Rapid Affinity and Microsomal Stability Ranking of Crude Mixture Libraries of Histone Deacetylase Inhibitors.

The science of drug discovery involves multiparameter optimization of molecular structures through iterative design-make-test cycles. For medicinal chemistry library synthesis, traditional workflows involve the isolation of each individual compound, gravimetric quantitation, and preparation of a standard concentration solution for biological assays. In this work, we explore ways to expedite this process by testing unpurified library mixtures using a combination of mass spectrometry-based assays for affinity selection and microsomal metabolic stability.

Radical Chlorination of Non-Resonant Heterobenzylic C-H Bonds and High-Throughput Diversification of Heterocycles.

Site-selective functionalization of the heterobenzylic C(sp)-H bonds of pyridines and related heteroaromatic compounds presents challenges associated with the basic nitrogen atom and the variable reactivity among different positions on the heteroaromatic ring. Methods for functionalization of 2- and 4-alkylpyridines are increasingly available through polar pathways that leverage resonance stabilization of charge build-up at these positions. In contrast, functionalization of 3-alkylpyridines is largely inaccessible.

Development of High-Throughput Experimentation Approaches for Rapid Radiochemical Exploration.

Positron emission tomography is a widely used imaging platform for studying physiological processes. Despite the proliferation of modern synthetic methodologies for radiolabeling, the optimization of these reactions still primarily relies on inefficient one-factor-at-a-time approaches. High-throughput experimentation (HTE) has proven to be a powerful approach for optimizing reactions in many areas of chemical synthesis.

Accessing three-dimensional molecular diversity through benzylic C-H cross-coupling.

Pharmaceutical and agrochemical discovery efforts rely on robust methods for chemical synthesis that rapidly access diverse molecules. Cross-coupling reactions are the most widely used synthetic methods, but these methods typically form bonds to C()-hybridized carbon atoms (e.g.

Parallel purification of microscale libraries via automated solid phase extraction.

High-throughput experimentation (HTE) has become more widely utilized in drug discovery for rapid reaction optimization and generation of large synthetic compound arrays. While this has accelerated medicinal chemistry design, make, test (DMT) iterations, the bottleneck of purification persists, consuming time and resources. Herein we describe a general parallel purification approach based on solid phase extraction (SPE) that provides a more efficient and sustainable workflow producing compound libraries with significantly upgraded purity.