Nature displays a remarkable ability to carry out site-selective post-translational modification of proteins, therefore enabling a dramatic increase in their functional diversity 1 . Inspired by this, chemical tools have evolved for the synthetic manipulation of protein structure and function, and have become essential to the continued advancement of chemical biology, molecular biology and medicine. However, the number of chemical transformations suitable for effective protein functionalization is limited because the stringent demands inherent to biological systems preclude the applicability of many potential processes 2 . Put simply, these chemical transformations often need to be selective at a single site on a protein, proceed with very fast reaction rates, operate under biologically ambient conditions and should provide homogeneous products with near perfect conversion 2 – 7 . While many elegant bioconjugation methods exist at cysteine, lysine and tyrosine, we reasoned that a method targeting a less explored amino acid would significantly expand the protein functionalization toolbox. Herein, we report the development of a multifaceted-approach to protein functionalization based on chemoselective labelling at methionine residues. By exploiting the unique electrophilic reactivity of a bespoke hypervalent iodine reagent, one can target the S -Me group in the side-chain of methionine. The bioconjugation reaction is fast, selective, operates at low µM concentrations and is complementary to existing bioconjugation strategies. Moreover, the new reaction produces a protein conjugate that is, itself, a high energy intermediate with reactive properties that can serve as a platform for the development of secondary, visible-light mediated bioorthogonal protein functionalization processes. Taken together, the merger of these approaches provides a versatile platform for the development of distinct transformations that can deliver versatile, information-rich protein conjugates directly from the native biomacromolecules.

Aliphatic small rings including cyclopropanes, cyclobutanes, oxetanes, azetidines and bicyclo[1.1.1]pentanes have been increasingly exploited in medicinal chemistry. This review summarises judicious successful application and reported limitations of these ring systems.

Inhibition of the protein-protein interaction between B-cell lymphoma 6 (BCL6) and corepressors has been implicated as a therapeutic target in diffuse large B-cell lymphoma (DLBCL) cancers and profiling of potent and selective BCL6 inhibitors are critical to test this hypothesis. We identified a pyrazolo[1,5-a]pyrimidine series of BCL6 binders from a fragment screen in parallel with a virtual screen. Using structure-based drug design, binding affinity was increased 100000-fold. This involved displacing crystallographic water, forming new ligand-protein interactions and a macrocyclization to favor the bioactive conformation of the ligands. Optimization for slow off-rate constant kinetics was conducted as well as improving selectivity against an off-target kinase, CK2. Potency in a cellular BCL6 assay was further optimized to afford highly selective probe molecules. Only weak antiproliferative effects were observed across a number of DLBCL lines and a multiple myeloma cell line without a clear relationship to BCL6 potency. As a result, we conclude that the BCL6 hypothesis in DLBCL cancer remains unproven.

An operationally simple and environmentally benign formal hydrogenation protocol has been developed using a highly abundant iron(iii) salt and an inexpensive, bench stable, stoichiometric reductant, NaBH4, in ethanol, under ambient conditions.