Cytotoxic Cardenolides from the Leaves of Acokanthera oblongifolia ^{[ 1 ]}

Abstract

Three previously undescribed cardenolides, acovenosigenin A 3-O-α-L-acofriopyranoside (1), 14-anhydroacovenosigenin A 3-O-[β-D-glucopyranosyl-(1″→4′)-O-α-L-acofriopyranoside] (2), and 14-anhydroacovenosigenin A 3-O-[β-D-glucopyranosyl-(1″→4′)-O-α-L-acovenopyranoside] (3), together with the two already known ones, 14-anhydrodigitoxigenin 3-O-β-D-glucopyranoside (4) and acospectoside A (5), were isolated from the leaves of Acokanthera oblongifolia. The influence of cardenolides 1 – 3 and acovenoside A (found in the Acokanthera genus) on three cancer cell lines (HT29, HCT116, and AGS) was also investigated. The most promising results, in comparison with oxaliplatin, were obtained for compound 1, which was found to be highly cytotoxic for all tested cell lines, HT29 (IC₅₀ = 63.49 nM), HCT116 (IC₅₀ = 67.35 nM), and AGS (IC₅₀ = 80.92 nM). Unfortunately, 1 also showed similar toxicity towards normal lymphocytes (IC₅₀ = 98.03 nM).

Key words

Acokanthera oblongifolia - cardenolide - cancer - cytotoxicity - Apocynaceae

¹ Dedicated to Professor Dr. Cosimo Pizza 70th birthday in recognition of his outstanding contribution to natural product research.

• References

• 1 Schmelzer GH, Gurib-Fakim A. Plant resources of tropical Africa 11(1) – medicinal plants 1. Wageningen, Netherlands: PROTA Foundation; 2008
• 2 Hassan RA, Hassan EM, Ibrahim NA, Nazif NM. Triterpenes and cytotoxic activity of Acokanthera oblongifolia Hochst. growing in Egypt. Res J Pharm Biol Chem Sci 2015; 6: 1677-1686
• 3 El-Mallakh RS, Brar KS, Yeruva RR, El-Mallakh RS, Brar KS, Yeruva RR. Cardiac glycosides in human physiology and disease: update for entomologists. Insects 2019; 10: 102
• 4 De Villiers JP. The cardiac glycosides of Acokanthera oblongifolia . South African J Chem 1962; 15: 82-84
• 5 Cragg GM, Pezzuto JM. Natural products as a vital source for the discovery of cancer chemotherapeutic and chemopreventive agents. Med Princ Pract 2016; 25: 41-59
• 6 Wen S, Chen Y, Lu Y, Wang Y, Ding L, Jiang M. Cardenolides from the Apocynaceae family and their anticancer activity. Fitoterapia 2016; 112: 74-84
• 7 Mijatovic T, Ingrassia L, Facchini V, Kiss R. Na+/K+-ATPase α subunits as new targets in anticancer therapy. Expert Opin Ther Targets 2008; 12: 1403-1417
• 8 Kapadia GJ. Acospectoside A. II. The structure of the cardenolide glycoside. J Pharm Sci 1969; 58: 1555-1557
• 9 Kingston DGI, Reichstein T. Cytotoxic cardenolides from Acokanthera longiflora Stapf. and related species. J Pharm Sci 1974; 63: 462-464
• 10 Xue R, Han N, Ye C, Wang H, Yin J. Cardenolide glycosides from root of Streptocaulon juventas . Phytochemistry 2013; 88: 105-111
• 11 Pérez AJ, Simonet AM, Calle JM, Pecio Ł, Guerra JO, Stochmal A, Macías FA. Phytotoxic steroidal saponins from Agave offoyana leaves. Phytochemistry 2014; 105: 92-100
• 12 Weckesser J, Mayer H, Drews G. The identification of 3-O-methyl-L-rhamnose (L-acofriose) as constituent of the lipopolysaccharide of Rhodopseudomonas capsulata . Eur J Biochem 1970; 16: 158-160
• 13 Kitanaka S, Takido M, Mizoue K, Nakaike S. Cytotoxic cardenolides from woods of Euonymus alata . Chem Pharm Bull (Tokyo) 1996; 44: 615-617
• 14 Yu B, van Ingen H, Vivekanandan S, Rademacher C, Norris SE, Freedberg DI. More accurate 1J(CH) coupling measurement in the presence of 3J(HH) strong coupling in natural abundance. J Magn Reson 2012; 215: 10-22
• 15 Vine J, Brown L, Bontagy J, Thomas R, Nelson D. Cardenolide analogues: 10–characterization of cardiac glycosides by chemical ionization mass spectrometry. Biol Mass Spectrom 1979; 6: 415-421
• 16 Hanna AG, Elgamal MHA, Hassan AZ, Duddeck H, Simon A, Kovács J, Tóth G. Complete ¹H and ¹³C signal assignments of 5β-cardenolides isolated from Acokanthera spectabilis Hook F. Magn Reson Chem 1998; 36: 936-942
• 17 Xue R, Han N, Ye C, Wang L, Yang J, Wang Y, Yin J. The cytotoxic activities of cardiac glycosides from Streptocaulon juventas and the structure-activity relationships. Fitoterapia 2014; 98: 228-233
• 18 Levrier C, Kiremire B, Guéritte F, Litaudon M. Toxicarioside M, a new cytotoxic 10β-hydroxy-19-nor-cardenolide from Antiaris toxicaria . Fitoterapia 2012; 83: 660-664
• 19 Rashan LJ, Franke K, Khine MM, Kelter G, Fiebig HH, Neumann J, Wessjohann LA. Characterization of the anticancer properties of monoglycosidic cardenolides isolated from Nerium oleander and Streptocaulon tomentosum . J Ethnopharmacol 2011; 134: 781-788
• 20 Zhao M, Bai L, Wang L, Toki A, Hasegawa T, Kikuchi M, Abe M, Sakai J, Hasegawa R, Bai Y, Mitsui T, Ogura H, Kataoka T, Oka S, Tsushima H, Kiuchi M, Hirose K, Tomida A, Tsuruo T, Ando M. Bioactive cardenolides from the stems and twigs of Nerium oleander . J Nat Prod 2007; 70: 1098-1103
• 21 Kozachok S, Pecio Ł, Kolodziejczyk-Czepas J, Marchyshyn S, Nowak P, Mołdoch J, Oleszek W. γ-Pyrone compounds: flavonoids and maltol glucoside derivatives from Herniaria glabra L. collected in the Ternopil region of the Ukraine. Phytochemistry 2018; 152: 213-222
• 22 Tanaka T, Nakashima T, Ueda T, Tomii K, Kouno I. Facile discrimination of aldose enantiomers by reversed-phase HPLC. Chem Pharm Bull (Tokyo) 2007; 55: 899-901