G. Paul Savage

Small Molecule Inhibitors of the Ledgf Site of Human Immunodeficiency Virus Integrase Identified by Fragment Screening and Structure Based Design.

A fragment-based screen against human immunodeficiency virus type 1 (HIV) integrase led to a number of compounds that bound to the lens epithelium derived growth factor (LEDGF) binding site of the integrase catalytic core domain. We determined the crystallographic structures of complexes of the HIV integrase catalytic core domain for 10 of these compounds and quantitated the binding by surface plasmon resonance. We demonstrate that the compounds inhibit the interaction of LEDGF with HIV integrase in a proximity AlphaScreen assay, an assay for the LEDGF enhancement of HIV integrase strand transfer and in a cell based assay. The compounds identified represent a potential framework for the development of a new series of HIV integrase inhibitors that do not bind to the catalytic site of the enzyme.

Cycloaddition Reactions of Nitrile Oxides with Alkenes

Publisher Summary This chapter reviews the cycloaddition reactions of nitrile oxides with alkenes. It covers the literature published between 1985 and 1992. The chapter emphasizes on the dramatic improvements in the degree of stereocontrol that has been attained in intermolecular reactions and to the developments in the use of intramolecular nitrile oxide cycloaddition (INOC) reactions, where the predisposition of the reacting groups within a molecule greatly enhances the regio and stereo-selectivity. The synthesis of benzonitrile oxide by chlorination of benzaldoxime, in order to give benzhydroximinoyl chloride followed by dehydrohalogenation with sodium carbonate forms the basis of the most common approach for the synthesis of nitrile oxides. The reactions of nitrile oxides with alkenes are essentially 1,3-dipolar cycloadditions and their mechanism have been subject of numerous investigations. The chapter also describes reactivity, regioselectivity, stereoselectivity, and the uses of isoxazolines. In specific, cycloaddition rates range over several orders of magnitude and to predict the likely success of a reaction, when alternative reaction pathways, such as nitrile oxide dimerization are possible, it becomes necessary to understand the reactivity of the system.

Reversal of regiochemistry in the synthesis of isoxazoles by nitrile oxide cycloadditions

Abstract The isoxazolines 2a , 2b and 8 obtained from nitrile oxide cycloadditions to cyclohex-2-enone 1a and its analogues 1b and 7 reacted with nickel peroxide to give the isoxazoles 3a , 3b and 9 . In contrast, the corresponding 2-bromocyclohex-2-enones 4a , 4b and 10 , prepared by bromination of the corresponding alkenes 1a , 1b and 7 , underwent nitrile oxide cycloadditions to afford the regioisomeric isoxazoles 6a , 6b and 12 , respectively.

Synthesis of biotinylated episilvestrol: highly selective targeting of the translation factors eIF4AI/II.

Silvestrol (1) and episilvestrol (2) are protein synthesis inhibitors, and the former has shown efficacy in multiple mouse models of cancer; however, the selectivity of these potent cytotoxic natural products has not been described. Herein, it is demonstrated that eukaryotic initiation factors eIF4AI/II were the only proteins detected to bind silvestrol (1) and biotinylated episilvestrol (9) by affinity purification. Our study demonstrates the remarkable selectivity of these promising chemotherapeutics.

Spiro Isoxazolines via Nitrile Oxide 1,3-Dipolar Cycloaddition Reactions

The 1,3-dipolar cycloaddition reaction of nitrile oxides with carbon dipolarophiles is a versatile and powerful synthetic method to prepare isoxazolines. In particular nitrile oxide cycloaddition reactions with exocyclic methylene or alkylidene compounds generally proceed regioselectively leading to spiro heterocyclic compounds. This review deals with progress in the field of nitrile oxide cycloaddi- tion chemistry for the synthesis of spiro isoxazolines.

Reducing the Cost, Smell, and Toxicity of the Barton Reductive Decarboxylation: Chloroform as the Hydrogen Atom Source

When used as solvent, chloroform was found to act as a hydrogen atom donor in Barton reductive decarboxylation reactions. Chloroform offers a substantial practical advantage over pre-existing hydrogen atom donors.

Validating Eaton's Hypothesis: Cubane as a Benzene Bioisostere

Pharmaceutical and agrochemical discovery programs are under considerable pressure to meet increasing global demand and thus require constant innovation. Classical hydrocarbon scaffolds have long assisted in bringing new molecules to the market place, but an obvious omission is that of the Platonic solid cubane. Eaton, however, suggested that this molecule has the potential to act as a benzene bioisostere. Herein, we report the validation of Eatons hypothesis with cubane derivatives of five molecules that are used clinically or as agrochemicals. Two cubane analogues showed increased bioactivity compared to their benzene counterparts whereas two further analogues displayed equal bioactivity, and the fifth one demonstrated only partial efficacy. Ramifications from this study are best realized by reflecting on the number of bioactive molecules that contain a benzene ring. Substitution with the cubane scaffold where possible could revitalize these systems, and thus expedite much needed lead candidate identification.

Exploiting the 1,3-dithiane of 2-oxopropanenitrile oxide to limit competing dimerization in 1,3-dipolar cycloaddition reactions

Abstract The 1,3-dithiane of 2-oxopropanenitrile oxide is less prone to dimerization than the parent compound and, as a consequence, it undergoes more efficient cycloaddition reactions with a range of mono- and 1,1- and 1,2-di-substituted alkenes.

Regioselective 1,3-Dipolar Cycloaddition Reactions of 4-Methylene-2-oxazolidinones with Benzonitrile Oxide

Substituted 4-methylene-2-oxazolidinones were prepared in two steps by cyclizing O-propargyl carbamates, which in turn were prepared from propargyl alcohols and phenyl isocyanate. The 4-methylene-2-oxazolidinones underwent a 1,3-dipolar cycloaddition reaction with benzonitrile oxide to give the corresponding spiro heterocycles. Where the substitution pattern on the oxazolidinone engendered facial asymmetry, the cycloadditon reaction proceeded with 5:1 selectivity for the less hindered face of the dipolarophile.

Application of olefin metathesis to the synthesis of ABE ring analogues of methyllycaconitine

The synthesis of four novel ABE ring analogues of methyllycaconitine (MLA) is reported, employing olefin metathesis as the key step for appending the seven-membered B ring onto an AE bicyclic ring system. This strategy allows the stereodivergent synthesis of ABE ring analogues in which the stereochemistry of the AB ring junction is well defined. The compounds are designed as ligands to study binding and function of the α7-nAChR.