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A series of phosphonamide-based hydroxamate derivatives were synthesized, and the inhibitory activities were evaluated against various metalloproteinases in order to clarify its selectivity profile. Among the four diastereomeric isomers resulting from the chirality at the C-3 and P atoms, the compound with a (R,R)-configuration both at the C-3 position and the phosphorus atom was found to be potently active, while the other diastereomeric isomers were almost inactive. A number of (R,R)-compounds synthesized here exhibited broad spectrum activities with nanomolar K(i) values against MMP-1, -3, -9, and TACE and also showed nanomolar IC(50) values against HB-EGF shedding in a cell-based inhibition assay. The modeling study using X-ray structure of MMP-3 suggested the possible binding mode of the phosphonamide-based inhibitors.

A review into the aza-Diels-Alder reaction, mainly concentrating on literature examples that form piperidin-4-ones from the reaction of imines and electron rich dienes or enones, either through a Lewis acidic/Brønsted acid approach or through the use of an organocatalyst. This review questions whether the mechanism of the aza-Diels-Alder reaction is step wise as opposed to concerted when using oxygenated dienes.

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