TY - JOUR
T1 - The relationship between Taxol and (+)-discodermolide
T2 - Synthetic analogs and modeling studies
AU - Martello, Laura A.
AU - LaMarche, Matthew J.
AU - He, Lifeng
AU - Beauchamp, Thomas J.
AU - Smith, Amos B.
AU - Horwitz, Susan Band
N1 - Funding Information:
We thank Michael Cammer and Frank Macaluso of the Analytical Imaging Facility for assistance with the microtubule measurements and Dr. Fred Brewer for the use of computers for the modeling studies (AECOM). The work at AECOM was supported in part by USPHS Grants CA 39821 and CA 77263 (S.B.H.), Cancer Core Support Grant CA 13330, and the National Institute of General Medical Sciences Training Program in Pharmacological Sciences Grant 5T32 GM07260 (L.A.M.). At the University of Pennsylvania, work was supported by the Department of the Army through Grant DAMD 17-00-1-0404 and Novartis Pharmaceutical Company.
PY - 2001
Y1 - 2001
N2 - 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 β-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 δ-lactone ring of (+)-discodermolide overlays with the C13 side chain of Taxol, concurred with the results of the SAR analysis.
AB - 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 β-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 δ-lactone ring of (+)-discodermolide overlays with the C13 side chain of Taxol, concurred with the results of the SAR analysis.
KW - Discodermolide
KW - Microtubule
KW - Pharmacophore
KW - Taxol
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U2 - 10.1016/S1074-5521(01)00055-2
DO - 10.1016/S1074-5521(01)00055-2
M3 - Article
C2 - 11564553
AN - SCOPUS:0034826406
SN - 1074-5521
VL - 8
SP - 843
EP - 855
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 9
ER -