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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Aromatase Inhibition by an 11,13-Dihydroderivative of a Sesquiterpene Lactone

Javier G. Blanco, Roberto R. Gil, José L. Bocco, Tamara L. Meragelman, Susana Genti-Raimondi and Alfredo Flury
Journal of Pharmacology and Experimental Therapeutics June 2001, 297 (3) 1099-1105;
Javier G. Blanco
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Roberto R. Gil
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José L. Bocco
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Tamara L. Meragelman
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Susana Genti-Raimondi
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Alfredo Flury
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Abstract

Compounds that inhibit aromatase activity are used for the treatment of breast cancer. A group of sesquiterpene lactones inhibit aromatase activity and also exert cytotoxicity through their reactive α-methylene-γ-lactone group. To synthesize sesquiterpene lactones with greater specificity for aromatase inhibition and lower cytotoxicity, we chemically reduced the α-methylene-γ-lactone group in the active aromatase inhibitor 10-epi-8-deoxycumambrin B (compound1), to obtain the new compound 11βH,13-dihydro-10-epi-8-deoxycumambrin B (compound 2). Reduction of the α-methylene-γ-lactone group abrogated the cytotoxic activity of compound 1 against the JEG-3, HeLa, and COS-7 cell lines. Compound 2 had higher aromatase inhibitory activity than compound 1(IC50 = 2 ± 0.5 μM versus 7 ± 0.5 μM, Ki = 1.5 μM versus 4.0 μM) and was a more potent type II ligand to the heme iron present in the cytochrome P450arom active site. Compound2 inhibited aromatase activity in JEG-3 cells in a comparable manner to the inhibitor aminoglutethimide (AG) used clinically for the treatment of breast cancer. Additionally, compound2 inhibited androstenedione-induced uterine hypertrophy in sexually immature mice (41% of uterine weight suppression for compound2 versus 51% for AG). We conclude that the anti-aromatase activity of sesquiterpene lactones does not depend on the presence of the highly reactive α-methylene-γ-lactone group, whereas their cytotoxicity does. These findings may facilitate the development of safer agents for breast cancer therapy.

Footnotes

  • Send reprint requests to: Dr. Javier G. Blanco, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 North Lauderdale St., Memphis, TN 38105-2794. E-mail:javier.blanco{at}stjude.org

  • This study was supported in part by the Consejo Nacional de Investigaciones Cientı́ficas y Técnicas (CONICET), Consejo de Investigaciones Cientı́ficas y Tecnológicas de la Provincia de Córdoba (CONICOR), Secretarı́a de Ciencia y Tecnologı́a de la Universidad Nacional de Córdoba (SECYT), and the Fundación Antorchas and Fundación Alberto P. Roemmers. J.G.B. and R.R.G. contributed equally to this work.

  • Abbreviations:
    SQL
    sesquiterpene lactone
    compound 1
    10-epi-8-deoxycumambrin B
    compound 2
    11βH,13-dihydro-10-epi-8-deoxycumambrin B
    EIMS
    electron impact mass spectroscopy
    COSY
    homonuclear correlation spectroscopy
    HETCOR
    heteronuclear correlation spectroscopy
    P450
    cytochrome P450
    MTS
    tetrazolium compound
    DMSO
    dimethyl sulfoxide
    Ksapp.
    spectral binding constant
    • Received December 22, 2000.
    • Accepted February 12, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 297 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 297, Issue 3
1 Jun 2001
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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Aromatase Inhibition by an 11,13-Dihydroderivative of a Sesquiterpene Lactone

Javier G. Blanco, Roberto R. Gil, José L. Bocco, Tamara L. Meragelman, Susana Genti-Raimondi and Alfredo Flury
Journal of Pharmacology and Experimental Therapeutics June 1, 2001, 297 (3) 1099-1105;

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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Aromatase Inhibition by an 11,13-Dihydroderivative of a Sesquiterpene Lactone

Javier G. Blanco, Roberto R. Gil, José L. Bocco, Tamara L. Meragelman, Susana Genti-Raimondi and Alfredo Flury
Journal of Pharmacology and Experimental Therapeutics June 1, 2001, 297 (3) 1099-1105;
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