Structure-activity profiles of eleutherobin analogs and their cross-resistance in Taxol-resistant cell lines

Cancer Chemother Pharmacol. 1999;44(2):131-7. doi: 10.1007/s002800050957.


Purpose: Eleutherobin, a natural product, is an antimitotic agent that promotes the polymerization of stable microtubules. Although its mechanism of action is similar to that of Taxol, its structure is distinct. A structure-activity profile of synthetic eleutherobin derivatives that have modifications at C3, C8 and C15 was undertaken to define the structural requirements for microtubule stabilization and cross-resistance in Taxol-resistant cell lines.

Methods: The biological activity of five eleutherobin analogs was assessed using three techniques: (1) cytotoxicity and drug-resistance in three paired Taxol-sensitive and -resistant cell lines; (2) polymerization of microtubule protein in vitro in the absence of GTP and (3) induction of microtubule bundle formation in NIH3T3 cells.

Results: Eleutherobin had an IC50 value comparable to that of Taxol, whereas neoeleutherobin, which has a carbohydrate domain that is enantiomeric with that of the parent compound, was less cytotoxic and had 69% of the maximum microtubule polymerization ability of eleutherobin. Both of these compounds exhibited cross-resistance in MDRI-expressing cell lines. Removal or replacement of the C15 sugar moiety resulted in reduced microtubule polymerization and cytotoxicity compared to eleutherobin and loss of cross-resistance in the cell lines SKVLB and J7-T3-1.6, both of which express high levels of P-glycoprotein. By contrast, removal of the urocanic acid group at C8 resulted in virtually complete abrogation of biological activity. The compound lost its ability to polymerize microtubules, and its cytotoxicity was reduced by a minimum of 2000-fold in lung carcinoma A549 cells.

Conclusions: Removal or modification of the sugar moiety alters the cytotoxic potency of eleutherobin and its pattern of cross-resistance in Taxol-resistant cells, although such compounds retain a small percentage of the microtubule-stabilizing activity of eleutherobin. The N(1)-methylurocanic acid moiety of eleutherobin, or perhaps some other substituent at the C8 position, is essential for Taxol-like activity. These findings will be important for the future design and the synthesis of new and more potent eleutherobin derivatives.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / analysis
  • Alkaloids / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Calcium / pharmacology
  • Diterpenes*
  • Drug Resistance, Neoplasm
  • Humans
  • Microtubules / drug effects
  • Paclitaxel / pharmacology*
  • Structure-Activity Relationship
  • Tubulin / metabolism
  • Tumor Cells, Cultured


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Alkaloids
  • Antineoplastic Agents
  • Diterpenes
  • Tubulin
  • eleutherobin
  • Paclitaxel
  • Calcium