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DOI: 10.1055/s-2004-827191
© Georg Thieme Verlag KG Stuttgart · New York
Structure-Activity Relationships for Euphocharacins A - L, a New Series of Jatrophane Diterpenes, as Inhibitors of Cancer Cell P-Glycoprotein
Publication History
Received: December 7, 2003
Accepted: March 31, 2004
Publication Date:
15 July 2004 (online)
Abstract
The Mediterranean spurge Euphorbia characias L. afforded twelve new diterpenes based on a jatrophane skeleton named euphocharacins A - L. Their chemical structures were elucidated by extensive nuclear magnetic resonance and mass spectrometry methods. Euphocharacins A - L were tested as inhibitors of the daunomycin-efflux activity of P-glycoprotein from cancer cells. The results were used to extend the structure-activity relationship established for this class of compounds, highlighting the positive effects of propyl and benzoyl groups at positions 3 and 9, respectively, and evidencing the negative effect of a free hydroxyl group at position 2. Among the tested compounds, euphocharacins C and I showed an activity higher than cyclosporin to inhibit Pgp-mediated daunomycin transport.
Key words
Euphorbiaceae - Euphorbia characias - diterpenes - jatrophanes - P-glycoprotein - SAR studies
References
- 1 Leveille-Webster C R, Arias I M. The biology of the P-glycoprotein. J Membrane Biol. 1995; 143 89-102
- 2 Sharom F J. The P-glycoprotein efflux pump: how does it transport drugs?. J Membrane Biol. 1997; 160 161-75
- 3 Scala S, Akhmed N, Rao U S, Paull K, Lan L B, Dickstein B, Lee J S, Elgemeie G H, Stein W, Bates S E. The P-glycoprotein substrates and antagonists cluster into two distinct groups. Mol Pharmacol. 1997; 51 1024-33
- 4 Juliano R L, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta. 1976; 455 152-62
- 5 Endicott J A, Ling V. The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu Rev Biochemistry. 1989; 58 137-71
- 6 Wang R B, Kuo C L, Lien L L, Lien E J. Structure-activity relationship: analyses of P-glycoprotein substrates and inhibitors. J Clin Pharm Ther. 2003; 28 203-228
- 7 Robert J, Jarry C. Multidrug resistance reversal agents. J Med Chem. 2003; 46 4805-17
- 8 Hohmann J, Molnár J, Rédei D, Evanics F, Forgo P, Kálmán A, Argay G, Szabó P. Discovery and biological evaluation of a new family of potent modulators of mutidrug resistance: reversal of multidrug resistance of mouse lymphoma cells by new natural jatrophane diterpenoids isolated from Euphorbia species. J Med Chem. 2002; 45 2425-31
- 9 Corea G, Fattorusso E, Lanzotti V, Tagliatatela-Scafati O, Appendino G, Ballero M, Simon P -N, Dumontet C, Di Pietro A. Jatrophane diterpenes as P-glycoprotein inhibitors. First insights of structure-activity relationship and discovery of a new powerful lead. J Med Chem. 2003; 46 3395-402
- 10 Corea G, Fattorusso E, Lanzotti V, Taglialatela-Scafati O, Appendino G, Ballero M, Simon P -N, Dumontet C, Di Pietro A. Modified jatrophane diterpenes as modulators of multidrug resistance from Euphorbia dendroides L. Bioorg & Med Chem. 2003; 11 5221-7
- 11 Corea G, Fattorusso E, Lanzotti V, Motti R, Simon P -N, Dumontet C, Di Pietro A. Jatrophane diterpenes as modulators of multidrug resistance. Advances of structure-activity relationship and discovery of the potent lead pepluanin A. J Med Chem. 2004; 47 988-92
- 12 Comte G, Daskiewicz J -B, Bayet C, Conseil G, Viornery-Vanier A, Dumontet C, Di Pietro A, Barron D. C-Isoprenylation of flavonoids enhances binding affinity toward P-glycoprotein and modulation of cancer cell chemoresistance. J Med Chem. 2001; 44 763-768
- 13 Simon P -N, Chaboud A, Darbour N, Di Pietro A, Dumontet C, Lurel F, Raynaud J, Barron D. Modulation of cancer cell multidrug resistance by an extract of Ficus citrifolia . Anticancer Res. 2001; 21 1023-8
- 14 Hohmann J, Vasas A, Gunther G, Mathe I, Evanics F, Dombi G, Jerkovich G. Macrocyclic diterpene polyester of the jatrophane type from Euphorbia esula . J Nat Prod. 1997; 60 331-5
- 15 Appendino G, Jakupovic S, Tron G C, Jakupovic J, Milon V, Ballero M. Macrocyclic diterpenoids from Euphorbia semiperfoliata . J Nat Prod. 1998; 61 749-56
Virginia Lanzotti
DISTAAM
Università degli Studi del Molise
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Italy
Phone: +39-874-404-649
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Email: lanzotti@unimol.it