Potential Anti-Tumor-Promoting Activity of 3α-Hydroxy-D:A-friedooleanan-2-one from the Stem Bark of Mallotus philippensis

Abstract

Four known friedelane-type triterpenoids, friedelin (1), 3-hydroxy-D:A-friedoolean-3-en-2-one (2), 2β-hydroxy-D:A-friedooleanan-3-one (3), and 3α-hydroxy-D:A-friedooleanan-2-one (4), and two known lupane-type triterpenoids, lupeol (5) and betulin (6), were isolated from the stem bark of Mallotus philippensis. Isolates 1 - 4 and their synthetic analogues, 3-acetoxy-D:A-friedoolean-3-en-2-one (2a) and 3α-acetoxy-D:A-friedooleanan-2-one (4a), were tested for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol 13-acetate (TPA). The inhibitory effect of compounds 2 (IC₅₀ = 292 mol ratio/32 pmol/TPA) and 4 (IC₅₀ = 288) was stronger than those of the other compounds tested and the positive control, curcumin (IC₅₀ = 343). Compound 4 strongly inhibited mouse skin tumor promotion in an in vivo two-stage carcinogenesis model. Studies have been conducted to identify the biologically active compounds extracted from the leaves, bark, and cones of trees that currently have no specific commercial use and are therefore treated as waste in the forestry industry.

Key words

Mallotus philippensis - Euphorbiaceae - stem bark - 3α-hydroxy-D:A-friedooleanan-2-one - Epstein-Barr virus early antigen - two-stage mouse skin carcinogenesis - DMBA - TPA

References

• 1 Daikonya A, Katsuki S, Wu J -B, Kitanaka S. Anti-allergic agents from natural sources (4): Anti-allergic activity of new phloroglucinol derivatives from Mallotus philippensis (Euphorbiaceae).  Chem Pharm Bull. 2002;  50 1566-9
• 2 Furusawa M, Ido Y, Tanaka T, Ito T, Nakaya K, Ibrahim I. et al . Novel, complex flavonoids from Mallotus philippensis (Kamala tree).  Helv Chim Acta. 2005;  88 1048-58
• 3 Tanaka R, Matsunaga S. Triterpene dienols and other constituents from the bark of Phyllanthus flexuosus. .  Phytochemistry. 1988;  27 2273-7
• 4 Kikuchi T, Toyoda T. Isolation and structure determination of pachysandiol-A and a note on the stereochemistry of cerin.  Tetrahedron Lett. 1967;  33 3181-5
• 5 Talapatra S K, Pradhan D K, Talapatra B. Terpenoids and related compounds: part XV. 3α-Hydroxyfriedel-2-one and 2β-acetoxyfriedel-3-one (epicerin acetate), two new pentacyclic triterpenoids from cork waste, their partial syntheses and one-step conversions to friedelin.  Ind J Chem Sect B. 1978;  16B 361-5
• 6 Tanaka R, Tabuse M, Matsunaga S. Triterpenes from the stem bark of Phyllanthus flexuosus.  Phytochemistry. 1988;  27 3563-7
• 7 Sporn M B. Prevention of cancer in the next millennium: report of the chemoprevention working group to the American Association for Cancer Research.  Cancer Res. 1999;  59 4743-58
• 8 Ohigashi H, Takamura H, Koshimizu K, Tokuda H, Ito Y. Search for possible anti-tumor promoters by inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced Epstein-Barr virus activation; ursolic acid and oleanolic acid from an anti-inflammatory Chinese medical plant.  Cancer Lett. 1986;  30 143-51
• 9 Fukuda Y, Sakai K, Matsunaga S, Tokuda H, Tanaka R. Cancer chemopreventive activity of lupane- and oleanane-type triterpenoids from the cones of Liquidamber styraciflua. .  Chem Biodiv. 2005;  2 421-8
• 10 Ukiya M, Akihisa T, Tokuda H, Hirano M, Oshikubo M, Nobukuni Y. et al . Inhibition of tumor-promoting effects by poricoic acids G and H and other lanostane-type triterpenes and cytotoxic activity of poricoic acids A and G from Poria cocos. .  J Nat Prod. 2002;  65 62-5
• 11 Shoji S. Chemistry and cancer preventing activities of ginseng saponins and some related triterpenoid compounds.  J Korean Med Sci. 2001;  16 S28-S37
• 12 Akihisa T, Tokuda H, Ichiishi E, Mukainaka T, Toriumi M, Ukiya M. et al . Anti-tumor promoting effects of multiflorane-type triterpenoids and cytotoxic activity of karounidiol against human cancer cell lines.  Cancer Lett. 2001;  173 9-14
• 13 Tanaka R, Minami T, Tsujimoto K, Matsunaga S, Tokuda H, Nishino H. et al . Cancer chemopreventive agents, serratane-type triterpenoids from Picea jezoensis. .  Cancer Lett. 2001;  172 119-26
• 14 Zheng G -Q. Cytotoxic terpenoids and flavonoids from Artemisia annua. .  Planta Med. 1994;  60 54-7
• 15 Takaishi Y, Wariishi N, Tateishi H, Kawazoe K, Nakano K, Ono Y. et al . Triterpenoid inhibitors of interleukin-1 secretion and tumor-promotion from Tripterygium wilfordii var. regelii. .  Phytochemistry. 1997;  45 969-74
• 16 Huang M T, Smart R C, Wong C Q, Conney A H. Inhibition effect of curcumin, chlorogenic acid, caffeic acid, and ferulic acid on tumor promotion in mouse skin by 12-O-tetradecanoylphorbol 13-acetate.  Cancer Res. 1988;  48 5941-6
• 17 Henle G, Henle W. Immunofluorescence in cells derived from Burkit’s lymphoma.  J Bacteriol. 1966;  91 1248-56