Distinct binding and cellular properties of synthetic (+)- and (-)-discodermolides

Cell permeable ligands of low molecular weight can be used to dissect complex cellular processes. During the past several years this approach has been particularly important in the study of intracellular signal transduction. Discodermolide, a marine natural product, appears to inhibit a signaling pathway in immune cells. The structure of natural discodermolide is known, but its absolute stereochemistry is not. We set out to make both enantiomers and to investigate their biological activity.

Both enantiomers of discodermolide were prepared by total synthesis. Surprisingly, both enantiomers have biological activity, and their effects seem to be distinct in that they arrest cells at different stages of the cell cycle. A specific binding activity was identified for (+)-discodermolide but not for (-)-discodermolide, and the binding of the two enantiomers was not competitive.

Both enantiomers of discodermolide have antiproliferative activity, but they act by distinct mechanisms and appear to have distinct cellular targets. The natural product is the (+)-enantiomer, which blocks the cell cycle in the G2 or M phase. The (-)-enantiomer blocks cells in S phase. Both may be useful in studies of the regulation of the cell cycle; we have also identified a specific binding activity for (+)-discodermolide, and have provided evidence that it interacts with a functionally relevant receptor.