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.

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The versatility of the hydrogenating system NaBH4/cat.

Introduction: Advances in surgical and medical therapies have increased the life expectancy for patients with congenital heart disease. Arrhythmias in these patients are common and multi-factorial, often due to a disruption of the hearts’ intrinsic electrical system and degenerative remodeling, secondary to varying pressure and volume loads. The aim of this study is to better characterize the association between type of structural heart disease (SHD) and clinically significant arrhythmias. Methods: We identified all adults with diagnosed congenital heart disease seen at a large tertiary care referral center between 2000 and 2014. Patients were categorized based on gender, SHD, and type of arrhythmia. We used the American Thoracic Society guidelines to group SHD into discrete categories and grouped arrhythmias as tachyarrhythmias (atrial/ventricular) and bradyarrhythmias. Results: We identified 1355 individuals with at least one congenital structural heart defect and at least one arrhythmia. Of those, the most common structural abnormality was left-sided outflow tract obstruction and the least common was congenitally corrected transposition of the great arteries. The most common category of arrhythmia identified was atrial arrhythmia and the least common was sinoatrial node dysfunction (Figure). The most common association between SHD and arrhythmia was atrial arrhythmia in patients with left-sided outflow tract obstruction. Conclusions: This study is one of the largest single-center reports linking specific structural heart defects to type of rhythm disturbance. These data may help providers better anticipate future arrhythmia development based on a patient’s underlying structural defect and offer prognostic information to patients and families. Future studies to more closely evaluate the relationship between arrhythmia patterns and specific risk factors within each category of SHD are needed.

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