Novel Piperidinyl-Azetidines as Potent and Selective CCR4 Antagonists Elicit Antitumor Response as a Single Agent and in Combination with Checkpoint Inhibitors.

The C-C chemokine receptor 4 (CCR4) is broadly expressed on regulatory T cells (T) as well as other circulating and tissue-resident T cells. T can be recruited to the tumor microenvironment (TME) through the C-C chemokines CCL17 and CCL22. T accumulation in the TME has been shown to dampen the antitumor immune response and is thought to be an important driver in tumor immune evasion.

Discovery of a Potent and Selective CCR4 Antagonist That Inhibits T Trafficking into the Tumor Microenvironment.

Recruitment of suppressive CD4 FOXP3 regulatory T cells (T) to the tumor microenvironment (TME) has the potential to weaken the antitumor response in patients receiving treatment with immuno-oncology (IO) agents. Human T express CCR4 and can be recruited to the TME through the CC chemokine ligands CCL17 and CCL22. In some cancers, T accumulation correlates with poor patient prognosis.

Enantioselective Syntheses of Heteroyohimbine Natural Products: A Unified Approach through Cooperative Catalysis.

Alstonine and serpentine are pentacyclic indoloquinolizidine alkaloids (referred to as "anhydronium bases") containing three contiguous stereocenters. Each possesses interesting biological activity, with alstonine being the major component of a plant-based remedy to treat psychosis and other nervous system disorders. This work describes the enantioselective total syntheses of these natural products with a cooperative hydrogen bonding/enamine-catalyzed Michael addition as the key step.

Enantioselective annulations for dihydroquinolones by in situ generation of azolium enolates.

A convergent, catalytic asymmetric formal [4 + 2] annulation for the synthesis of dihydroquinolones has been developed. Carboxylic acids can be employed as precursors to NHC enolates through an in situ activation strategy. Simultaneous generation of a reactive aza-o-quinone methide under the basic conditions employed for NHC generation leads to a dual activation approach.

Stereoselective synthesis of γ-lactams from imines and cyanosuccinic anhydrides.

A reaction between imines and anhydrides has been developed with chiral disubstituted anhydrides and chiral imines. The synthesis of highly substituted γ-lactams with three stereogenic centers, including one quaternary center, proceeds at room temperature in high yield and with high diastereoselectivity in most cases. Enantiomerically pure alkyl-substituted anhydrides proceed with no epimerization, thus providing access to enantiomerically pure penta-substituted lactam products.

Diastereoselective synthesis of (±)-heliotropamide by a one-pot, four-component reaction.

The first synthesis of heliotropamide is reported. The preparation of this 2-oxopyrrolidine (γ-lactam) natural product relied on a diastereoselective one-pot, four-component reaction (4CR) for the assembly of the core structure. On the basis of chemical shift correlation and NOESY experiments, the previously unknown alkene geometry of heliotropamide is assigned as E.

Recent advances in multicomponent reactions for diversity-oriented synthesis.

Interest in multicomponent reactions (MCRs) has surged during the past two decades as interest in the efficient synthesis of small molecule libraries has gained prominence. MCRs fill an important niche in library synthesis by providing direct access to library compounds and by serving as starting points for Diversity-Oriented Synthesis (DOS). Recent advances in the area of MCR chemistry have included the discovery of new reactions, development of the first asymmetric catalysts, and the application of MCRs to natural products and other targets of biological interest.