A New Sesquiterpene-Coumarin Ether and a New Abietane Diterpene and their Effects as Inhibitors of P-Glycoprotein

Abstract

A new sesquiterpene-coumarin ether (5′β,9′α,10′α)-7-O-(3α-methoxy-8′(12′)-drimen-11′-yl)-scopoletin, designated driportlandin (1) and a new abietane quinoid diterpene 16-hydroxyabieta-8,12-diene-11,14-dione, named portlanquinol (2) together with lupeol, nepehinol, wrightial, formonetin and davidigenin were isolated and characterized from the Me₂CO extract of whole dried plant of Euphorbia portlandica. The structures of the new compounds were elucidated from spectral data including 2D-NMR experiments of COSY, HMQC, HMBC and NOESY. When examined for their effects on the reversal of multidrug resistance (MDR) on mouse lymphoma cells, compound 1 proved to be more active than the positive control verapamil and compound 2 was found to be toxic. This is the first report on the isolation of a sesquiterpene-coumarin and a quinoid-type diterpenoid from Euphorbia.

Euphorbia portlandica - Euphorbiaceae - sesquiterpene-coumarin - abietane diterpene - triterpenes - multidrug resistance - P-glycoprotein

References

• 1 Molnar J, Hever A, Fakla I, Fischer J, Ocsovski I, Aszalos A. Inhibition of the transport function of membrane proteins by some substituted phenothiazines in E. coli and multidrug resistant tumor cells.  Anticancer Res. 1997;  17 481-6 and related references cited therein
• 2 Wiese M, Pajeva I K. Structure-activity relationships of multidrug resistance reversers.  Curr Med Chem. 2001;  8 685-713
• 3 Ikegawa T, Ohtani H, Koyabu N, Juichi M, Iwase Y, Ito C, Furukawa H, Naito M, Tsuruo T, Sawada Y. Inhibition of P-glycoprotein by flavonoid derivatives in adriamycin-resistant human myelogenous leukemia (K562/ADM) cells.  Cancer Lett. 2002;  177 89-93
• 4 Mi Q, Cui B, Chavez D, Chai H, Zhu H, Cordell G A, Hedayat S, Kinghorn A D, Pezzuto J M. Characterization of tropane alkaloid aromatic esters that reverse the multidrug-resistance phenotype.  Anticancer Res. 2002;  223 1385-97
• 5 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 multidrug 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
• 6 Appendino G, Porta C D, Conseil G, Sterner O, Mercalli E, Dumontet C, Pietro A D. A new P-glycoprotein inhibitor from the caper spurge (Euphorbia lathyris).  J Nat Prod. 2003;  66 140-2
• 7 Madureira A M, Gyémánt N, Ugocsai K, Ascenso J R, Abreu P M, Hohmann J, Molnár J, Ferreira M J U. Rearranged jatrophane-type diterpenes from Euphorbia species. Evaluation of their effects on the reversal of multidrug resistance.  Planta Medica. 2004;  70 45-49
• 8 Cornwell M M, Pastan I, Gottesmann M M. Certain calcium channel blockers bind specifically to multidrug-resistance human KB carcinoma membrane vesicles and inhibit drug binding to P-glycoprotein.  J Biol Chem. 1987;  262 2166-70
• 9 Weaver J L, Szabo G, Pine P S, Gottesman M M, Goldenberg S, Aszalos A. The effect of ion channel blockers, immunosuppressive agents, and other drugs on the activity of the multidrug transporter.  Int J Cancer. 1993;  54 456-61
• 10 Kessel D. Exploring multidrug resistance using rhodamine 123.  Cancer Commun. 1989;  1 145-9
• 11 Kwak J H, Jang W Y, Zee O P, Lee K R. Artekeiskeanin A: a new coumarin-monoterpene ether from Artemisia keiskeana .  Planta Medica. 1997;  63 474-6
• 12 Razdan T K, Qadri B, Qurishi M A, Khuroo M A, Kachroo P K. Sesquiterpene esters and sesquiterpene-coumarin ethers from Ferula jaeskeana .  Phytochemistry. 1989;  28 3389-94
• 13 Hofer O, Weissensteiner W, Widhalm M. Absolute configurations and circular dichroism of sesquiterpene-coumarin ethers.  Monatsh Chem. 1983;  114 1399-1411
• 14 Shi J G, Shi Y P, Jia Z J. Sesquiterpenoids from Euphorbia wangii .  Phytochemistry. 1997;  45 343-8
• 15 Hao C, Jian J Z. Diterpenes and sesquiterpenes from two Euphorbia species - Structure elucidation of euphorhylonal A and euphoranin E.  Indian J Chem Sect B. 1996;  35 1308-10
• 16 Shishido K, Nakano K, Wariishi N, Tateishi H, Omodani T, Shibuya M, Goto K, Ono Y, Takaishi Y. Diterpene quinoids from Tripterygium wilfordii var. regelii which are interleukin-1 inhibitors.  Phytochemistry. 1994;  35 731-8
• 17 Tan N, Kaloga M, Radtke O A, Kiderlen A F, Oksuz S, Ulubelen A, Kolodziej H. Abietane diterpenoids and triterpenoic acids from Salvia cilicica and their antileishmanial activities.  Phytochemistry. 2002;  61 881-4
• 18 Ahmad V U, Bano S, Mohammad F V. Nepehinol - a new triterpene from Nepeta hindostana .  Planta Medica. 1985;  51 521-3
• 19 Ramchandra M, Basheermiya M, Krupadanam G L D, Srimannarayana G. Wrightial, a new terpene from Wrightia tinctoria .  J Nat Prod. 1983;  56 1811-12
• 20 Mabry T J, Markham M R, Thomas M B. The systematic identification of flavonoids. 1st ed New York; Springer-Verlag 1970: pp 110, 312
• 21 Jensen S R, Nielsen B J, Norn V. Dihydrochalcones from Viburnum davidii and V. lantanoides .  Phytochemistry. 1977;  16 2036-38
• 22 Torssell K B J. Natural product chemistry. A mechanistic, biosynthetic and ecological approach. 2nd edn Stockholm; Apotekarsocieteten, Swedish Pharmaceutical Press 1997: pp 42-79