Phytochemistry and pharmacology of the genus Macaranga: A review

The genus Macaranga Thou. (Euphorbiaceae) comprises of about 300 species that are native mainly to the tropics of Africa, Asia, Australia and the Pacific regions. Plants of this genus have a long history of use in traditional medicine to treat cuts, swellings, boils, bruises and sores. Phytochemical work on this genus has reported over 190 secondary metabolites being isolated mainly from the leave extracts of different species of this genus. The isolated compounds included stilbenes, flavonoids, coumarins, terpenoids, tannins and other types of compounds. The crude extracts and isolated compounds showed a wide spectrum of pharmacological activities including anti-cancer, anti-inflammatory, anti-oxidant, anti-microbial and anti-plasmodial activities. The aim of this review is to coherently document the valuable but scattered reports on the phytochemistry and pharmacology of medicinal plants of the genus Macaranga collected from different parts of the global.


INTRODUCTION
The genus Macaranga Thou.belongs to the family Euphorbiaceae.Plants are shrubs or trees that grow up to 15 m tall.Members of this genus are known for their mutual associations with ants (Fiala et al., 1990).The trees of this genus benefit because the ants attack or feed on herbivorous insects.In folk medicine, traditional healers use fresh or dried leaves of some Macaranga species to treat swellings, cuts, sores, boils and bruises (Nick et al., 1995).A phytochemical review of literatures indicates the genus Macaranga to be a rich source of the isoprenylated, geranylated and farnesylated flavonoids (Schutz et al., 1995;Jang et al., 2002;Phormmart et al., 2005;Kawakami et al., 2008;Thanh et al., 2012) and stilbenes (Beutler et al., 1998;Yoder et al., 2007;Thanh et al., 2012).Furthermore, more classes of secondary metabolites like terpenes (Salah et al., 2003;Jang et al., 2004;Phormmart et al., 2005;Kawakami et al., 2008), tannins (Lin et al., 1990;Gunawan-Puteri and Kawabata, 2010;Ngoumfo et al., 2008), coumarins (Sutthivaiyakit et al., 2002;Darmawan et al., 2012) and other types of compounds (Ramaiah et al., 1979;Ngoumfo et al., 2008;Matsunami et al., 2009;Zakaria et al., 2010) are known to be isolated from different species of the genus Macaranga.Flavonoids and stilbenes are regarded as the major constituents and are most likely responsible for most of the activities found in the plants of this genus.An increasing number of phytochemical studies are being carried out on plants belonging to the genus Macaranga due to their various traditional uses.Thus, the isolated natural products from this genus have been reported to display interesting biological activities including antitumor (Kaaden et al., 2001;Yoder et al., 2007;Zakaria et al., 2012), antioxidant (Sutthivaiyakit et al., 2002;Phormmart et al., 2005;Matsunami et al., 2009), antimicrobial (Salah et al., 2003;Lim et al., 2009) and anti-inflammatory (Jang, et al., 2002).This is a resourceful area of research as many species of Macaranga are used in traditional medicine as well as exhibits various pharmacological properties while their chemistry indicates varied chemical structures.Hence, it is necessary that a systematic and critical assessment of the future directions of research in this field and its application be undertaken.The present work evaluates the scientific evidence for the therapeutic claims for Macaranga in traditional medical use and summarizes its bioactive chemical constituents.It also highlights the scientific basis for future research on plants in this genus, including their potential for development as herbal drugs.

Distribution of the genus
Macaranga is the largest genera in the Euphorbiaceae family.It is known to consist of about 300 species native mainly to the tropics of Africa, South-East Asia, Australia and the South Pacific region (Davies, 1998).The genus is most diverse in South-East Asia and New Guinea (200 species) but also occurs in Africa and Madagascar (37 species), continental Asia (30 species), the Pacific Islands (24 species) and Australia (7 species) (Siregar and Sambas, 2000).In East Africa (Tanzania Kenya and Uganda), there are 7 species growing mainly in forest margins (Bampss et al., 1978) while in South Africa there is only one species (Pujol, 1990).

Phytochemistry
Very little phytochemical work has been done on the genus Macaranga.An overview of the literature search indicated that only twenty six (26) Macaranga species have been investigated phytochemically as compared to about 300 plant species known from this genus.The species for which their chemical constituents have been investigated includes Macaranga alnifolia, Macaranga barteri, Macaranga bicolour, Macaranga  Interestingly, about 90% of the isolated compounds have been reported from the leaves while 10% is from the other parts.This calls for further and extensive research work to be done from other parts like stem and root barks, fruits, seeds and flowers.Further observation of Macaranga plants in their natural environment has revealed that they produce threadlike wax crystals on their stems.Chemical analysis has indicated that terpenoids make up a majority of the wax bloom content that helps maintain this symbiotic relationship between plant and insect (Markstaedter, et al., 2000).The names of these constituents and the plant parts from which they are derived are listed in Table 1.

Studies of the pharmacological activities of the genus
Macaranga indicate the potential of extracts and pure compounds to display specific medical effects.Previous investigation on the chemistry and pharmacology of this genus showed that its crude extracts and compounds displayed interesting bioactivity profiles, possessing various bioactivities including anticancer (Yoder et al., 2007;Zakaria et al., 2012), antioxidant (Phormmart et al., 2005;Matsunami et al., 2009), antmicrobial (Schutz et al., 1995;Lim et al., 2009), anti-inflammatory (Jang et al., 2002;Ngoumfo et al., 2008) and other different types of biological activities (Thanh et al., 2012;Zakaria et al., 2012).

Anticancer activity
Cancer is one of the leading causes of mortality, accounting for about 8 million deaths worldwide.
Currently, there are about 20 million people with cancer worldwide and the number is projected to increase to 30 million by the year 2020 (WHO, 2008).The report indicates the most prevalent types of cancer being lung, liver, colon, cervical, prostate and breast cancer.Since many people in the tropics live in rural areas, treatment of cancerrelated illnesses has mostly involved plant extracts.It is estimated that over 60% of anticancer agents presently in clinical use are derived from natural sources, including plants, marine organisms and micro-organisms (Cragg and Newman, 2005).Some examples of anticaner drugs originating in plants include paclitaxel, irinotecan, topotecan, vinblastine, vincristine, camptothecin, and etoposide (Pan et al., 2010).
Although several anticancer drugs such as taxol derivatives are already in the clinic, they are expensive and thus not affordable by these communities.Therefore, there remains a great need for affordable and reliable anticancer drugs particularly of plant origin.Currently, several anticancer compounds from medicinal plants have been characterized and their activities against different types of human cancer cell lines established (Balunas and Kinghorn, 2005).For instance, extracts and purified compounds from Macaranga species have been studied for their potential as anticancer agents.Thus, the bioassay guided-isolation from the leaves of M. schweinfurthii gave schweinfurthii A (86) and schweinfurthii B (87) which indicated high sensitivity against central nervous system (CNS) tumorderived lines SF-295 and SF-539.Compound 86 displayed a mean panel GI 50 of 0.36 µM while compound 87 gave a mean panel GI 50 of 0.81 µM (Beutler et al., 1999).
In another study from the leaves of M. mappa, the crude extract of the leaves indicated potent cytotoxicity against both drug-resistant (SKVLB-1) and drug-sensitive (SK-OV-3) ovarian cancer cell lines with an IC 50 value of 3.5 µg/ml.From the active extract, a cytotoxic compound named mappain (89) was isolated which was cytotoxic but noted to be a poor substrate for Pglycoprotein-mediated transport as it is equally potent and effective against the drug-sensitive (SK-OV-3) and drug-resistant (SKVLB-1) ovarian cancer cell lines, indicating an IC 50 value of 1.3 µM in both cases (Kaaden et al., 2001).
Yoder and co-researchers investigated a fruit extract of the Malagasy plant, M. alnifolia.This extract was found to be active in the A2780 ovarian cancer anti-proliferative activity assay, with an IC 50 value of 3.5 µg/ml.Ten compounds were isolated and tested for anti-proliferative activity in the A2780 human ovarian cancer cell lines, Table 2 (Yoder et al., 2007).In this study, vedelianin (85) showed the greatest activity among all isolates, exhibiting the IC 50 value of 0.13 µM (Yoder et al., 2007).
A study on the anticancer activity from the leaves of M. tanarius collected in Japan gave prenylated flavanones that were assayed against the KB and A549 cell lines by means of the 3-[4-5dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) method.It was reported that the isolated compounds did not show any selectivity between these cell lines.However, macaflavanone G (41) showed the most potent compound against both cell lines with an IC 50 values of 12.3 ± 3.0 and 13.4 ± 2.1 μM for KB and A549 cells, respectively (Kawakami et al., 2008).Phytochemical investigation of an endemic plant from Indonesia, M. gigantea gave three cytotoxic flavonoids, macagigantin (46), glyasperin A (47) and apigenin (48) from the acetone extract of the leaves.The cytotoxic properties of all compounds were evaluated against murine leukemia P-388 cell lines according to the method of MTT.The results indicated that compounds 46 to 48 exhibited an IC 50 values of 11.3 ± 0.4, 6.0 ± 0.9, and 5.1 ± 0.7 µM, respectively (Tanjung et al., 2009).Artonin E, which was used as a positive control, showed the IC 50 value of 1.38 ± 0.2.In another study by Li and co-workers, a series of prenylated flavonols (42 to 45) were isolated from the leaves of M. sampsonii.The isolated compounds were evaluated for their cytotoxicity potential using MTT method against human cancer cell lines [lung cancer (A549), pulmonary carcinoma (LAC), gastric carcinoma (SGC-7901) and hepatoma (HepG2)].However, all compounds were inactive at 20 µg/ml except for macaranone A (42) that exhibited weak activity against HepG2 cell line with the IC 50 value of 6.9 µg/ml (Li et al., 2009).Further search for anticancer compounds from Macaranga plants was done on the leaves of M. rhizinoides using the MTT method against murine leukemia P-388 cell lines (Tanjung et al., 2010).Bioassay-guided isolation from the methanol extract of the leaves led to the isolation of two cytotoxic flavonoids named macarhizinoidins A (55) and B (56).On cytotoxic evaluation against murine leukemia P-388 cell lines, compounds 55 and 56 indicated the IC 50 values of 11.4 and 13.9 µM, respectively (Tanjung et al., 2010).
A recent study by Zakaria and co-researchers investigated the dichloromethane extract of the inflorescences of M. triloba.Phytochemical analysis of the active extract resulted in the isolation of five flavonoids (10, 28, 53 and 54) which were tested for their activity against three cancer cell lines, namely HL-60 (human leukemia), MCF-7 (human breast cancer) and HeLa (human cervical cancer) using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) dye-reduction assay.The results are recorded in Table 3, indicating compound 54 to exhibit very strong activity against HeLa and HL-60 cell lines with IC 50 values of 1.3, 3.3 μg/ml, respectively and also a strong inhibition against MCF-7 cells with IC 50 value 5.6 μg/ml, others were moderately active (Zakaria et al., 2012).
Phytochemical investigations from the leaves of Macaranga kurzii lead to the isolation of a series of flavonoids and stilbenes (Thanh et al., 2012).Compound 100 indicated significant activity with IC 50 of 4 μM, while compounds 67and 72 displayed IC 50 values of 13 and 10 μM, respectively.The other isolated compounds were non-cytotoxic at 20 μM (Thanh et al., 2012).Continued search for anticancer compounds from Macaranga plants was done from an Indonesian species, M. lowii.Two isoprenylated dihydroflavonol derivatives (75 to 76) and a flavone (77) were isolated from the methanol extract of the leaves of M. lowii.Preliminary cytotoxic investigation of compounds 75 to 77 against murine leukemia P-388 cells showed weak activity values at 119.3, 166.6 and 58.7 µM, respectively (Agustina et al., 2012).Flavonoids (78-81) from M. recurvata, isolated by Tanjung and coworkers were evaluated for cytotoxic activity against murine leukemia P-388 cells using MTT assay.These compounds were noted to be active at the IC 50 values < 10 µM, with compound 79 being the most active with the IC 50 value of 0.83 µM (Tanjung et al., 2012).
Another study on the anticancer activity from the leaves of M. gigantifolia collected in Indonesia gave a cytotoxic coumarin derivative compound named scopoletin (157).Its cytotoxicity was evaluated using MTT assay method against murine leukemia P-338 cells.Compound 157 showed moderate cytotoxic activity with IC 50 value of 17.42 µg/ml (Darmawan et al., 2012).

Antioxidant activity
Antioxidants are secondary metabolites produced by plants to protect against oxidative damage by free radicals (Larson, 1988).Plants have for so long shown to be important in the human diet as well as in health maintenance.The well known beneficial role provided by plants is protection against cellular damage caused by exposure to high levels of free radicals such as reactive oxygen species (ROS) (Aruoma, 1996).Different parts of Macaranga plant species are known to contain high levels of antioxidant compounds such as polyphenols, phenolic acids, flavonoids and carotenoids (Matsunami et al., 2006).These antioxidants are thought to prevent chronic complications in part through their interactions with reactive species and ability to scavenge free radicals  (Seifried et al., 2007).Investigation for antioxidant compounds from M. denticulata lead to the isolation of phenolic compounds (3 and 157) which indicated to have significant antioxidant properties (Sutthivaiyakit et al., 2002).These compounds were evaluated for their antioxidant properties using 1,1diphenyl-2-picrylhydrazyl (DPPH) stable radical.
M. tanarius is well known in Thai traditional medicine as an antipyretic and emetic agent (Phupattanapong and Wongprasert, 1987).Phytochemical work on the leaves of this species gave five flavonols (10, 25 to 28) that were tested for antioxidant activity with the DPPH stable radical (Phormmart et al., 2005).The results indicated that compounds 26 to 28 and 10 indicated comparable radical scavenging properties with IC 50 values of 20 ± 1, 14 ± 1, 13 ± 2 and 15 ± 2 mM, respectively.These IC 50 values were higher than that of compound 25 and a standard (BHT) which showed IC 50 values of 33 ± 1 and 30 ± 1, respectively (Phormmart et al., 2005).
In 2006, Matsunami and co-workers investigated the radical-scavenging activity of the leaves of M. tanarius and isolated nine secondary metabolites of the megastigmane-type glucosides (173 to 180).The free radical scavenging activity of these compounds was evaluated by its ability to quench the stable radical 1,1diphenyl-2-picryl-hydrazyl (DPPH) using Trolox as a reference compound whereas Trolox equivalent (µM) was determined for each isolate.The results indicated compounds 173 to 176 had more potent radicalscavenging activity than the well-known antioxidant flavonoids, quercetin glycosides.
The rest of the compounds could not quench DPPH radical.From the structural point of view, it was established that the radical scavenging activity of these galloylated megastigmane glucosides depended on the galloyl moiety and not megastigmane glucoside moiety (Matsunami et al., 2006).
In the study of the methanolic fresh leaves of four Macaranga species (M.gigantea, M. pruinosa, M. tanarius and M. triloba), the antioxidant properties (AOP) of the crude extracts were evaluated.Three antioxidant techniques namely 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging, ferric-ion reducing power (FRAP) and ascorbic acid equivalent antioxidant activity (AEAC) were used.The results indicate moderate activities to most extracts except M. triloba extract that showed the highest ascorbic acid equivalent antioxidant activity (AEAC) and FRAP values.M. tanarius showed the lowest AEAC and FRAP activities as indicated in Table 4 (Lim et al., 2009).
Further study on the methanol extract of M. tanarius by Matsunami and co-workers lead to the isolation of a lignan glucoside (172) and two megastigmane glucosides, ( 173) and ( 174).Thus, the free radical-scavenging activity of these compounds was evaluated using 1,1diphenyl-2-picrylhydrazyl (DPPH) radical with Trolox being used as a standard compound.Compounds 172 and 173 showed potent radical-scavenging activities of 1.07 and 0.55 times of Trolox, respectively (Matsunami et al., 2009).

Antimicrobial activity
The use of plant extracts in the treatment of infectious diseases has been a known practice for many years now (Recio et al., 1989).As a result, a large number of reports of antimicrobial natural products have been documented from various parts of the world.However, owing to the continuing development of microbial resistance, discovery of new antimicrobial substances is of great importance.Macaranga plants have been investigated for antimicrobial natural products that yielded several bioactive compounds.One of the reports from Macaranga species was the characterization of antibacterial prenylated flavanones isolated from M. pleiostemona.This species is well known in New Guinea and is used to relieve headache (Schutz et al., 1995).Bioassay-guided isolation of the dichloromethane extract of M. pleiostemona yielded four compounds (4 to 7) which were assayed for antibacterial activities against Escherichia coli (ATCC 25922) and Micrococcus luteus (ATCC 9341) using a bioautographic method (Orjala et al., 1994).All compounds exhibited significant antibacterial activities with minimum growth inhibition of 0.5 µg/ml each for both bacterial species (Schutz et al., 1995).
Investigation of the Cameroonian plant, M. monandra for possible antifungal compounds was undertaken by Salah et al. (2003).Bioassay-guided fractionation of the hexane and ethyl acetate fractions of the methanol extract led to the isolation of two active clerodane-type diterpenes (146 and 147).A 96-well microbioassay revealed that kolavenic acid (146) and 2-oxo-kolavenic acid (147) produced moderate growth inhibition in Phomopsis viticola and Botrytis cinerea (Salah et al., 2003).Compound 146 was slightly more active against P. viticola and showed 50% growth inhibition at 30 µM,  (Salah et al., 2003).
Four methanolic extracts from M. gigantea, M. pruinosa, M. tanarius and M. triloba were screened for their antibacterial activities using the disc-diffusion method (Chan et al., 2007) against the gram-positive bacteria (Bacillus cereus, Micrococcus luteus and Staphylococcus aureus) and the gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae and Salmonella cholerosius).The results indicated the inhibition was only observed for all gram-positive species which showed moderate inhibition for all Macaranga extracts.M. triloba showed the best antibacterial activity against grampositive bacteria species, with minimal inhibition dosage (MID) values as low as 10 µg/disc (Lim et al., 2009).No activity was observed for the gram-negative species which is most likely due to lipoproteins and lipopolysaccharides of the outer membrane.

Anti-inflammatory activity
Inflammation is one of the biological responses of vascular tissue to harmful stimuli like pathogens or damaged cells.The conventional signs of acute inflammation are pain, heat, redness and swelling (Ferrero-Milian et al., 2007).Furthermore, inflammation is regarded as defensive response that induces physiological adaptations to limit tissue damage and removes the pathogenic infections (Roussin et al., 1997).Currently, many synthetic drugs are used to treat inflammation conditions, leading to many side effects.Herbal drugs of plant origin are of most important to produce safe anti-inflammatory drugs.
Plants of the genus Macaranga has been reported to be the good source of anti-inflammatory compounds.Isolation of prenylated flavonoids was performed from the ethyl acetate extract of M. conifera and tested for their inhibition effects against both cyclooxygenases-1 and -2 (Jang et al., 2002).Cyclooxygenase-2 (COX-2) is responsible for the biosynthesis of prostaglandins under acute inflammatory conditions (O'Banion et al., 1992).Thus, the regulation of the COX pathway provides an excellent approach for the discovery of cancer chemopreventive agents (Cuendet and Pezzuto, 2000).Six compounds (14 to 19) were isolated and tested to exhibit potent inhibitory activities with compound 14 indicating to be a promising cancer chemopreventive agent.Compounds 14 to 19 were also evaluated in a mouse mammary organ culture assay and the results are recorded in Table 5 (Jang et al., 2002).
A study by Ngoumfo and co-workers investigated the anti-inflammatory activity of the methanol extract of the stem bark of M. barteri in a cell-based respiratory burst assay.This assay involved water-soluble tetrazolium salt (WST-1) to measure the superoxide production of neutrophils activated by opsonized zymosan, which induces phagocytic activation of neutrophils (Costantino et al., 1998).Compounds 108, 157, 167 to 170 were tested for their anti-inflammatory potential in a cell-based respiratory burst assay indicating good activity (Table 6).Compound 108 was found to be the best inhibitor of the superoxides produced in the cellular system (Ngoumfo et al., 2008).
In another search for anti-inflammatory compounds from leaves of M. triloba, an array of phenolic compounds was isolated and evaluated for their potential to inhibit cyclooxygenases-1 and -2 by measuring PGE2 production (Cuendet and Pezzuto, 2000).Compounds 22 to 24 and 183 to 184 showed significant inhibitory activity against cyclooxygenase-1 (COX-1) and -2 (COX-2) as indicated in Table 7 (Jang et al., 2004).Gandhimathi (2013) studied the leaves of M. peltata for anti-inflammatory activity.The petroleum ether extract of this species was evaluated for anti-inflammatory activity at the doses of 200 and 400 mg/kg body weight.The results indicated that the oral administration of extract exhibited a significant and dose dependent protective effect on chemical and thermic painful stimuli at the doses of 200 and 400 mg/kg.This implied that the extract possess both peripheral and central effects.It was further noted that the petroleum ether extract possesses an anti-inflammatory activity against carrageenan induced paw edema in rats.The activity was assumed to be due to the presence of phenolic compounds in the leaves of M. peltata (Gandhimathi, 2013).

Other biological activities
Macaranga species are also reported to produce compounds that have different biological effects.Recently, Thanh and co-workers isolated flavonoids (66 to 74) and stilbenes (97 to 100) from M. kurzii which were evaluated for their acetylcholinesterase inhibitory activities (Thanh et al., 2012).Acetylcholinesterase (AChE) inhibitors are the therapeutic agents for the treatment of neurological  (Thanh et al., 2012).
The study on the dichloromethane crude extract of the inflorescences of M. triloba for its in vitro antiplasmodial activity against a chloroquine sensitive strain of Plasmodium falciparum (3D7) was done for the material collected in Malaysia (Zakaria et al., 2012).The IC 50 value of the crude extract was 2.01 μg/ml, indicating to be a good source of antiplasmodial compounds.Bioassayguided isolation gave three flavonoids (10, 28 and 54) that were screened for their antiplasmodial activity.Compound 54 displayed strong antiplasmodial activities with an IC 50 value of 0.06 μM, followed by a moderate activity for 10 and 28 with IC 50 values of 2.04 and 4.02 μM, respectively (Zakaria et al., 2012).

Conclusion
This article has reviewed the existing knowledge regarding species of the genus Macaranga.It is a valuable undertaking as it aims to document the important but scattered reports on phytochemistry and pharmacology of medicinal plants of the genus Macaranga collected from different parts of the world.Despite the fact that a wide range of traditional uses of Macaranga plants are known and that several plant extracts and pure compounds indicated diverse biological activities (Lim et al., 2009;Zakaria et al., 2012), there are few studies regarding such properties.For instance, out of the 300 known species of Macaranga plants, less than 30 plant species have been investigated phytochemically (Table 1).This calls for further work to be done on other known species of this genus.The data provided should help to serve as the basis for further scientific research on this genus.In addition, it is equally important to understand the pharmacological studies on this genus as may be valuable to validate the claimed traditional uses.Many reviewed literature have shown different species of Macaranga to be the good source of various types of natural compounds having diverse and fascinating chemical structures.The major classes of compounds reported in the literature included flavonoids, stilbenes, terpenes, tannins, coumarins and others (Table 1) (Lin et al., 1990;Jang et al., 2002;Salah et al., 2003;Yoder et al., 2007).The pharmacological review of the genus indicated many flavonoids and stilbenes to be isolated from the leaves and exhibited strong, moderate to weak anticancer properties (Kaaden et al., 2001).These two classes of compounds also showed significant antioxidant activities (Sutthivaiyakit et al., 2002).Other compounds indicated anti-inflammatory and antimicrobial properties (Schutz et al., 1995;Ngoumfo et al., 2008).Furthermore, both pharmacological and phytochemical investigations have established that phytochemicals and crude extracts from various parts of Macaranga species possess versatile biological activities.However, modern drugs can be developed after extensive investigation of its bioactivity, mechanism of action, toxicity and after proper standardization as well as and clinical trials.Although many efforts have been made to study some of the plants of this genus, there are profound issues to be considered and improved: 1.There are approximately 300 recorded species of the Macaranga genus worldwide, but only approximately 10% of them have been studied, phytochemically or pharmacologically.This implies more efforts to continue with the documentation of the traditional uses, phytochemical and pharmacological investigations should be further encouraged aiming at validating already existing information and for discovering more traditional claims as well as getting leads for drug discovery.2. Interestingly, this review demonstrated that it is about 90% of the isolated secondary metabolites from Macaranga species have been obtained from the leaves while 10% is from the other parts.This calls for further and extensive research work to be done from other plant parts like stem and root barks, fruits, seeds and flowers.3. Tannins (101 to 144) (Table 1) are characteristic phytochemicals in some species of this genus like M. sinensis and M. tanarius (Lin et al., 1990).However, presentations of the structures lacked establishment of stereochemistry which is the basic tool in structure identification as well as in biological activities.These compounds were isolated before the discovery of new and advanced spectroscopic techniques.Hence, further study is required to understand the structures as well as the possible structure-activity relationships of these phytoconstituents.4. Some species of Macaranga are well known for their mutual relationship with ants (Figure 1), however, a little is known about the chemical compositions of the hollow shoots that always house the ants.Further study is also needed to discover the phytochemicals therein.Special attention should be paid to the Macaranga genus to validate and establish its medicinal potential and to utilize the various plant sources it contains.

Figure 1 .
Figure 1.One of the conserved Macaranga species and a branch with ants climbing.
In summary, the chemical constituents obtained provides an understanding of the general biological and chemical information like pharmacological activity of the species, mechanisms of action, quality control principles as well as for further exploitation of the plant resources in this genus.So far, 190 secondary metabolites have been isolated and identified from the Macaranga plants.The isolated compounds include flavonoids (1 to 84), stilbenes (85 to 100), tannins (101 to 144), terpenes (145 to 156), coumarins (157 to 158), steroids (159 to 161) and other types of compounds (162 to 190).

Table 1 .
Compounds isolated from the genus Macaranga.

Table 2 .
Antiproliferative Activity of M. alnifolia compounds to A2780 cells.

Table 4 .
Antioxidant activities of four Macaranga species.
* = used as positive control.