Just a spoonful of sugar

Sweet inhibition. Starting with a template of β--glucose (A) and its glucosyl carbenium ion transition state (B), researchers synthesized a 1R bicycloheptane (C) that acts as a glucosidase inhibitor and its 1S diastereomer (D).

Because these enzymes play roles in many disease processes, inhibitors with improved binding and specificity are needed. Glycosidase inhibitors were first identified and isolated from plants and microorganisms decades ago, and many derivatives of these compounds have been synthesized. Often, the inhibitors are conformationally restricted to resemble the oxacarbenium ion transition state of the glycosylation–deglycosylation reaction pathway.

In a quest for new glycosidase inhibitors, Andrew Bennet and colleagues at Simon Fraser University in Vancouver (BC) have synthesized and determined the X-ray structure of two bicycloheptane derivatives that differ in the orientation of their cyclopropyl rings (J. Am. Chem. Soc. 2001, 132, 998–999). The researchers demonstrated that one compound, the 1R diastereomer, competes with substrate for binding to the active site of commercially available yeast α-glucosidase. With a K_i value of 107 nM, this compound is the tightest binding inhibitor of yeast α-glucosidase yet identified.

There is an excellent chance that analogues of the bicycloheptane inhibitors will be effective against other glycosidases.

“It is difficult to predict the exact magnitude for inhibition of various medically relevant glucosidases by our compounds,” says Bennet, “although it is possible that we may see selectivity between the various glucosidase enzymes.”