The conformations of discodermolide in DMSO.

(+)-Discodermolide (1), a polyhydroxylated lactone isolated from the marine sponge Discodermia dissoluta,1 is currently a high-profile substance for its promise as an immunosuppressive agent1,2 and an anti-cancer drug. The compound induces apoptosis in human breast cancer cells,3 inhibits the in vitro proliferation of murine P388 leukemia cells,1 and combines synergistically with Taxol to suppress the proliferation of human carcinoma cells.4 Biomechanistically, discodermolide resembles Taxol and epothilone in its ability to bind to microtubules, effect tubulin polymerization, and promote mitotic arrest.5 Not surprisingly, these optimistic findings have stimulated a number of laboratories to pursue the total synthesis of the compound.6,7

[1]  J. Snyder,et al.  A Test of the Single-Conformation Hypothesis in the Analysis of NMR Data for Small Polar Molecules: A Force Field Comparison , 1999 .

[2]  S. Kuduk,et al.  A common pharmacophore for cytotoxic natural products that stabilize microtubules. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[3]  B. Day,et al.  Increased Sensitivity of the Antiestrogen‐Resistant MCF‐7/LY2 Human Breast Carcinoma Cell Line to Apoptosis Induced by the Novel Microtubule Stabilizing Agent (+)‐Discodermolide , 1998 .

[4]  Kenneth H. Downing,et al.  Structure of the αβ tubulin dimer by electron crystallography , 1998, Nature.

[5]  L. Amos,et al.  Crystal structure of the bacterial cell-division protein FtsZ , 1998, Nature.

[6]  B. Day,et al.  The potent microtubule-stabilizing agent (+)-discodermolide induces apoptosis in human breast carcinoma cells—preliminary comparisons to paclitaxel , 1998, Anti-cancer drugs.

[7]  P. Giannakakou,et al.  The microtubule-stabilizing agent discodermolide competitively inhibits the binding of paclitaxel (Taxol) to tubulin polymers, enhances tubulin nucleation reactions more potently than paclitaxel, and inhibits the growth of paclitaxel-resistant cells. , 1997, Molecular pharmacology.

[8]  O Jardetzky,et al.  On the nature of molecular conformations inferred from high-resolution NMR. , 1980, Biochimica et biophysica acta.

[9]  R. Bazzo,et al.  NMR Analysis of Molecular Flexibility in Solution: A New Method for the Study of Complex Distributions of Rapidly Exchanging Conformations. Application to a 13-Residue Peptide with an 8-Residue Loop , 1995 .