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Article ID: WMC001311 2046-1690

The Pharmacological Properties Of TerpenoidsFrom Sandoricum KoetjapeCorresponding Author:Dr. Amin Malik Shah Abdul Majid,Lecturer in Universiti Sains Malaysia , Department of Pharmacology, School of Pharmaceutical Sciences,Universiti Sains Malaysia, , Minden 11800, Pulau Penang, Malaysia, 11800 - Malaysia

Submitting Author:Mr. Zeyad D Nassar,Master Student , Department of Pharmacology , School of Pharmacy , University Sains Malaysia , School ofPharmaceutical Sciences, USM , 11800 - Malaysia

Article ID: WMC001311

Article Type: Review articles

Submitted on:09-Dec-2010, 06:33:14 PM GMT Published on: 10-Dec-2010, 07:35:24 PM GMT

Article URL: http://www.webmedcentral.com/article_view/1311

Subject Categories:COMPLEMENTARY MEDICINE

Keywords:Terpenoids, Koetjapic acid, Sandoricum koetjape, Natural compounds, complementary medicine

How to cite the article:Nassar Z , Aisha A , Abdul Majid A . The Pharmacological Properties Of TerpenoidsFrom Sandoricum Koetjape . WebmedCentral COMPLEMENTARY MEDICINE 2010;1(12):WMC001311

Source(s) of Funding:

This work was financially supported by Universiti Sains Malaysia (USM) Research University Grant [Grant1001/PFARMASI/81144]

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The Pharmacological Properties Of TerpenoidsFrom Sandoricum KoetjapeAuthor(s): Nassar Z , Aisha A , Abdul Majid A

Abstract

Sandoricum koetjape is a traditional plant belonging tothe family of Meliaceae. It is native to Southeast Asiancountries, including Malaysia and Philippines. InMalaysia, it is locally known as Santol. The tree is amedium-sized with edible fruit. In Malaysia, theaqueous extract of the bark is traditionally consumedas a tonic after giving birth. Number of comprehensivestudies on its phytochemical and pharmacologicalproperties has been reported. Various bioactivecompounds have been isolated from fruits, seeds,leaves and bark. More than 10 terpenoids have beenisolated and studied for their potential medicinalproperties. Terpenoids represent the largest class ofsecondary metabolites from the natural source. Thisarticle aims to review the pharmacological propertiesof the isolated terpenoids from Sandoricum koetjape.

Review

Influence of medicinal plants on diseasestreatment: Plants have formed the basis of sophisticatedtraditional medicine systems that have been inexistence for thousands of years [1]. Plants have beenutilized to heal ailments from alleviating headache totreating heart diseases [2].The first illustrated book about gathering, preparationand use of medicinal plants was written by ChineseEmperor Shen Nung before 3000 thousand years [1].The Greeks also contributed in the development of theherbal drugs. “De Materia Medica” written byDioscorides, the Greek physician (100 A.D.),described more than 600 medicinal plants [2]. Theexpertises of Greeks in herbal medicine werepreserved only by Arabs, during the dark and middleAges. Arabs developed this science using their ownresources and together with Greco-Roman, Chineseand Indian herbs [1].The shift from using ordinary herbal medicines tomodern pharmaceuticals was just started in 1800s.This transfer was due starting isolation of purecompounds from plants. In 1805, morphine was

purified from the opium .Following the isolation ofsalicylic acid from the bark of the willow tree,Hoffmann synthesized aspirin in 1897. Ephedrine wasisolated from the Chinese herb mahuang (Ephedra) in1887. The antimalarial drug artemisinin was developedin 1972 from the Chinese herb qinghao (sweetwormwood, Artemisia annua L.) [3].Although, humans depend on plants from thousandsyears, the science of medicinal plants is still a vastlyunknown. Scholars estimate that 5 % of 250000species of plants have been investigated [2]. This factpoints in the importance of screen new plants for theirpharmacological properties.Natural products and cancer treatment:Some secondary metabolites of the plants such asalkaloids, terpenoids and glycosides serve either asprotective agents against various pathogens (e.g.insects, fungi or bacteria) or growth regulatorymolecules (e.g. hormone-like substances), as a result,secondary metabolites can serve as potentialanticancer drugs, either by direct cytotoxic activityagainst cancer cells or by modulating the tumordevelopment process [4]. In fact, natural products areconsidered as a mainstay in cancer treatment, as 60%of worldwide anticancer drugs between 1983 and 1994were from natural origin [5]. The most famous examples are vinblastine andvincristine from Catharanthus roseus, paclitaxel fromTaxus brevifolia Nutt, etoposide and teniposide whichare epimers of podophyllotoxin which isolated fromroots of various species of the genus podophyllum,and camptothecin which isolated from the Chinesetree Camptotheca acuminata [6]. The impact of theseproducts in cancer treatment is very obvious,paclitaxel and camptothecin were estimated toaccount for nearly one-third of the global anticancermarket or about $3 billion of $9 billion in total annuallyin 2002 [7].Terpenoids:Terpenoids are defined as secondary metabolites withmolecular structures containing carbon backbonesmade up of isoprene (2-methylbuta- 1, 3-diene) units.Isoprene contains five carbon atoms and as a result,the number of carbon atoms in any terpenoids is amultiple of five. The terpenoids consists of twoisoprene units, i .e. ten carbon atoms. Theclassification of terpenoids based on the number ofisoprene units [8] (Table 1).



More than 36000 terpenoids compounds have beenidentified, making terpenoids the largest class of plantmetabolites. Most of the thousands of terpenoidsproduced by plants have no discernible role in growthand development and are, therefore, often classifiedas ‘secondary’ metabolites. Although comparativelyfew of these substances have been investigated indepth, they are thought to serve primarily in ecologicalroles, providing defence against and acting asattractants for animals that disperse pollen or seeds oras inhibitors of germination and growth ofneighbouring plants [9-11]

The te rpeno ids g roup show s ign i f i can tpharmacological activities, such as anti-viral,anti-bacterial, anti-malarial, anti-inflammatory,inhibition of cholesterol synthesis and anti-canceractivities [12].Sandoricum koetjape:S. koetjape is traditional medicinal plant belonging tothe family Meliaceae, it is native to Malaysia,Cambodia and Southern Laos. It has been introducedinto the Philippines, India, Indonesia, and AndamanIslands since long time ago. A few samples wereintroduced into North and South America such asHonduras and Costa Rica, and Miami and Florida inUSA [13]. S .koetjape is an evergreen tree grows 15-45 m tall infast manner, as the plant gets older the trunk getbuttressed and branched close to the ground. Youngerbranches have dense brown hair. The 3 leaflets leavesare compound, elliptic to oblong-ovate, 20-25 cm long,blunt at the base and pointed at the apex. The flowersare 1 cm long consist of 5 petals stalked panicles15-30 cm in length, and have green, yellow, orpinkish-yellow colour Plate 1.1 shows picture of leaves, seeds and fruits of S. koetjape .There are two types of S. koetjape fruit, viz, red oryellow. The rind of the former type is sour, havethicker rind and the amount of pulp is less. While theyellow fruits are sweet, have thin rind and a thickerpulp. However, nowadays only the yellow variety isavailable in Malaysia [13,14].In Malaysia, S. koetjape is known as sentieh, sentol,setol, sentul, setul, setui, kechapi or ketapi. Thetraditional Indonesian names are ketjapi or sentool.While in Thailand it is called saton, satawn, katon, orka-thon [13,14].The classification of S. koetjape is demonstrated intable 2. Traditional medicinal uses of S. koetjape: In Malaysia, the aqueous extract of the bark istraditionally consumed as a tonic after giving birth [15],while in Indonesia it is used by folk medicalpractitioners to treat leucorrhoea and colic with the

decoction prepared from the bark of the plant [16].Phytochemistry and pharmacological activities of S.koetjape: The seeds, leaves, fruits and the stem bark of S.koetjape have been rigorously studied for the chemicalconstituents. Various S. koetjape’s extracts and manyisolated chemicals showed potential pharmacologicalactivities.Andirobin-type limonoids have been isolated from S.koet jape’s seeds, namely sandoric in and6-hydroxysandoricin. These limonoids showedremarkable anti-feedant activities [17].Bryononic acid and bryonolic acid terpenoids andmeso-inositol and dimethyl mucate polyalcohol havebeen isolated from the S. koetjape’s fruits hulls [18]The leaves have been yielded trijugin limonoidsnamely Sandrapins A, B, C, D and E, and sandoripin Aand B [19].Several comprehensive studies have been carried outon the stem bark. A number of triterpenoids have beenisolated from the stem bark such as, katonic acid,i n d i c i c a c i d [ 2 0 ] , k o e t j a p i c a c i d ,3-oxo-12-oleanen-29-oic acid, alloaromadendrene,caryophyllene oxide, spathulenol [21], bryononic acid,secobryononic acid, secoisobryononic acid [22],20-epikoetjapic acid, 3-epikatonic acid and sandorinicacid A, B and C [23]. Figure 1.3 shows chemicalstructure of some terpenoids extracted from the bark.Many pharmacological properties have beeninvestigated for the majority of the isolated terpenoids.The cytotoxic properties of Koetjapic acid, Katonic acidand 3-oxo-12-oleanen-29-oic acid were investigatedagainst ten cancer cell lines. Katonic acid and3-oxo-12-oleanen-29-oic were cytotoxic against manyof cancer cell lines (i.e. IC50 < 20 µg/ml), they werevery potent against murine lymphocytic leukaemiaP-388 cell l ine (IC50 = 0.11 and 0.61 µg/mlrespectively). In contrast, koetjapic acid was inactiveagainst all of tested cancer cell lines [21].Although koetjapic acid has not been reported as acytotoxic compound till now, it showed notable DNApolymerase inhibition activity [24]. Ismail et al.,reporetd ichthyotoxic properties of koetjapic acid and3-oxo-12-oleanen-29-oic acid [25]. However, katonicacid has not exhibited significant ichthyotoxic activity.In the same study, the all three terpenoids wasconsidered as anti-tumor promoting agents as theyshow significant inhibiory effect on induced-Epstin-Barr virus early antigen activation. Koetjapicacid was the most potent agents among the threeterpenoids in the lastest two mentioned assays(Ichthyotoxicity and anti-tumor promoion studies).Koetjapic acid also appears to be a promising cancerchemoprevintive compound, as it remarkably delayed



tumor promotion in two stage mouse carcinogenesisinduced by 7,12 dimethylbenz(a)anthracin andprompoted by 12-O-tetradecanoylphorbol 13-acetate(TBA) [25]. In TBA-induced mouse ear odema assay to explorethe anti- inflammatory properties, methanolic extract,oxo-12-oleanen-29-oic acid, Katonic acid andKoetjapic acid inhibits inflammation by 94 % 94 %, 81% and 13 % respectively [26]. Koetjapic acid alsoinhibited the growth of Staphylococcus aureus,methicillin-resistant S. aureus and Pseudomonasaeruginosa, with MIC range of 3.125-6.25 µg/ml [27].Recently, hexan extract of S.koetjape showsnoteworthy anti-angiogenicactivity in a study depended on ex-vivo rat aortic ringassay. Hexan extract also shows selective cytotoxicityagainst colorectal carcinoma HCT 116 cell line. Theapoptotic propoties of S.koetjape hexan extarct havebeen confirmed on two cancer cell lines, MCF-7 andHCT 116 [28,29].Koetjapic acid which is the main compound in S.koetjape was isolated successfully with simplenon-chromotgraphic method with high percentageyeild (Table 3). The remarkaple pharmacologicalactivity make this compound as good candidite as adrug, however, a comprehinsive toxicity study has tobe carried out. Besides, it is very critical to find asolution of poor solubilty of it as well as itsbioavailabilty.

Acknowledgement(s)

Zeyad D. Nassar and A.F.A. Aisha would like toacknowledge USM for the USM Fellowship. This work was financially supported by Universiti SainsMalaysia (USM) Research University Grant [Grant1001/PFARMASI/81144].

References

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27, 297-309.4. Kintzios, S.E. (2003) what do we know about cancerand its therapy ? In Kintzios, S.E. and Barberaki, M.G.(eds.), plants that fight cancer CRC press pp. 1-14.5. Cragg, G.M., Newman, D.J. and Snader, K.M.(1997) Natural Products in Drug Discovery andDevelopment. Journal of Natural Products, 60, 52-60.6. Newman, D.J., Cragg, G.M. and Snader, K.M.(2000) The influence of natural products upon drugdiscovery. Nat Prod Rep, 17, 215-34.7. Oberlies, N.H. and Kroll, D.J. (2004) Camptothecinand Taxol:â€‰ Historic Achievements in NaturalProducts Researchâ?¥. Journal of Natural Products,67, 129-135.8. Ashour, M., Wink , M. and J., G. (2010)Biochemistry of terpenoids : monoterpenes ,sesquiterpenes and diterpenes In Wink, M. (ed.),Biochemistry of Plant Secondary Metabolism. JohnWiley & Sons, vol. 40.9. Wink, M. (ed.) (2010) Function and Biotechnology ofPlant Secondary Metabolites. Wiley-Blackwell, Oxford.10. Langenheim, J.H. (1994) Higher plant terpenoids:A phytocentric overview of their ecological roles.Journal of Chemical Ecology, 20, 1223-1280.11. Harborne, J.B. and Tomas-Barberan, F.A. (eds.)(1991) Ecological Chemistry and Biochemistryof PlantTerpenoids, Clarendon, Oxford.12. Mahato, S.B. and Sen, S. (1997) Advances intriterpenoid research, 1990-1994. Phytochemistry, 44,1185-236.13. Morton, J.F. (ed.) (1987) Fruits of warm climatesJulia F. Morton Miami , FL.14. Uphof, J.C. (1959) Dictionary of Economic Plants.Hafner, New York.15. Burkill, I.H. (1966) Dictionary of the EconomicProducts of the Malay Peninsula. Ministry ofAgriculture and Cooperatives, Kuala Lumpur, Malaysia.16. Perry, L.M. (1980) Medicinal Plants of East andSoutheast Asia. The MIT Press, Cambridge.17. Powell, R.G., Mikolajczak, K.L., Zilkowski, B.W.,Mantus, E.K., Cherry, D. and Clardy, J. (1991)Limonoid Antifeedants from Seed of Sandoricumkoetjape. Journal of Natural Products, 54, 241-246.18. Sim, K.Y. and Lee, H.T. (1972) Triterpenoid andother constituents from Sandoricum indicum.Phytochemistry, 11, 3341-3343.19. Ismail, I.S., Ito, H., Hatano, T., Taniguchi, S. andYoshida, T. (2003) Modified limonoids from the leavesof Sandoricum koetjape. Phytochemistry, 64,1345-1349.20. King, F.E. and Morgan, J.W.W. (1960) 923. Thechemistry of extractives from hardwoods. Part XXX.The constitution of katonic acid, a triterpene fromsandoricum indicum. Journal of the Chemical Society



(Resumed), 4738-4747.21. Kaneda, N., Pezzuto, J.M., Kinghorn, A.D.,Farnsworth, N.R., Santisuk, T., Tuchinda, P.,Udchachon, J. and Reutrakul, V. (1992) Plantanticancer agents, L. cytotoxic triterpenes fromSandoricum koetjape stems. J Nat Prod, 55, 654-9.22. Kosela, S., Yulizar, Y., Chairul, Tori, M. andAsakawa, Y. (1995) Secomultiflorane-type triterpenoidacids from stem bark of Sandoricum koetjape.Phytochemistry, 38, 691-694.23. Tanaka, T., Koyano, T., Kowithayakorn, T.,Fujimoto, H., Okuyama, E., Hayashi, M., Komiyama, K.and Ishibashi, M. (2001) New Multiflorane-TypeTriterpenoid Acids from Sandoricum indicum. Journalof Natural Products, 64, 1243-1245.24. Hu, H.Y., Horton, J.K., Gryk, M.R., Prasad, R.,Naron, J.M., Sun, D.A., Hecht, S.M., Wilson, S.H. andMullen, G.P. (2004) Identification of small moleculesynthetic inhibitors of DNA polymerase beta by NMRchemical shift mapping. J Biol Chem, 279, 39736-44.25. Ismail, I.S., Ito, H., Mukainaka, T., Higashihara, H.,Enjo, F., Tokuda, H., Nishino, H. and Yoshida, T.(2003) Ichthyotoxic and anticarcinogenic effects oftriterpenoids from Sandoricum koetjape bark. BiolPharm Bull, 26, 1351-3.26. Rasadah, M.A., Khozirah, S., Aznie, A.A. and Nik,M.M. (2004) Anti-inflammatory agents fromSandoricum koetjape Merr. Phytomedicine, 11, 261-3.27. Muhammad, I., El Sayed, K.A., Mossa, J.S.,Al-Said, M.S., El-Feraly, F.S., Clark, A.M., Hufford,C.D., Oh, S. and Mayer, A.M.S. (2000) Bioactive12-Oleanene Triterpene and Secotriterpene Acidsfrom Maytenus undata. Journal of Natural Products,63, 605-610.28. Aisha, A.F.A., Alrokayan, S.A., Abu-Salah, K.M.,Darwis, Y. and Abdul Majid, A.M.S. (2009) In vitroCytotoxic and Apoptotic Properties of the Stem BarkExtract of Sandoricum koetjape on Breast CancerCells. Int. J. Cancer Res., 5, 123-129.29. Aisha, A.F.A., Sahib, H.B., Abu-Salah, K.M.,Darwis, Y. and Abdul Majid, A.M.S. (2009) Cytotoxicand Anti-Angiogenic Properties of the Stem BarkExtract of Sandoricum koetjape. Int. J. Cancer Res., 5,105-114.30. Nassar, Z.D., Aisha, A.F.A., Majid, A.M.S.A., Yeap,C.S. and Fun, H.-K. (2010) Koetjapic acid chloroformhemisolvate. Acta Crystallographica Section E, 66,o1301-o1302.



Class Magnoliopsida, Dicotyledons

Subclass Rosidae

Order Rutales

Suborder Meliineae

Family Meliaceae

Genus Sandoricum

Specific epithet koetjape Merr.

Botanical name Sandoricum koetjape

Synonyms Sandoricum indicum Cav., Sandoricum nervosum

Blume, and Melia koetjape Burm. f.[13]

Illustrations

Illustration 1

Table 1 The classification of Sandricum koetjape



Name No. of isoprene units No. of carbon atoms

Hemiterpenoids 1 5

Monoterpenoids 2 10

Sesquiterpenoids 3 15

Diterpenoids 4 20

Sesterterpenoids 5 25

Triterpenids 6 30

Tetraterpenoids 8 40

Polyisoprenoids >8 >40

Illustration 2

Table 2 The nomenclature of terpenoids.



Reference Percentage yield %

Kaneda et al., 1992 [21] 0.11 %

Tanaka et al., 2001 [23] 0.14%

Rasadah et al., 2004 [26] 0.0036%

Ismail et al., 2003 [25] 0.0825%

Nassar, et al., 2010 [30] 0.2 %

Illustration 3

Table 3 The percentage yield of koetjapic acid gained by previous studies



Illustration 4

Figure 1 Pictures of leaves, seeds and fruits of S.koetjape



Illustration 5

Figure 2 Chemical structures of triterpene isolated from S. koetjape



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