthermore, it became apparent that the descriptor used to analyze chemical space dictates how structures cluster, with the effects of topology being apparent when using three-dimensional descriptors but not with common two-dimensional descriptors. This outcome points to potential challenges of attempts to predict DEL productivity based on chemical space analyses alone. While topology is rather inconsequential for defining the chemical space of encoded compounds, it greatly affects possible interactions with target proteins as illustrated in docking studies using NAD/NADP binding proteins as model receptors.

Direct radical functionalization methods to access substituted adamantanes and diamondoids.

Adamantane derivatives have diverse applications in the fields of medicinal chemistry, catalyst development and nanomaterials, owing to their unique structural, biological and stimulus-responsive properties, among others. The synthesis of substituted adamantanes and substituted higher diamondoids is frequently achieved via carbocation or radical intermediates that have unique stability and reactivity when compared to simple hydrocarbon derivatives. In this review, we discuss the wide range of radical-based functionalization reactions that directly convert diamondoid C-H bonds to C-C bonds, providing a variety of products incorporating diverse functional groups (alkenes, alkynes, arenes, carbonyl groups, etc.). Recent advances in the area of selective C-H functionalization are highlighted with an emphasis on the H-atom abstracting species and their ability to activate the particularly strong C-H bonds that are characteristic of these caged hydrocarbons, providing insights that can be applied to the C-H functionalization of other substrate classes.

Synthesis of amino-diamondoid pharmacophores via photocatalytic C-H aminoalkylation.

We report a direct C-H aminoalkylation reaction using two light-activated H-atom transfer catalyst systems that enable the introduction of protected amines to native adamantane scaffolds with C-C bond formation. The scope of adamantane and imine reaction partners is broad and deprotection provides versatile amine and amino acid building blocks. Using readily available chiral imines, the enantioselective synthesis of the saxagliptin core and rimantadine derivatives is also described.

A Heck-Based Strategy To Generate Anacardic Acids and Related Phenolic Lipids for Isoform-Specific Bioactivity Profiling.

A synthetic strategy for phenolic lipids such as anacardic acid and ginkgolic acid derivatives using an efficient and selective redox-relay Heck reaction followed by a stereoselective olefination is reported. This approach controls both the alkene position and stereochemistry, allowing the synthesis of natural and unnatural unsaturated lipids as single isomers. By this strategy, the activities of different anacardic acid and ginkgolic acid derivatives have been examined in a matrix metalloproteinase inhibition assay.