Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker.

Inhibition of neuronal nitric oxide synthase (nNOS) is a promising therapeutic approach to treat neurodegenerative diseases. Recently, we have achieved considerable progress in improving the potency and isoform selectivity of human nNOS inhibitors bearing a 2-aminopyridine scaffold. However, these inhibitors still suffered from too low cell membrane permeability to enter into CNS drug development.

Electrostatic Control of Isoform Selective Inhibitor Binding in Nitric Oxide Synthase.

Development of potent and isoform selective nitric oxide synthase (NOS) inhibitors is challenging because of the structural similarity in the heme active sites. One amino acid difference between NOS isoforms, Asp597 in rat neuronal NOS (nNOS) versus Asn368 in bovine endothelial NOS (eNOS), has been identified as the structural basis for why some dipeptide amide inhibitors bind more tightly to nNOS than to eNOS. We now have found that the same amino acid variation is responsible for substantially different binding modes and affinity for a new class of aminopyridine-based inhibitors.

Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker.

Neuronal nitric oxide synthase (nNOS) is an important therapeutic target for the treatment of various neurodegenerative disorders. A major challenge in the design of nNOS inhibitors focuses on potency in humans and selectivity over other NOS isoforms. Here we report potent and selective human nNOS inhibitors based on the 2-aminopyridine scaffold with a central pyridine linker.

Preparation of α-imino aldehydes by [1,3]-rearrangements of O-alkenyl oximes.

The synthesis of α-imino aldehydes has been achieved through the thermal [1,3]-rearrangement of O-alkenyl benzophenone oximes. A copper-mediated C-O bond coupling between benzophenone oxime and alkenyl boronic acids provides facile access to the required O-alkenyl oximes and a Horner-Wadsworth-Emmons olefination can be applied to the α-imino aldehyde products to give γ-imino-α,β-unsaturated esters. The scope of the method is described and mechanistic experiments are discussed.

Interrupted Fischer-indole intermediates via oxyarylation of alkenyl boronic acids.

The oxyarylation of alkenyl boronic acids with N-arylbenzhydroxamic acids has been achieved under both copper-mediated and copper-catalyzed conditions to provide access to interrupted Fischer-indole intermediates. This transformation is believed to proceed through a copper-promoted C-O bond forming event followed by a [3,3] rearrangement. The scope of the method is described and mechanistic experiments are discussed.

Preparation of α-oxygenated ketones by the dioxygenation of alkenyl boronic acids.

Two in two: Dioxygenation of alkenyl boronic acids has been achieved with N-hydroxyphthalimide. The two-step process involves etherification of an alkenyl boronic acid with N-hydroxyphthalimide followed by a [3,3] rearrangement. The dioxygenated product can then be hydrolyzed to form either the corresponding α-hydroxy ketone or the α-benzoyloxy ketone.

Regioselective synthesis of 2,3,4- or 2,3,5-trisubstituted pyrroles via [3,3] or [1,3] rearrangements of O-vinyl oximes.

The regioselective synthesis of 2,3,4- or 2,3,5-trisubstituted pyrroles has been achieved via [3,3] and [1,3] sigmatropic rearrangements of O-vinyl oximes, respectively. Iridium-catalyzed isomerization of easily prepared O-allyl oximes enables rapid access to O-vinyl oximes. The regioselectivity of pyrrole formation can be controlled by either the identity of the α-substituent or through the addition of an amine base.

Carbon-carbon bond formation and pyrrole synthesis via the [3,3] sigmatropic rearrangement of O-vinyl oxime ethers.

A new method for the synthesis of 2,4- and 2,3,4-substituted pyrroles in two or three steps from commercially available ketones and allyl hydroxylamine is described. An iridium-catalyzed isomerization reaction has been developed to convert O-allyl oximes to O-vinyl oximes, which undergo a facile [3,3] rearrangement to form 1,4-imino aldehyde Paal-Knorr intermediates that cyclize to afford the corresponding pyrroles. Optimization and examples of the isomerization and pyrrole formation are discussed.

Synthesis of 5-radioiodoarabinosyl uridine analog for probing HSV-1 thymidine kinase gene: an unexpected chelating effect.

Tumor cells transduced with herpes simplex virus thymidine kinase gene has been intensively applied to the field of positron emission tomography via imaging of its substrate. As a pilot synthesis approach, a facial preparation of 5-[125I]iodoarabinosyl uridine starting from commercial available uridine is reported herein. Interestingly, the tin group in 5-trimethylstannyl arabinosyluridine was easily removed during purification.