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

Hayley M. McDaid, Samit K. Bhattacharya, Xiao Tao Chen, Lifeng He, Heng Jia Shen, Clare E. Gutteridge, Susan Band Horwitz, Samuel J. Danishefsky

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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 MDR1-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.

Original languageEnglish (US)
Pages (from-to)131-137
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume44
Issue number2
DOIs
StatePublished - 1999

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Paclitaxel
Cells
Microtubules
Cell Line
Polymerization
Cytotoxicity
Bioactivity
Sugars
Urocanic Acid
eleutherobin
Microtubule Proteins
Derivatives
Antimitotic Agents
P-Glycoprotein
Guanosine Triphosphate
Biological Products
Drug Resistance
Inhibitory Concentration 50
Stabilization
Carbohydrates

Keywords

  • Drug-resistance
  • Eleutherobin
  • Microtubules
  • Structure-activity
  • Taxol

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Structure-activity profiles of eleutherobin analogs and their cross- resistance in Taxol-resistant cell lines. / McDaid, Hayley M.; Bhattacharya, Samit K.; Chen, Xiao Tao; He, Lifeng; Shen, Heng Jia; Gutteridge, Clare E.; Band Horwitz, Susan; Danishefsky, Samuel J.

In: Cancer Chemotherapy and Pharmacology, Vol. 44, No. 2, 1999, p. 131-137.

Research output: Contribution to journalArticle

McDaid, Hayley M. ; Bhattacharya, Samit K. ; Chen, Xiao Tao ; He, Lifeng ; Shen, Heng Jia ; Gutteridge, Clare E. ; Band Horwitz, Susan ; Danishefsky, Samuel J. / Structure-activity profiles of eleutherobin analogs and their cross- resistance in Taxol-resistant cell lines. In: Cancer Chemotherapy and Pharmacology. 1999 ; Vol. 44, No. 2. pp. 131-137.
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AU - McDaid, Hayley M.

AU - Bhattacharya, Samit K.

AU - Chen, Xiao Tao

AU - He, Lifeng

AU - Shen, Heng Jia

AU - Gutteridge, Clare E.

AU - Band Horwitz, Susan

AU - Danishefsky, Samuel J.

PY - 1999

Y1 - 1999

N2 - 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 MDR1-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.

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