Synthesis of (Hetero)biaryls via Nickel Catalyzed Reductive Cross-Electrophile Coupling Between (Hetero)aryl Iodides and Bromides.

(Hetero)biaryls are fundamental building blocks in the pharmaceutical industry and rapid access to these scaffolds is imperative for the success of numerous medicinal chemistry campaigns. Herein, a highly general, mild, and chemoselective reductive cross-electrophile coupling between (hetero)aryl iodides and heteroaryl bromides is reported. By employing more reactive (hetero)aryl halides, a broad range of successful substrates (45 examples) were identified. The reaction was also found to be chemoselective for C(sp2)-C(sp2) bond formation between (hetero)aryl iodides and bromides over (hetero)aryl chlorides, which were generally inert under the described reaction conditions. The efficiency of the procedure is also further demonstrated in parallel synthesis library format, on gram scale, as well as in the formal synthesis of Ruxolitinib, a potent JAK inhibitor. As such, we anticipate this method will find widespread utility in the assembly of (hetero)biaryls for medicinal chemistry efforts.

Identification of 2-Sulfonyl/Sulfonamide Pyrimidines as Covalent Inhibitors of WRN Using a Multiplexed High-Throughput Screening Assay.

Werner syndrome protein (WRN) is a multifunctional enzyme with helicase, ATPase, and exonuclease activities that are necessary for numerous DNA-related transactions in the human cell. Recent studies identified WRN as a synthetic lethal target in cancers characterized by genomic microsatellite instability resulting from defects in DNA mismatch repair pathways. WRN's helicase activity is essential for the viability of these high microsatellite instability (MSI-H) cancers and thus presents a therapeutic opportunity. To this end, we developed a multiplexed high-throughput screening assay that monitors exonuclease, ATPase, and helicase activities of full-length WRN. This screening campaign led to the discovery of 2-sulfonyl/sulfonamide pyrimidine derivatives as novel covalent inhibitors of WRN helicase activity. The compounds are specific for WRN versus other human RecQ family members and show competitive behavior with ATP. Examination of these novel chemical probes established the sulfonamide NH group as a key driver of compound potency. One of the leading compounds, H3B-960, showed consistent activities in a range of assays (IC50 = 22 nM, KD = 40 nM, KI = 32 nM), and the most potent compound identified, H3B-968, has inhibitory activity IC50 ∼ 10 nM. These kinetic properties trend toward other known covalent druglike molecules. Our work provides a new avenue for screening WRN for inhibitors that may be adaptable to different therapeutic modalities such as targeted protein degradation, as well as a proof of concept for the inhibition of WRN helicase activity by covalent molecules.

N-Functionalization of 1,2-Azaborines.

General protocols for the N-functionalization of 1,2-azaborines with C(sp3), C(sp2), or C(sp) electrophiles are described. The syntheses of a new parental BN isostere of trans-stilbene and a BN isostere of a lisdexamfetamine derivative were accomplished with the developed methodology.

Fast calculation software for modified Look-Locker inversion recovery (MOLLI) T1 mapping.

BACKGROUND: The purpose of this study was to develop a software tool and evaluate different T1 map calculation methods in terms of computation time in cardiac magnetic resonance imaging. METHODS: The modified Look-Locker inversion recovery (MOLLI) sequence was used to acquire multiple inversion time (TI) images for pre- and post-contrast T1 mapping. The T1 map calculation involved pixel-wise curve fitting based on the T1 relaxation model. A variety of methods were evaluated using data from 30 subjects for computational efficiency: MRmap, python Levenberg-Marquardt (LM), python reduced-dimension (RD) non-linear least square, C++ single- and multi-core LM, and C++ single- and multi-core RD. RESULTS: Median (interquartile range) computation time was 126 s (98-141) for the publicly available software MRmap, 261 s (249-282) for python LM, 77 s (74-80) for python RD, 3.4 s (3.1-3.6) for C++ multi-core LM, and 1.9 s (1.9-2.0) for C++ multi-core RD. The fastest C++ multi-core RD and the publicly available MRmap showed good agreement of myocardial T1 values, resulting in 95% Bland-Altman limits of agreement of (- 0.83 to 0.58 ms) and (- 6.57 to 7.36 ms) with mean differences of - 0.13 ms and 0.39 ms, for the pre- and post-contrast, respectively. CONCLUSION: The C++ multi-core RD was the fastest method on a regular eight-core personal computer for pre- or post-contrast T1 map calculation. The presented software tool (fT1fit) facilitated rapid T1 map and extracellular volume fraction map calculations.

Photoredox Ni-catalyzed peptide C(sp2)-O cross-coupling: from intermolecular reactions to side chain-to-tail macrocyclization.

Ni/photoredox (4DPAIPN) dual catalysis enabled challenging peptide C(sp2)-O coupling reactions. Successful cross-coupling reactions were demonstrated with highly functionalized alcohols including side chains of amino acids (i.e., serine, threonine, tyrosine), trans-4-hydroxy-l-proline, alkyl alcohols, alkynylated alcohols, and carbohydrates. Coupling reactions between bromobenzoyl-capped peptides containing various side chains and either a protected serine building block or a serine-containing dipeptide also proceeded efficiently. Chemoselective C-O coupling (over C-N) was achieved in intermolecular reactions in the presence of a C-terminal primary amide. Furthermore, by judicious structural design in combination with computational modeling, we demonstrated side chain-to-tail macrocyclization of peptides containing a ß-turn motif via C-O coupling. The methodology developed in this work brings new opportunities for late-stage diversification of complex linear and macrocyclic peptides.

Development of a Platform To Enable Efficient Permeability Evaluation of Novel Organo-Peptide Macrocycles.

As more macrocycle structures are utilized to drug intracellular targets, new platforms are needed to facilitate the discovery of cell permeable compounds in this unique chemical space. Herein, a method is disclosed that allows for the efficient synthesis and permeability evaluation of novel organo-peptide macrocycle libraries. Thoughtful library design allows for the collection of crude permeability data using supercritical fluid chromatography mass spectrometry (SFC-MS) (EPSA) by mass-encoding the stereochemistry, ring size, and organic linker of the desired macrocycles. Library synthesis was aided via the development of a new on-resin N-arylation reaction. Further insights on the permeation of these organo-peptide macrocycles will be discussed, such as the permeability enhancement when utilizing a 2-substituted phenethyl linker versus a 3-substituted phenethyl linker. Lastly, selected macrocycles were scaled up and tested in the MDCK-II permeability assay, and the results of this assay reiterated the permeability trends from the crude SFC-MS data.

Synthesis of 1,2-Azaborines and the Preparation of Their Protein Complexes with T4 Lysozyme Mutants.

We describe a general synthesis of 1,2-azaborines using standard air-free techniques and protein complex preparation with T4 lysozyme mutants by vapor diffusion. Oxygen- and moisture-sensitive compounds are prepared and isolated under an inert atmosphere (N2) using either a vacuum gas manifold or a glove box. As an example of azaborine synthesis, we demonstrate the synthesis and purification of the volatile N-H-B-ethyl-1,2-azaborine by a five-step sequence involving distillation and column chromatography for the isolation of products. T4 lysozyme mutants L99A and L99A/M102Q are expressed with Escherichia coli RR1 strain. Standard protocols for chemical cell lysis followed by purification using carboxymethyl ion exchange column affords protein of sufficiently high purity for crystallization. Protein crystallization is performed in various concentrations of precipitant at different pH ranges using the hanging drop vapor diffusion method. Complex preparation with the small molecules is carried out by vapor diffusion method under an inert atmosphere. X-ray diffraction analysis of the crystal complex provides unambiguous structural evidence of binding interactions between the protein binding site and 1,2-azaborines.

Hydrogen Bonding of 1,2-Azaborines in the Binding Cavity of T4 Lysozyme Mutants: Structures and Thermodynamics.

Protein crystallography and calorimetry were used to characterize the binding of 1,2-azaborines to model cavities in T4 lysozyme in direct comparison to their carbonaceous counterparts. In the apolar L99A cavity, affinity for Ab dropped only slightly versus benzene. In the cavity designed to accommodate a single hydrogen bond (L99A/M102Q), Gln102═O···H-N hydrogen bonding for Ab and BEtAb was observed in the crystallographic complexes. The strength of the hydrogen bonding was estimated as 0.94 and 0.64 kcal/mol for Ab and BEtAb, respectively. This work unambiguously demonstrates that 1,2-azaborines can be readily accommodated in classic aryl recognition pockets and establishes one of 1,2-azaborine's distinguishing features from its carbonaceous isostere benzene: its ability to serve as an NH hydrogen bond donor in a biological setting.

Meta-selective C-H functionalization using a nitrile-based directing group and cleavable Si-tether.

A nitrile-based template that enables meta-selective C-H bond functionalization was developed. The template is applicable to a range of substituted arenes and tolerates a variety of functional groups. The directing group uses a silicon atom for attachment, allowing for a facile introduction/deprotection strategy increasing the synthetic practicality of this template.

Catalyst recognition of cis-1,2-diols enables site-selective functionalization of complex molecules.

Carbohydrates and natural products serve essential roles in nature, and also provide core scaffolds for pharmaceutical agents and vaccines. However, the inherent complexity of these molecules imposes significant synthetic hurdles for their selective functionalization and derivatization. Nature has, in part, addressed these issues by employing enzymes that are able to orient and activate substrates within a chiral pocket, which increases dramatically both the rate and selectivity of organic transformations. In this article we show that similar proximity effects can be utilized in the context of synthetic catalysts to achieve general and predictable site-selective functionalization of complex molecules. Unlike enzymes, our catalysts apply a single reversible covalent bond to recognize and bind to specific functional group displays within substrates. By combining this unique binding selectivity and asymmetric catalysis, we are able to modify the less reactive axial positions within monosaccharides and natural products.