The relationship between Taxol and (+)-discodermolide: synthetic analogs and modeling studies

Background: During the past decade, Taxol has assumed an important role in cancer chemotherapy. The search for novel compounds with a mechanism of act ion similar to that of Taxol, but with greater efficacy particularly in Tax ol-resistant cells, has led to the isolation of new natural products. One s uch compound, (+)-discodermolide, although structurally distinct from Taxol , has a similar ability to stabilize microtubules. In addition, (+)-discode rmolide is active in Taxol-resistant cell lines that overexpress P-glycopro tein, the multidrug-resistant transporter. Interestingly. (+)-discodermolid e demonstrates a profound enhancement of the initiation process of microtub ule polymerization compared to Taxol. Results: The synthesis of (+)-discodermolide analogs exploiting our highly efficient, triply convergent approach has permitted structure-activity rela tionship (SAR) studies. Small changes to the (+)-discodermolide structure r esulted in a dramatic decrease in the ability of all four discodermolide an alogs to initiate tubulin polymerization. Two of the analogs also demonstra ted a decrease in total tubulin polymerization, while a change in the olefi n geometry at the C8 position produced a significant decrease in cytotoxic activity. Conclusions: The availability of (+)-discodermolide and the analogs, and th e resultant SAR analysis, have permitted an exploration of the similarities and differences between (+)discodermolide and Taxol. Docking of the X-ray/ solution structure of (+)-discodermolide into the Taxol binding site of bet a -tubulin revealed two possible binding modes (models I and II). The prefe rred pharmacophore model (I), in which the C19 side chain of (+)-discodermo lide matches with the C2 benzoyl group of Taxol and the delta -lactone ring of (+)-discodermolide overlays with the C13 side chain of Taxol, concurred with the results of the SAR analysis. (C) 2001 Elsevier Science Ltd. All r ights reserved.