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
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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
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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