Development and Applications of Chimera Platforms for Tyrosine Phosphorylation.

Chimeric small molecules that induce post-translational modification (PTM) on a target protein by bringing it into proximity to a PTM-inducing enzyme are furnishing novel modalities to perturb protein function. Despite recent advances, such molecules are unavailable for a critical PTM, tyrosine phosphorylation. Furthermore, the contemporary design paradigm of chimeric molecules, formed by joining a noninhibitory binder of the PTM-inducing enzyme with the binder of the target protein, prohibits the recruitment of most PTM-inducing enzymes as their noninhibitory binders are unavailable. Here, we report two platforms to generate phosphorylation-inducing chimeric small molecules (PHICS) for tyrosine phosphorylation. We generate PHICS from both noninhibitory binders (scantily available, platform 1) and kinase inhibitors (abundantly available, platform 2) using cysteine-based group transfer chemistry. PHICS triggered phosphorylation on tyrosine residues in diverse sequence contexts and target proteins (e.g., membrane-associated, cytosolic) and displayed multiple bioactivities, including the initiation of a growth receptor signaling cascade and the death of drug-resistant cancer cells. These studies provide an approach to induce biologically relevant PTM and lay the foundation for pharmacologic PTM editing (i.e., induction or removal) of target proteins using abundantly available inhibitors of PTM-inducing or -erasing enzymes.

Proximity-inducing modalities: the past, present, and future.

Living systems use proximity to regulate biochemical processes. Inspired by this phenomenon, bifunctional modalities that induce proximity have been developed to redirect cellular processes. An emerging example of this class is molecules that induce ubiquitin-dependent proteasomal degradation of a protein of interest, and their initial development sparked a flurry of discovery for other bifunctional modalities. Recent advances in this area include modalities that can change protein phosphorylation, glycosylation, and acetylation states, modulate gene expression, and recruit components of the immune system. In this review, we highlight bifunctional modalities that perform functions other than degradation and have great potential to revolutionize disease treatment, while also serving as important tools in basic research to explore new aspects of biology.

Chiral Bismuth-Rhodium Paddlewheel Complexes Empowered by London Dispersion: The C-H Functionalization Nexus.

Heterobimetallic [BiRh] tetracarboxylate catalysts endowed with 1,3-disilylated phenylglycine paddlewheels benefit from interligand London dispersion. They were originally designed for asymmetric cyclopropanation but are now shown to perform very well in asymmetric C-H functionalization reactions too. Because of the confined ligand sphere about the derived donor/acceptor carbenes, insertions into unhindered methyl groups are kinetically favored, although methylene units also react with excellent levels of asymmetric induction; even gaseous ethane is a suitable substrate. Moreover, many functional groups in both partners are tolerated. The resulting products are synthetically equivalent to the outcome of traditional asymmetric ester alkylation, allylation, benzylation, propargylation and aldol reactions and therefore constitute a valuable nexus to more conventional chemical logic.

A New Ligand Design Based on London Dispersion Empowers Chiral Bismuth-Rhodium Paddlewheel Catalysts.

Heterobimetallic bismuth-rhodium paddlewheel complexes with phenylglycine ligands carrying TIPS-groups at the meta-positions of the aromatic ring exhibit outstanding levels of selectivity in reactions of donor/acceptor and donor/donor carbenes; at the same time, the reaction rates are much faster and the substrate scope is considerably wider than those of previous generations of chiral [BiRh] catalysts. As shown by a combined experimental, crystallographic, and computational study, the new catalysts draw their excellent application profile largely from the stabilization of the chiral ligand sphere by London dispersion (LD) interactions of the peripheral silyl substituents.

Highly Enantioselective [5 + 2] Annulations through Cooperative N-Heterocyclic Carbene (NHC) Organocatalysis and Palladium Catalysis.

The highly enantioselective [5 + 2] annulation of enals with vinylethylene carbonates through a cooperative N-heterocyclic carbene (NHC)/Pd catalytic system is reported. The use of a bidentate phosphine ligand was crucial to prevent coordination of the NHC organocatalyst to the active Pd catalyst. The complementary and matched combination of the chiral NHC catalyst and chiral phosphine ligand promotes high levels of both reactivity and enantioselectivity (mostly ≥99% ee).

Manganese(I)-Catalyzed C-H (2-Indolyl)methylation: Expedient Access to Diheteroarylmethanes.

An unprecedented MnI -catalyzed (2-indolyl)methylation of heteroarenes is reported. This method makes use of an aromatizing cascade strategy to install a (2-indolyl)methyl group into target molecules, thereby leading to the expedient synthesis of previously challenging and important unsymmetrical diheteroarylmethanes, in particular bis(2-indolyl)methanes. The proposed cascade process comprises the reorganization of multiple bonds with controlled regioselectivity and high atom economy and can be performed on a gram-scale. Furthermore, a metal-free C-H propargylation is observed. The diverse application of this method is also demonstrated.

NHC-Organocatalyzed CAr -O Bond Cleavage: Mild Access to 2-Hydroxybenzophenones.

A Truce-Smiles rearrangement of acyl-anion equivalents generated by N-heterocyclic carbene (NHC) catalysis has been achieved. The developed method includes CAr -O, CAr -S, or CAr -N bond cleavage for the formation of a CAr -C bond and enables access to 2-hydroxybenzophenones, an important structural motif that is present in several bioactive natural products. By utilizing this procedure, the alkaloid taxilamine was synthesized in three steps. DFT calculations and control experiments support a classical SN Ar mechanism with a catalyst-bound Meisenheimer-type intermediate. The method features mild reaction conditions, excellent functional-group tolerance, and a broad substrate scope, including various classes of (hetero)arenes.

Annulation of o-Quinodimethanes through N-Heterocyclic Carbene Catalysis for the Synthesis of 1-Isochromanones.

The activation of 2-(bromomethyl)benzaldehydes using N-heterocyclic carbenes represents a novel approach to the generation of o-quinodimethane (o-QDM) intermediates. Coupling with ketones such as phenylglyoxylates, isatins, or trifluoromethyl ketones via [4 + 2] annulation gives access to functionalized 1-isochromanones.

Directing group assisted meta-hydroxylation by C-H activation.

meta-Hydroxylated cores are ubiquitous in natural products. Herein, we disclose the first template assisted meta-hydroxylation reaction. Experimental and in silico studies helped us to gain valuable mechanistic insights, including the role of the hexafluoroisopropanol (HFIP) solvent, during C-H hydroxylation. The reactive intermediates, prior to the C-H activation, have been detected by spectroscopic techniques. Additionally, the C-O bond formation has been extended to meta-acetoxylation. The preparation of a phase II quinone reductase activity inducer and a resveratrol precursor illustrated the synthetic significance of the present strategy.

Retrocaval ureter: a rare cause of hydronephrosis in children.

Retrocaval ureter is a relatively rare developmental anomaly of the inferior vena cava. It commonly manifests in the third to fourth decade of life; however, pediatric reports of this condition are very rare. Individuals with this anomaly are symptomatic because of ureteric obstruction. All symptomatic patients need surgery where the ureter is divided and anastomosed anterior to inferior vena cava. We report our experience of a child who presented with flank pain and, on evaluation, were found to have right hydronephrosis. During surgery, retrocaval anomaly was noticed and appropriately dealt with.