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Nitric oxide synthase (NOS) enzymes synthesize nitric oxide, a signal for vasodilatation and neurotransmission at low concentrations and a defensive cytotoxin at higher concentrations. The high active site conservation among all three NOS isozymes hinders the design of selective NOS inhibitors to treat inflammation, arthritis, stroke, septic shock and cancer. Our crystal structures and mutagenesis results identified an isozyme-specific induced-fit binding mode linking a cascade of conformational changes to a new specificity pocket. Plasticity of an isozyme-specific triad of distant second- and third-shell residues modulates conformational changes of invariant first-shell residues to determine inhibitor selectivity. To design potent and selective NOS inhibitors, we developed the anchored plasticity approach: anchor an inhibitor core in a conserved binding pocket, then extend rigid bulky substituents toward remote specificity pockets, which become accessible upon conformational changes of flexible residues. This approach exemplifies general principles for the design of selective enzyme inhibitors that overcome strong active site conservation.

4-Methylaminopyridine (4-MAP) (5) is a potent but nonselective nitric oxide synthase (NOS) inhibitor. While simple N-methylation in this series results in poor activity, more elaborate N-substitution such as with 4-piperidine carbamate or amide results in potent and selective inducible NOS inhibition. Evidently, a flipping of the pyridine ring between these new inhibitors allows the piperidine to interact with different residues and confer excellent selectivity.

3-Phenyl-3.4-dihydro-1-isoquinolinamine is a weak inhibitor of iNOS and nNOS. Structural variation of 5a results in inhibitors with a range of potency and selectivity for the NOS enzymes, including a potent and very selective iNOS inhibitor 5j.

A range of functionalised spirocyclic systems have been prepared under mild and neutral conditions by tandem selective ring closing olefin metathesis reactions. Additionally, a marked preference for 5-membered ring closure over 7-membered ring closure was observed which appears to be a result of a kinetically favoured cyclisation process.

A variety of 1-amino-3,4-dihydroisoquinolines substituted at the 3-position and related thienopyridines were prepared by lithiation of ortho-methyl aromatic nitriles, addition to N-trimethylsilylimines and spontaneous cyclisation.

The Petasis reaction of electron-poor aromatic amines such as aminopyridines under microwave irradiation conditions is described. The process provides rapid access to a number of unnatural N-aryl-α-amino acids. The influence of the electronic demand of the boronic acids on the yields is discussed. A comparison with conventional heating is provided.

The synthesis of a series of novel 1,2-diaminobenzimidazoles is described. While the parent compound 4a is a weak, modestly selective inhibitor of the induced isoform of nitric oxide synthase (both mouse and human), a small structural change led to compound 5, a highly selective inhibitor of neuronal enzyme.

By careful analysis of experimental X-ray ligand crystallographic protein data across several inhibitor series we have discovered a novel, potent and selective series of iNOS inhibitors exemplified by compound 8.

A concise formal synthesis of (±)-sporochnol A 1 , a naturally occurring feeding deterrent towards herbivorous fish, is described. The target compound was prepared by the employment of a Ru-catalysed cyclobutene ring-opening metathesis reaction with gaseous ethylene followed by a site selective hydroboration reaction as the key steps. The optimisation of the metathesis process regarding the Ru-catalyst and reaction conditions is also delineated.

Synthesis and Baeyer–Villiger oxidation of the series of bicyclic ketones 3 and 6 is described. The ratio of methine to methylene carbon migration in the oxidation was found to vary depending on the 5-endo and 7-anti substituents of the ketones. Possible reasons for the observed regioselectivity are discussed.

The diethylaluminium chloride-catalysed cycloaddition of cyclopentadiene to the (S)-lactate-derived N-toluene-p-sulfonyliminoacetate 5 gives mainly (76% diastereoisomeric excess, d.e.) the adduct 9(X-ray structure); the (R)-pantolactone-derived iminoacetate 6 similarly gives (70% d.e.) the adduct 8 which is correlated via the methyl esters 11 with compound 9.

The synthesis of a series of novel 1,2-diaminobenzimidazoles is described. While the parent compound 4a is a weak, modestly selective inhibitor of the induced isoform of nitric oxide synthase (both mouse and human), a small structural change led to compound 5, a highly selective inhibitor of neuronal enzyme.

A range of functionalised spirocyclic systems have been prepared under mild and neutral conditions by tandem selective ring closing olefin metathesis reactions. Additionally, a marked preference for 5-membered ring closure over 7-membered ring closure was observed which appears to be a result of a kinetically favoured cyclisation process.

3-Phenyl-3,4-dihydro-1-isoquinolinamine is a weak inhibitor of iNOS and nNOS. Structural variation of 5a results in inhibitors with a range of potency and selectivity for the NOS enzymes, including a potent and very selective iNOS inhibitor 5j.

5-Substituted 7-amino-4,5-tetrahydrothieno[2,3-c]pyridines and 6-substituted 4-amino-6,7-dihydrothieno[3,2-c]pyridines were shown to be exceptionally potent inhibitors of inducible and neuronal nitric oxide synthase. Selectivity and potency could be modulated by variation of the 5- or 6-substituent. Compound 3e showed potent in vivo inhibition of iNOS.

The functionalisation of the potassium enolates of a series of racemic 7-, 8-, and 9-membered unsaturated lactams with trisyl azide and phenylselenenyl chloride afforded the corresponding 3,n-disubstituted lactams with good stereoselectivities.

Synthesis and Baeyer–Villiger oxidation of the series of bicyclic ketones 3 and 6 is described. The ratio of methine to methylene carbon migration in the oxidation was found to vary depending on the 5-endo and 7-anti substituents of the ketones. Possible reasons for the observed regioselectivity are discussed.

5-Substituted 7-amino-4,5-tetrahydrothieno[2,3-c]pyridines and 6-substituted 4-amino-6,7-dihydrothieno[3,2-c]pyridines were shown to be exceptionally potent inhibitors of inducible and neuronal nitric oxide synthase. Selectivity and potency could be modulated by variation of the 5- or 6-substituent. Compound 3e showed potent in vivo inhibition of iNOS.

A novel and highly efficient approach to angularly fused tricycles has been developed through the employment of selective tandem ring closing metathesis reactions.

The diethylaluminium chloride-catalysed cycloaddition of cyclopentadiene to the (S)-lactate-derived N-toluene-p-sulfonyliminoacetate 5 gives mainly (76% diastereoisomeric excess, d.e.) the adduct 9(X-ray structure); the (R)-pantolactone-derived iminoacetate 6 similarly gives (70% d.e.) the adduct 8 which is correlated via the methyl esters 11 with compound 9.