TY - JOUR
T1 - Structure-activity profiles of eleutherobin analogs and their cross- resistance in Taxol-resistant cell lines
AU - McDaid, Hayley M.
AU - Bhattacharya, Samit K.
AU - Chen, Xiao Tao
AU - He, Lifeng
AU - Shen, Heng Jia
AU - Gutteridge, Clare E.
AU - Horwitz, Susan Band
AU - Danishefsky, Samuel J.
N1 - Funding Information:
This research was supported by grants from the National Institutes of Health (CA 39821 to S.B.H and CA 28824 to S.J.D.) H.M. McDaid á L. He á H.-J. Shen á S.B. Horwitz (&) Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA Tel. +1-718-430-2163; Fax +1-718-430-8922
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.
AB - 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.
KW - Drug-resistance
KW - Eleutherobin
KW - Microtubules
KW - Structure-activity
KW - Taxol
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U2 - 10.1007/s002800050957
DO - 10.1007/s002800050957
M3 - Article
C2 - 10412947
AN - SCOPUS:0032988620
SN - 0344-5704
VL - 44
SP - 131
EP - 137
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 2
ER -