Synthesis of (2,4)-4-Amino-5-hydroxybicyclo[3.1.1]heptane-2-carboxylic Acid via an Asymmetric Intramolecular Mannich Reaction.

Inhibition of human ornithine aminotransferase interferes with glutamine and proline metabolism in hepatocellular carcinoma, depriving tumors of essential nutrients. A proposed mechanism-based inhibitor containing a bicyclo[3.1.

Potent GCN2 Inhibitor Capable of Reversing MDSC-Driven T Cell Suppression Demonstrates In Vivo Efficacy as a Single Agent and in Combination with Anti-Angiogenesis Therapy.

General control nonderepressible 2 (GCN2) protein kinase is a cellular stress sensor within the tumor microenvironment (TME), whose signaling cascade has been proposed to contribute to immune escape in tumors. Herein, we report the discovery of cell-potent GCN2 inhibitors with excellent selectivity against its closely related Integrated Stress Response (ISR) family members heme-regulated inhibitor kinase (HRI), protein kinase R (PKR), and (PKR)-like endoplasmic reticulum kinase (PERK), as well as good kinome-wide selectivity and favorable PK. In mice, compound engages GCN2 at levels ≥80% with an oral dose of 15 mg/kg BID.

Design, development, synthesis, and crystal structure of the prototype of a new class of deep blue-fluorescing boron heterocycle estrogen mimics.

To further the development of boron heterocyclic compounds that are useful to medicinal chemistry, we demonstrate how the class of compounds known as the diazaborines can be elaborated to produce an exceptionally close structural mimic of a natural estrogen. After building progressively closer models, a benzyloxy-substituted formylphenylboronic acid was ultimately condensed with a hydroxymethylated β-hydrazinocyclopentenone to give, after debenzylation, an isosteric mimic (diazaborine 1) of the naturally-occurring estrogen equilenin and the prototype of a new class of boron heterocycle estrogen mimics. X-ray crystallography revealed the prototype to be planar, with a transmolecular interoxygen distance virtually identical to that found in equilenin and with a strong hydrogen-bond-donating hydroxyl group.