Ketopiperazines: Conformationally Constrained Peptidomimetic of Arginine Amides

We have synthesized guanidine‐containing ketopiperazines designed to be conformational mimics of peptidomimetic arginine amides. D‐Allylglycine was converted by an efficient approach to give enantiopure ketopiperazines in which the trans stereochemistry of the C‐substituents resulted from stereospecific enolate alkylation.     

An unusual rearrangement during pyridine synthesis. Anomalous condensation of a β-keto enamine with a tetronic acid.

The condensation of β-keto enamine 1 with 5-methyltetronic acid takes an anomalous course. Single crystal X-ray analysis and chemical evidence establish the rearranged pyridine structure 15 for this condensation product.     

Synthesis of the spirocyclic center of fredericamycin a by phenoxy-enoxy radical coupling

Ferricyanide oxidation of the dianions of phenolic β-diketones $\text{2}$ effects intramolecular phenoxy-enoxy radical coupling to form spiro systems derived from C-C bond formation $\text{para}$ or $\text{ortho}$ to the phenolic oxygen.     

Synthesis of 2,4,5-trisubstituted tetrahydropyrans as peptidomimetic scaffolds for melanocortin receptor ligands

[reaction: see text] We have synthesized a series of 2,4,5-trisubstituted tetrahydropyran derivatives to determine the utility of this scaffold as a peptidomimetic platform. The key synthetic steps involved a palladium-mediated cross-coupling reaction of a dihydropyran-4-one moiety to introduce R(2) followed by a sequential regio- and diastereoselective reduction of sp(2) carbon centers. Selected compounds have shown biological activity at melanocortin receptors, indicating that this scaffold may be useful in the design of peptidomimetics relating to a tripeptide structure.     

A serendipitous phosphonocarboxylate complex of boron: when vessel becomes reagent

Under certain conditions, the phosphonocarboxylate analogue (3) of the bisphosphonate drug minodronate (4) in contact with borosilicate glassware reversibly forms an isolable dimer complex of boron, as revealed by the X-ray crystallographic structure of the (R,R/S,S) complex and supported by NMR and HRMS data.     

Molecular interactions of nitrogen-containing bisphosphonates within farnesyl diphosphate synthase

Bisphosphonates, known for their effectiveness in the treatment of osteoporosis, inhibit bone resorption via mechanisms that involve binding to bone mineral and cellular effects on osteoclasts. The major molecular target of nitrogen-containing bisphosphonates (N-BPs) in osteoclasts is farnesyl diphosphate synthase (FPPS). N-BPs likely inhibit this enzyme by mimicking one or more of the natural isoprenoid lipid substrates (GPP/DMAPP and IPP) but the mode of inhibition is not established. The active site of FPPS comprises a subsite for each substrate. Kinetic studies with recombinant human FPPS indicate that both potent (risedronate) and weak (NE-58051) enzyme inhibitors compete with GPP for binding to FPPS, however, binding to this site does not completely explain the difference in potency of the two inhibitors, suggesting that a second binding site may also be a target of bisphosphonate inhibition. Using the docking software suite Autodock, we explored a dual inhibitor binding mode for recombinant human FPPS. Experimental support for dual binding is suggested by Dixon plots for the inhibitors. N-BPs may inhibit by binding to both the GPP and a second site with differences in potency at least partly arising from inhibition at the second site.