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Reduction of (1 R ,6 R )-7,9-diazabicyclo[4.2.2]dec-3-ene-8,10-dione ( 5 ) with lithium aluminum hydride gave a mixture of the expected (1 R ,6 R )-7,9-diazabicyclo[4.2.2]dec-3-ene ( 2 ) as well as 7,9-diazabicyclo[4.3.1]dec-3-ene ( 3 ), resulting from 1,2-σ (C–C) migration of the pendant cis -2-butenyl ring. More of the rearranged product was observed in polar solvents and upon the addition of HMPA. The relief of ring strain imparted by the olefin may promote this rearrangement, as it was not observed when the olefin was reduced prior to the reduction.

The enediyne moiety is a versatile functional group found in natural anticancer and anti-infective agents, undergoing the Bergman cyclization reaction to afford a diradical which cleaves double-stranded DNA. We have incorporated the enediyne group into 10- (4-10) and 12-membered ring (11) cyclic amino acids and dipeptides, respectively, and explored their relative reactivity toward cyclization, varying N-substitution in the case of the 10-membered ring substrate, which gave the expected cyclization products in good yields when using either thermal conditions in the presence or absence of microwave irradiation. The N-tosyl substituted derivative (4) was shown to nick double-stranded supercoiled DNA. N-Arylsulfonyl substitution on the ring promoted the cyclization, when compared to N-mesyl or acyl substitution, possibly because of a pi-pi stacking effect as an endo-relationship of the aryl group with the enediyne was demonstrated in both the solid state and in solution. The 12-membered ring enediyne dipeptide (11) was inert to the Bergman cyclization under a variety of conditions. When this substrate was irradiated with ultraviolet light, regio- and stereospecific reduction was observed in which one of the alkynes was reduced to a Z-olefin (47).

The major human metabolite of atomoxetine (4-hydroxyatomoxetine) was tested against a panel of receptors and enzymes, and was found to interact with the mu, delta, and kappa-opioid receptors based upon studies involving both binding and functional assays. 4-hydroxyatomoxetine was determined to be a partial agonist of the kappa-opioid receptor.

The bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) are essential enzymes that control the topological state of DNA during replication. The high degree of conservation in the ATP-binding pockets of these enzymes make them appealing targets for broad-spectrum inhibitor development. A pyrrolopyrimidine scaffold was identified from a pharmacophore-based fragment screen with optimization potential. Structural characterization of inhibitor complexes conducted using selected GyrB/ParE orthologs aided in the identification of important steric, dynamic and compositional differences in the ATP-binding pockets of the targets, enabling the design of highly potent pyrrolopyrimidine inhibitors with broad enzymatic spectrum and dual targeting activity.

The structurally related bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as prime candidates for the development of broad spectrum antibacterial agents. However, GyrB/ParE targeting antibacterials with spectrum that encompasses robust Gram-negative pathogens have not yet been reported. Using structure-based inhibitor design, we optimized a novel pyrrolopyrimidine inhibitor series with potent, dual targeting activity against GyrB and ParE. Compounds were discovered with broad antibacterial spectrum, including activity against Pseudomonas aeruginosa, Acinetobacter baumannii and Escherichia coli. Herein we describe the SAR of the pyrrolopyrimidine series as it relates to key structural and electronic features necessary for Gram-negative antibacterial activity.

We report the design, synthesis, and binding affinities of a family of cyclic RGD peptides attached to type VI beta-turn scaffolds. The analogues prepared exhibit interesting binding data to the isolated receptors alphavbeta3 and alphavbeta5. The results demonstrate the utility of these type VI beta-turn scaffolds for the constraint of biologically relevant peptides.

As part of a program to identify novel scaffolds that adopt defined secondary structure when incorporated into peptides, we have designed and prepared a library of constrained eight-membered ring lactams based upon 7-amino-8-oxo-1,2,3,6,7-pentahydroazocine-2-carboxylic acid. Ring closing metathesis (RCM) was employed as the key step, proceeding in high yields to afford the Z olefin. In this reaction sequence, the first generation benzylidene ruthenium RCM catalyst was superior to the second-generation imidazoline catalyst, which gave extensive oligomerization at higher concentrations. Conformational analysis of the 2S,7S and 2R,7S stereoisomers revealed that the 2R,7S isomer is a Type VIa β-turn in the solid state (X-ray crystal structure) and in water (NMR analysis). The Type VIa β-turn is relatively rare, typically bearing the cis amide bond found in proline-containing sequences. The 2S,7S diastereomer has an extended geometry of the pendent amide chains. The corresponding saturated derivatives (7-amino-8-oxoazocane-2-carboxylic acid) were also synthesized and investigated. The 2S,7S azocane bears an extended geometry and mimics the C+ conformer of ox-[Cys-Cys], found in a variety of naturally occurring peptides. The scaffolds described here are useful for the design of constrained peptidomimics with defined secondary structure.