Discovery of LYC-55716: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor-γ (RORγ) Agonist for Use in Treating Cancer.

Retinoic acid receptor-related orphan receptor γ (RORc, RORγ, or NR1F3) is the nuclear receptor master transcription factor that drives the function and development of IL-17-producing T helper cells (Th17), cytotoxic T cells (Tc17), and subsets of innate lymphoid cells. Activation of RORγ+ T cells in the tumor microenvironment is hypothesized to render immune infiltrates more effective at countering tumor growth. To test this hypothesis, a family of benzoxazines was optimized to provide LYC-55716 (37c), a potent, selective, and orally bioavailable small-molecule RORγ agonist. LYC-55716 decreases tumor growth and enhances survival in preclinical tumor models and was nominated as a clinical development candidate for evaluation in patients with solid tumors.

Synthesis of (-)-PNU-286607 by asymmetric cyclization of alkylidene barbiturates.

PNU-286607 is the first member of a promising, novel class of antibacterial agents that act by inhibiting bacterial DNA gyrase, a target of clinical significance. Importantly, PNU-286607 displays little cross-resistance with marketed antibacterial agents and is active against methicillin-resistant staphylococcus aureus (MRSA) and fluoroquinoline-resistant bacterial strains. Despite the apparent stereochemical complexity of this unique spirocyclic barbituric acid compound, the racemic core is accessible by a two-step route employing a relatively obscure rearrangement of vinyl anilines, known in the literature as the "tert-amino effect." After a full investigation of the stereochemical course of the racemic reaction, starting with the meso cis-dimethylmorpholine, a practical asymmetric variant of this process was developed.

Discovery and characterization of QPT-1, the progenitor of a new class of bacterial topoisomerase inhibitors.

QPT-1 was discovered in a compound library by high-throughput screening and triage for substances with whole-cell antibacterial activity. This totally synthetic compound is an unusual barbituric acid derivative whose activity resides in the (-)-enantiomer. QPT-1 had activity against a broad spectrum of pathogenic, antibiotic-resistant bacteria, was nontoxic to eukaryotic cells, and showed oral efficacy in a murine infection model, all before any medicinal chemistry optimization. Biochemical and genetic characterization showed that the QPT-1 targets the beta subunit of bacterial type II topoisomerases via a mechanism of inhibition distinct from the mechanisms of fluoroquinolones and novobiocin. Given these attributes, this compound represents a promising new class of antibacterial agents. The success of this reverse genomics effort demonstrates the utility of exploring strategies that are alternatives to target-based screens in antibacterial drug discovery.

Evidence for facile atropisomerism and simple (non-nucleophilic) biradical-forming cycloaromatization within kedarcidin chromophore aglycon.

The kinetics and thermodynamics of atropisomerism within the protected kedarcidin chromophore aglycon 8, as well as a series of ansa-bridged synthetic intermediates leading to 8, were determined by 1H NMR spectroscopy. The data show that the ratio of atropisomeric forms of chloropyridine-bridged ansa intermediates is subject to wide variation with seemingly subtle structural variation. The vinyl bromide 4, for example, in the first X-ray structure determination of a kedarcidin ansa-bridged system, was found to exist as a single atropisomer in the solid state, but a nearly equal mixture (K = 0.70) of isomers in solution (t1/2 for isomer interconversion approximately 0.2 s at 20 degrees C). The aglycon 8, a 2.2:1 mixture of atropisomers, was found to undergo direct unimolecular biradical-forming cycloaromatization at ambient temperature in a mixture of 1,4-cyclohexadiene-benzene, without nucleophilic activation. The product 9 was formed as a single atropisomer (k = 2 x 10-4 s-1, t1/2 = 58 min, 81% yield), suggesting that the rate of atropisomerism within 8 is rapid with respect to cycloaromatization. The rate of cycloaromatization of 8 was found to be highly solvent-dependent, being more rapid in the presence of a good hydrogen-atom donor, consistent with the earlier model studies of Hirama et al. that showed that certain nine-membered cyclic (Z)-enediynes may equilibrate with their biradical cycloaromatization products. Incubation of 8 with beta-mercaptoethanol, under conditions mimicking experiments leading to DNA cleavage with kedarcidin, showed no evidence for nucleophilic activation. The product of direct cycloaromatization (9) was isolated instead. The evidence suggests that kedarcidin, like the enediyne agent C-1027, is capable of spontaneous thermal biradical formation without prior chemical activation.