Six New Sesquiterpenes from Euonymus nanoides and Their Antitumor Effects

Abstract

Six new dihydro-β-agarofuran [5,11-epoxy-5β,10α-eudesm-4 (14)-ene] sesquiterpenes were isolated from the seeds of Euonymus nanoides Loes, including five with a novel substitution pattern: (1R,2S,4S,5R,7R,9S,10R)-1α-benzoyloxy-2α,15-diacetoxy-4β-hydroxy-9β-cinnamoyloxy-β-dihydroagarofuran (1), 1α-(α-methyl)-butanoyl-2α,15-diacetoxy-4β-hydroxy-9β-(β-)furoyloxy-β-dihydroagarofuran (2), 1α,2α-di-(α-methyl)-butanoyl-4β-hydroxy-9β-(β-)furoyloxy-15-acetoxy-β-dihydroagarofuran (3), 1α-(α-methyl)-butanoyl-2α-(α-methyl)-propynoyloxy-4β-hydroxy-9β-(β-)furoyloxy-15-acetoxy-β-dihydroagarofuran (4) and 1α,2α, 9β-tri-(β-)furoyloxy-4β-hydroxy-15-acetoxy-β-dihydroagarofuran (5). The other dihydroagarofuran sesquiterpene was 1α,2α,6β,15-tetraacetoxy-3α-(α-methyl)-butanoyl-4β-hydroxy-9β-(β-)furoyloxy-β-dihydroagarofuran (6). The structures of 1 - 6 were elucidated by means of ¹H- and ¹³C-NMR spectroscopic studies, including 2D heteronuclear COSY (HMQC), long-range correlation spectra with inverse detection (HMBC), ¹H-¹H COSY and NOESY. The absolute configuration of compound 1 was determined by application of the CD exciton chirality method. Six compounds were evaluated for their in vitro antitumor effects (IC₅₀ values: 27.71 - 50.69 μg/mL) and the structure-activity relationship is discussed.

Euonymus nanoides - Celastraceae - sesquiterpene - β-dihydroagarofuran - CD exciton chirality method - antitumor activity

References

• 1 Brüning R, Wagner H. Übersicht über die Celastraceen-Inhaltsstoffe: Chemie, Chemotaxonomie, Biosynthese, Pharmakologie.  Phytochemistry. 1978;  17 1821-58
• 2 Zheng Y L, Xu Y, Lin J F. Immunesuppresive effects of wifortrine and euonine.  Acta Pharm Sin. 1989;  24 568-72
• 3 Kuo Y, King M, Chen G, Chen H, Chen C, Chen . et al . Two new macrolide sesquiterpene pyridine alkaloids from Maytenus emarginata: emarginatine G and the cytotoxic emarginatine F.  J Nat Prod. 1994;  57 263-9
• 4 González A G, Jiménez I A, Ravelo A G, Coll J, González J A, Lioria J. Antifeedant activity of sesquiterpenes from Celastraceae.  Biochem Systematic Ecol. 1997;  25 513-9
• 5 Duan H, Takaishi Y, Bando M, Kido M, Imakura Y, Lee K. Novel sesquiterpene esters with alkaloid and monoterpene and related compounds from Tripterygium hypoglaucum: a new class of potent anti-HIV agents.  Tetrahedron Lett. 1999;  40 2969-72
• 6 Pérez-Victoria J M, Tincusi B M, Jiménez I A, Bazzocchi I L, Gupta M P, Castanys S. et al . New natural sesquiterpenes as modulators of daunomycin resistance in a multidrug-resistant Leishmania tropica line.  J Med Chem. 1999;  42 4388-93
• 7 Wang H, Tian X, Chen Y Z. Two new sesquiterpenes from Euonymus nanoides .  Chin Chem Lett. 2002;  11 1063-6
• 8 Lee S K, Nam K A, Heo Y H. Cytotoxic activity and G2/M cell cycle arrest mediated by antofine, a phenanthroindolizidine alkaloid isolated from Cynanchum paniculatum .  Planta Med. 2003;  69 21-5
• 9 Takaishi Y, Ujita K, Nakano K, Tomimatsu T. Structural elucidation of triptofordins F-1, F-2, F-3, and F-4, new sesquiterpene polyesters from Tripterygium wilfordii Hook fil. var. regelii makino.  Chem Pharm Bull. 1988;  36 4275-83
• 10 Takaishi Y, Tamai S, Nakano K, Murakami K, Tomimatsu T. Structures of sesquiterpene polyol esters from Tripterygium wilfordii var. regelii.  Phytochemistry. 1991;  30 3027-31
• 11 Takaishi Y, Ujita K, Kida K, Shibuya M, Tomimatsu T. Polyhydroxyagarofuran derivatives from Tripterygium wilfordii H.  Phytochemistry. 1987;  26 2581-4
• 12 Begley M J, Crombie L, Fleming R A, Whiting D A, Rozsá Z, Kelényi M. et al .New sesquiterpene esters from Euonymus verrucosus: the ‘ever’ series. X-ray molecular structure of ever-1. J Chem Soc Perkin Trans I 1986: 535-9
• 13 Harada N, Nakanishi K. Circular Dichroism Spectroscopy Exciton Coupling in Organic Stereochemistry. 1983 University Science Books Mill Valley, CA;
• 14 González A G, Nuñez M P, Ravelo A G, Sazatornil J G, Vázquez J T, Bazzocchi I L. et al .Structural elucidation and absolute configuration of novel β-agarofuran (epoxyeudesmene) sesquiterpenes from Maytenus magellanica (Celastraceae). J Chem Soc Perkin Trans 1 1992: 1437-41
• 15 Wakabayashi N, Wu W J, Waters R M, Redfern R E, Mills Jr G D, Demilo A B. et al . Celangulin: a nonalkaloidal insect antifeedant from Chinese bittersweet, Celastrus angulatus .  J Nat Prod. 1988;  51 537-42
• 16 González A G, Tincusi B M, Bazzocchi I L, Tokuda H, Nishino H, Konoshima T. et al . Anti-tumor promoting effects of sesquiterpenes from Maytenus cuzcoina (Celastraceae).  Bioorganic & Medicinal Chemistry. 2000;  8 1773-8
• 17 Takaishi Y, Ujita K, Tokuda H, Nishino H, Iwashima A, Fujita T. Inhibitory effects of dihydroagarofuran sesquiterpenes on Epstein-Barr virus activation.  Cancer Lett. 1992;  65 19-26
• 18 Wang M A, Wu W J, Zhou W M, Zhu J B. HR-FAB and EIMS of β-dihydroagarofuran sesquiterpene polyol esters.  Natural Product Research And Development. 2001;  13 5-8
• 19 Canel C, Moraes R M, Dayan F e, Ferreira D. Molecules of interest - podophyllotoxin.  Phytochemistry. 2000;  54 115-20