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 action similar to that of Taxol, but with greater efficacy particularly in Taxol-resistant cells, has led to the isolation of new natural products. One such compound, (+)-discodermolide, although structurally distinct from Taxol, has a similar ability to stabilize microtubules. In addition, (+)-discodermolide is active in Taxol-resistant cell lines that overexpress P-glycoprotein, the multidrug-resistant transporter. Interestingly, (+)-discodermolide demonstrates a profound enhancement of the initiation process of microtubule polymerization compared to Taxol.


RESULTS
The synthesis of (+)-discodermolide analogs exploiting our highly efficient, triply convergent approach has permitted structure-activity relationship (SAR) studies. Small changes to the (+)-discodermolide structure resulted in a dramatic decrease in the ability of all four discodermolide analogs to initiate tubulin polymerization. Two of the analogs also demonstrated a decrease in total tubulin polymerization, while a change in the olefin geometry at the C8 position produced a significant decrease in cytotoxic activity.


CONCLUSIONS
The availability of (+)-discodermolide and the analogs, and the 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 beta-tubulin revealed two possible binding modes (models I and II). The preferred pharmacophore model (I), in which the C19 side chain of (+)-discodermolide 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.
Martello
L A
LA
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
LaMarche
M J
MJ
He
L
L
Beauchamp
T J
TJ
Smith
A B
AB
Horwitz
S B
SB
D000473:Alkanes; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D002219:Carbamates; D005434:Flow Cytometry; D006801:Humans; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000187:drug effects; D008958:Models, Molecular; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology*; D011753:Pyrones; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000473:Alkanes; D000972:Antineoplastic Agents, Phytogenic; D002219:Carbamates; D007783:Lactones; D011753:Pyrones; D014404:Tubulin; C071229:discodermolide; D017239:Paclitaxel