Remarkable and Unexpected Mechanism for ()-3-Amino-4-(difluoromethylenyl)cyclohex-1-ene-1-carboxylic Acid as a Selective Inactivator of Human Ornithine Aminotransferase.

Human ornithine aminotransferase (OAT) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that was recently found to play an important role in the metabolic reprogramming of hepatocellular carcinoma (HCC) via the proline and glutamine metabolic pathways. The selective inhibition of OAT by compound exhibited potent antitumor activity. Inspired by the discovery of the aminotransferase inactivator (1,3)-3-amino-4-(difluoromethylene)cyclopentane-1-carboxylic acid (), we rationally designed, synthesized, and evaluated a series of six-membered-ring analogs.

Fluorinated Nucleotide Modifications Modulate Allele Selectivity of SNP-Targeting Antisense Oligonucleotides.

Antisense oligonucleotides (ASOs) have the potential to discriminate between subtle RNA mismatches such as SNPs. Certain mismatches, however, allow ASOs to bind at physiological conditions and result in RNA cleavage mediated by RNase H. We showed that replacing DNA nucleotides in the gap region of an ASO with other chemical modification can improve allele selectivity.

Synthesis of 2-Ethenylcyclopropyl Aryl Ketones via Intramolecular S2-like Displacement of an Ester.

The efficient synthesis of trans-2-ethenylcyclopropyl aryl ketones via an intramolecular S2-like displacement of an allylic ester is reported. A novel 1,5-acyl shift process is also observed that contributes to the product mixture. Theoretical calculations provide a rationale for the observed product ratio.

Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.

In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties.

Synthesis and duplex-stabilizing properties of fluorinated N-methanocarbathymidine analogues locked in the C3'-endo conformation.

The efficient synthesis, antiviral activity, and duplex-stabilizing properties of both isomers of the 2'-fluoro analogue of Northern methanocarbathymidine (N-MCT), 2 and 3, are reported. We show that 2'-F incorporation on the N-MCT scaffold has a strong stabilizing effect on duplex thermal stability.

Oxidant-controlled regioselectivity in the oxidative arylation of N-acetylindoles.

N-Acetylindoles can be oxidatively coupled with arenes such as benzene or pentafluorobenzene in dioxane. The use of Cu(OAc)(2) as the stoichiometric oxidant produces selective arylation at the 3-position of indole while AgOAc produces selective arylation at indole's 2-position.

C-C bond formation via double C-H functionalization: aerobic oxidative coupling as a method for synthesizing heterocoupled biaryls.

The aerobic oxidative coupling of arenes such as benzofuran and N-substituted indoles with benzene and derivatives thereof is described. The reaction is shown to take place in both inter- and intramolecular scenarios.