Original Papers

In Vitro Antiplasmodial Activity of Benzophenones and Xanthones from Edible Fruits of Garcinia Species

Authors

James T. Lyles 1, 2, Adam Negrin 1, Shabana I. Khan 3, 4, Kan He 5, Edward J. Kennelly 1

Affiliations

1 2 3 4 5

Key words " Garcinia l " Clusiaceae l " benzophenone l " xanthone l " antiplasmodial activity l " structure‑activity relationl ships

Lehman College and The Graduate Center, City University of New York, New York, NY, USA Present address: Center for the Study of Human Health, Emory University, Atlanta, GA, USA National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS, USA Department of Pharmacognosy, School of Pharmacy, The University of Mississippi, University, MS, USA Present address: Herbalife International, Torrance, CA, USA

Abstract !

Species of Garcinia have been used to combat malaria in traditional African and Asian medicines, including Ayurveda. In the current study, we have identified antiplasmodial benzophenone and xanthone compounds from edible Garcinia species by testing for in vitro inhibitory activity against Plasmodium falciparum. Whole fruits of Garcinia xanthochymus, G. mangostana, G. spicata, and G. livingstonei were extracted and tested for antiplasmodial activity. Garcinia xanthochymus was subjected to bioactivity-guided fractionation to identify active partitions. Purified benzophenones (1–9) and xanthones (10–18) were then screened in the plasmodial lactate dehydrogenase assay and tested for cytotoxicity against mammalian (Vero) cells. The benzophenones guttiferone E

Introduction ! received revised accepted

May 12, 2014 May 12, 2014 May 14, 2014

Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1368585 Planta Med 2014; 80: 676–681 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0032‑0943 Correspondence Dr. Edward J. Kennelly Lehman College and The Graduate Center City University of New York 250 Bedford Park Blvd. W., Bronx New York 10468 USA Phone: + 1 71 89 60 11 05 Fax: + 1 71 89 60 82 36 edward.kennelly@ lehman.cuny.edu

The genus Garcinia (Clusiaceae) consists of over 250 pantropical species, mainly medium-sized trees and small shrubs found in lowland tropical forests of Africa, Madagascar, India, and Southeast Asia [1]. Several species have been documented as ethnobotanically important plants used traditionally as food and medicine [2, 3] and reported as antiprotozoal and antiplasmodial ethnomedicines to prevent malaria [3–6]. Xanthones are a major class of compounds identified in members of the Clusiaceae family [7], including edible species of Garcinia [8], and have demonstrated bioactivity against American trypanosomiasis [9], leishmaniasis [10], and malaria [11–14]. Benzophenones are biosynthetic precursors to xanthones which have been isolated from many species in the Clusiaceae, including Garcinia [15–17], and have also been identified as inhibitors of malaria [18, 19]. In light of such evidence, the authors sought to identify active antiplasmodial com-

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Planta Med 2014; 80: 676–681

(4), isoxanthochymol (5), and guttiferone H (6), isolated from G. xanthochymus, and the xanthones α-mangostin (15), β-mangostin (16), and 3-isomangostin (17), known from G. mangostana, showed antiplasmodial activity with IC50 values in the range of 4.71–11.40 µM. Artemisinin and chloroquine were used as positive controls and exhibited IC50 values in the range of 0.01– 0.24 µM. The identification of antiplasmodial benzophenone and xanthone compounds from G. xanthochymus and G. mangostana provides evidence for the antiplasmodial activity of Garcinia species and warrants further investigation of these fruits as dietary sources of chemopreventive compounds. Supporting information available online at http://www.thieme-connect.de/products/

pounds from fruits of edible Garcinia species using classical bioactivity-guided fractionation and modern analytical phytochemistry techniques. In order to identify antimalarial compounds in fruits of Garcinia species, the pulp and rind of G. xanthochymus, G. mangostana, G. livingstonei, and G. spicata were extracted and tested for antimalarial activity against P. falciparum through an in vitro assay. Benzophenones, xanthones, and xanthone glycosides from Garcinia spp. were then isolated by open column chromatography and confirmed by spike-recovery experiments with available standards using RP HPLC‑PDA and LC‑MS/TOF. Purified compounds were screened for antiplasmodial activity.

Results !

The methanolic extracts of G. livingstonei, G. mangostana, G. spicata, and G. xanthochymus fruit pulp were tested and compared in vitro for anti-

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Table 1 Antiplasmodial activity and cytotoxicity of benzophenones and xanthones. Compound

4 Guttiferone E 5 Isoxanthochymol 6 Guttiferone H 15 α-Mangostin 16 β-Mangostin 17 3-Isomangostin Artemisinin Chloroquine Doxorubicin a

D6 clone

Cytotoxicitya

W2 clone b

IC50 (µg/mL)

IC50 (µM)

SI

4.76 ± 0.00 4.20 ± 0.89 3.20 ± 0.21 4.76 ± 0.00 3.15 ± 0.21 3.23 ± 0.77 0.01 ± 0.00 0.01 ± 0.00 NT

7.90 ± 0.00 6.97 ± 1.48 5.31 ± 0.35 11.40 ± 0.00 7.42 ± 0.49 7.88 ± 1.88 0.02 ± 0.01 0.03 ± 0.01 NT

> 1.0 > 1.1 > 1.5 > 1.0 > 1.5 > 1.0 > 23.8 > 23.8

b

IC50 (µg/mL)

IC50 (µM)

SI

4.50 ± 0.32 4.76 ± 0.00 3.20 ± 0.00 4.18 ± 0.82 2.00 ± 0.28 2.52 ± 0.99 0.01 ± 0.01 0.13 ± 0.02 NT

7.47 ± 0.54 7.90 ± 0.00 5.31 ± 0.00 10.20 ± 2.00 4.71 ± 0.67 6.15 ± 2.41 0.02 ± 0.02 0.24 ± 0.04 NT

> 1.1 > 1.0 > 1.5 > 1.1 > 2.5 > 1.6 > 23.8 > 1.8

IC50 (µg/mL) NC NC NC NC NC NC NC* NC* >5

Vero cells; b selectivity index (SI) = IC50 Vero cells/IC50 P. falciparum. NC = No cytotoxicity up to a concentration of 4.76 µg/mL; NC* = no cytotoxicity up to a concentration of

0.238 µg/mL; NT = not tested

plasmodial activity in a primary screening against the chloroquine-sensitive strain of P. falciparum (D6). The extract of G. mangostana inhibited the growth of P. falciparum by 89% as measured by the plasmodial lactate dehydrogenase (pLDH) activity assay. The extract of G. xanthochymus showed 24 % inhibition of growth, while both G. livingstonei and G. spicata did not exhibit any activity. The extracts of G. xanthochymus and G. mangostana were not cytotoxic towards Vero cells. The ethanolic extract of G. xanthochymus seeds and its hexanes, EtOAc, and n-BuOH partitions were also screened against the chloroquine-sensitive strain of P. falciparum (D6). The hexanes partition inhibited the growth of the parasite by 58%, while the EtOAc and n-BuOH partitions showed no inhibitory activity. Garcinia xanthochymus was prioritized for further study due to avail-

ability and activity. Open column chromatography and fractionation of the crude methanol extract and hexanes partition of G. xanthochymus was used to purify benzophenones, xanthones, and biflavonoids. The resulting work led to a small library of isolated benzophenone and xanthone compounds which was then subjected to further investigation of their antimalarial activity. The antiplasmodial activity of benzophenone compounds 1–9 " Fig. 1) was evaluated against both chloroquine-sensitive (D6) (l and chloroquine-resistant (W2) strains of P. falciparum. Of these compounds, guttiferone E (4), isoxanthochymol (5), and guttifer" Table 1). The one H (6) showed activity against both strains (l IC50 values for these three benzophenones ranged from 5.31– 7.90 µM, with guttiferone H (6) showing the highest activity. None of these compounds showed cytotoxicity towards Vero

Lyles JT et al. In Vitro Antiplasmodial …

Planta Med 2014; 80: 676–681

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Fig. 1 Chemical structures of the benzophenones (1–9) and xanthones (10–18) used in this study.

Original Papers

cells. The antiplasmodial activity of compounds 4 and 6 has not been previously reported. This is the first report of compound 5 having antiplasmodial activity against both D6 and W2 clones. Previous studies have reported antiplasmodial activity for benzophenone 3 against a chloroquine-resistant strain of P. falciparum [18] and compound 5 against the drug sensitive P. falciparum isolate NF54 [20]. " Fig. 1) were tested for antiplasmodial activXanthones 10–18 (l ity, with α-mangostin (15), β-mangostin (16), and 3-isomangostin (17) showing activity against both P. falciparum clones D6 " Table 1). The IC and W2 (l 50 values for these three xanthones ranged from 6.15–11.40 µM, with β-mangostin showing the highest activity. None of these compounds showed cytotoxicity towards Vero cells. Neither 15 nor 16 have been previously screened against the P. falciparum clone D6, and this is the first report of antimalarial activity for 17. Previous studies have shown 15 to be active against various nonresistant and drug-resistant clones of P. falciparum [13, 21] and compound 16 against the drug-resistant P. falciparum clones K1 and W2 [22, 23].

Discussion !

A group of structurally similar benzophenones were screened for " Table 1). Structure-activity relationantiplasmodial activity (l ships regarding the 3-(3,4-dihydroxybenzoyl)-4-hydroxy-8,8-dimethyl-1,7-bis(3-methyl-2-buten-1-yl)bicyclo[3.3.1]non-3-ene2,9-dione benzophenone skeleton and various side chains were examined. Regarding the effect of functional groups on the benzophenone C-8 side chain, the activities of compounds 4 and 5 in comparison with their respective inactive isomers 7 and 8 suggest the influence of isoprenylation on antiplasmodial activity by the presence of a dimethylallyl chain at the C-30 position. Nevertheless, compound 6 with a terminal methylene on C-35 on the base skeleton shows activity against both the D6 and W2 clones. This finding indicates that both the presence and position of the terminal methylene group impacts antiplasmodial activity of benzophenones. In reviewing the effect of a geminal dimethyl group on C-5 or the presence of hydroxyl groups on C-13 and C14 of the benzophenone skeleton, it was observed that these functional groups were not correlated to inhibition of either the D6 or W2 clones, thus they are not likely to be involved in the antiplasmodial activity of benzophenones. Regarding the structure-activity relationships of the xanthones, the substitution pattern of both the A and B rings was shown to be important in determining the extent of antiplasmodial activity. An isopentenyl chain was necessary on C-8 for antiplasmodial activity as evidenced by the activity of compounds 15, 16, and 17. These results reveal that antiplasmodial activity is conferred by additional factors other than the hydroxylation of C-4 and C-5 alone as other structure-activity studies have indicated [24]. Other work on synthetic analogues of compound 15 has suggested that a C-3 hydroxyl (15) or a C-2 prenyl side-chain (15 and 16) enhances the antiplasmodial activity of the basic xanthone skeleton [13]. The present results suggest a more complex mechanism of action than that previously proposed using xanthone binding interaction experiments [24]. The structural similarity of compound 14 with 15, 16, and 17 indicates that the substitution patterns on both the A and B rings influence the antiplasmodial activity of the compound. The lack of an isoprenyl chain at C-8 on 14, when compared with 15, 16, and 17, suggests the importance of this isoprenyl group and is

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Planta Med 2014; 80: 676–681

supported by a previous study on prenylated xanthones from Pentadesma butyracea (Clusiaceae) [23]. While both 15 and 17 showed activities against the D6 and W2 clones, 17 with the cyclization between C-2 and C-3 had a lower IC50 against both clones. The “xanthone hypothesis” emphasizes the requirement of hydroxyl groups at C-4 and C-5 for antiplasmodial activity [25], which is supported by a spectroscopic study of the binding between 4,5-dihydroxyxanthone and heme that led to stabilization of the hematin µ-oxo-dimer [24]. However, the results presented here indicate that other positions, mainly C-8, and the presence of isoprenyl groups also affect the activity of xanthones against P. falciparum. Studies have established xanthones as effective antimalarials and proposed several mechanisms of action [26]. The “xanthone hypothesis” was proposed as a means whereby a xanthone precursor and a prooxidant in the parasiteʼs digestive vacuole creates an environment suitable for the production of xanthones which subsequently act as the antimalarial compounds [25]. The antimalarial function of xanthones may also be due to a mechanism similar to chloroquine and related quinoline drugs [27]. The stabilization of hematin in its hematin µ-oxo-dimer form prevents the parasite from sequestering it as a non-toxic hemozin crystal leading to the parasiteʼs death [28]. Research has shown that this is one mechanism of action for quinoline and artemisinin derivative drugs [29, 30]. Spectroscopic, structure-activity studies, receptor binding studies, and electronic profiles have indicated that xanthones bind heme, preventing its aggregation into hematin both in vitro and in vivo and thus act as antiplasmodial compounds [26, 27]. Additionally, surveys of the P. falciparum genome revealed the absence of protein geranylgeranyltransferase-I (PGGT-1) [31], and thus the requirement for post-translational prenylation of several GTPase signaling molecules by protein farnesyl transferase (PFT). Since PFT activity is present in all stages of the parasiteʼs life cycle and its inhibition is not toxic to mammalian cells it is an excellent antiplasmodial target [31, 32]. Benzophenone and synthesized benzophenone derivatives have shown PFT inhibitory activity both in vitro and in vivo [33, 34]. The identification of antiplasmodial xanthone and benzephenone compounds in pulp, rind, and seeds of edible Garcinia species provides further support for their reported activity. While none of the benzophenones found in G. xanthochymus, 4, 5, or 6, nor the xanthones found in G. mangostana, 15, 16, and 17 showed strong antiplasmodial activity, they could still be used in chemotherapy as there are multiple lines of evidence for their bioavailability. For example, after the consumption of a xanthone-rich G. mangostana rind product an increase in the blood serum levels of 15 was identified via LC‑MS and remained elevated for 6 hours [35]. Other research has shown that the benzophenone 4,4′-dihydroxybenzophenone-2,4-dinitrophenylhydrazone was orally bioavailable in rats and monkeys as part of preclinical cancer trials [36] and the common sunscreen component, benzophenone3, is applied topically and its metabolite is detected in urine samples [37]. Based on these previous studies, the benzophenones 4, 5, and 6, as well as, xanthones 15, 16, and 17 are likely bioavailable. Further research is necessary to determine the absorption rate of these compounds and their metabolites. Since all species of Plasmodium have a quiescent developmental stage in the liver, this is an ideal target for prophylactic treatment and a diet including Garcinia benzophenones and/or xanthones consumed during or prior to this stage of the infection could reduce the duration and severity of the disease. Even if the treatment does not entirely

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678

Original Papers

Materials and Methods !

Plant material Whole fruits of G. livingstonei were collected at The Kampong of the National Tropical Botanical Garden (Coconut Grove, FL, USA), G. spicata fruits (Lot #1320) were collected from the Rare Fruit and Vegetable Council of Broward County (Southwest Ranches, FL, USA), and G. xanthochymus fruits were collected at The Fruit and Spice Park (Homestead, FL, USA). All fruits were collected and shipped in dry ice via overnight carrier. G. mangostana fruits were imported from Thailand and purchased from a local vendor (NY, USA). All fresh plant material was weighed, catalogued, and stored at − 20 °C until extracted. G. xanthochymus was identified by Chris Rollins (The Fruit and Spice Park), G. spicata by Margaret Basile (Rare Fruit and Vegetable Council of Broward County), G. livingstonei by Larry Shockman (The Kampong) and G. mangostana was identified by Edward Kennelly (Lehman College). Voucher specimens for G. xanthochymus (Kennelly 4006), G. livingstonei (Kennelly 4010), and G. spicata (Kennelly 4067) were deposited at The New York Botanical Gardenʼs William and Lynda Steere Herbarium (NY, USA).

Extraction G. mangostana, G. xanthochymus, G. livingstonei, and G. spicata fruits were washed and then deseeded. The fruit pulp and skin were homogenized with MeOH and then extracted for one hour at room temperature. The resulting crude MeOH extracts were filtered, concentrated in vacuo at 35–40 °C and then screened for antiplasmodial activity. A large-scale extraction of G. xanthochymus seeds was performed by Naturex. The seeds were pulverized then homogenized with 80 % aqueous EtOH. This crude extract was dried to 66.36 % solids in vacuo at temperatures not exceeding 40 °C. An aliquot of the resulting semi-dry seed extract was redissolved into 8 : 2 MeOH : H2O, filtered, and partitioned using hexanes, EtOAc, and n-BuOH (Fig. 1S, Supporting Information). The resulting partitions were evaporated to dryness in vacuo and then screened for antiplasmodial activity.

Isolation of compounds Several compounds were purified and isolated from available plant material for use during this research (Figs. 2S–6S, Supporting Information). Aristophenone A, cycloxanthochymol, gambogenone A, guttiferone E, guttiferone H, isoxanthochymol, xanthochymol, and alloathyriol as well as the biflavonoids and their glycosides, amentoflavone, fukugetin, fukugiside, and volkensiflavone were isolated from G. xanthochymus fruit pulp by open column chromatography [39]. Open column chromatography was done over the size-exclusion matrix, Sephadex LH-20, and eluted with MeOH. The resulting fractions were dried in vacuo at 35– 40 °C. Guttiferone A was isolated from G. livingstonei fruit pulp after repeated open column chromatography, followed by preparative RP HPLC [40]. The benzophenone 32-hydroxy-ent-guttiferone M was isolated from Rheedia edulis (Clusiaceae) seeds by open column chromatography and preparative RP HPLC [41]. Mangiferin was precipitated and isolated from a MeOH leaf extract of Phaleria nisidai (Thymelaeaceae) [42]. Purified standards were used to verify the identity of isolated compounds via HPLC spiking experiments. Several standards were purchased for use in this research; 8-desoxygartanin, α-mangostin, β-mangostin, and 3-isomangostin were obtained from Chromadex, 4-methoxyxanthone from Sigma-Aldrich, and 1,5,6-trihydroxyxanthone from Quality Phytochemicals LLC. The purity of purchased standards was verified via RP HPLC‑PDA and by comparison of LC‑MS data with published values. The chromatograms are included in the Supporting Information.

Instrumentation HPLC analyses of samples were performed on a Waters 2695 equipped with a Waters 2996 PDA and monitored using Waters Empower 2 software. Either a Phenomenex Nucleosil RP C18 column (250 × 4.6 mm, 5 µM) or a Phenomenex Synergi Hydro RP C18 (250 × 4.6 mm, 4 µM) column was used. The HPLC samples were prepared in HPLC grade MeOH and passed through Phenomenex 15 mm 0.45 µm PVDF syringe filters. HPLC analyses employed an optimized gradient profile using 10 mM ammonium acetate (solvent A) and MeCN (solvent B) as follows: 0– 4 min, 90 % A; 4–34 min, 90–0 % A; 34–44 min, 0 % A; 44–54 min, 65 % A. Mass spectra were obtained using a Waters LCT Premier XE Time of Flight (ToF) mass spectrometer (Waters MS Technologies). Ionization was achieved using an EScI source at the following conditions: +ESI capillary 3000 V, cone: 20 V, aperture 1: 0 V, ion guide 1: 0 V, multichannel plate: 2600 V. Nitrogen was used with a cone gas flow of 20 L/h, and desolvation gas flow of 600 L/ h at 400 °C. The source temperature was 120 °C. Leucine-enkephaline was the reference mass infused by a secondary probe and scanned once every five scans. Positive ESI data was collected using a scan time of 0.5 s, with an interscan time of 0.02 s. MS data was collected and analyzed in centroid mode using the program MassLynx V4.1 Scn 727.

Antiplasmodial assay Antimalarial activity was determined by measuring pLDH [43]. For the assay, a suspension of red blood cells infected with D6 or W2 strains of P. falciparum (200 µL, with 2% parasitemia and 2 % hematocrit in RPMI 1640 medium supplemented with 10% human serum and 60 µg/mL Amikacin) was added to duplicate wells of a 96-well plate containing 10 µL of serially diluted test samples (plant extracts, column fractions, or pure compounds). The plate was flushed with a gas mixture of 90 % N2, 5 % O2, and 5 % CO2, subsequently placed in a modular incubation chamber Lyles JT et al. In Vitro Antiplasmodial …

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prevent the infection, a reduction in the parasite load in the liver has been shown to reduce the severity of the overall infection, in turn, leading to a lower mortality and a faster recovery [38]. Fruits and vegetables represent promising sources of chemopreventive compounds for many diseases since they are renewable and can be inexpensive. Disease resistance and prevention in low-income areas with limited access to commercial medicines make the nutritional chemoprevention of malaria most potentially beneficial in areas with the greatest impact of the disease. This work focused on benzophenone and xanthone compounds found in G. xanthochymus and G. mangostana, which are consumed throughout their distribution ranges and exported in a variety of products. As much of the tropical and subtropical parts of the world susceptible to malaria are also areas fit for cultivation of Garcinia, there may be a potential to use such fruits as sources of antiplasmodial and chemopreventive compounds. Further investigation is warranted to identify other antiplasmodial constituents in Garcinia fruits, to better understand their mechanisms of bioactivity, determine cytotoxicity, and evaluate the in vivo activity of benzophenones and xanthones.

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(Billups-Rothenberg) and incubated for 72 h at 37 °C. Twenty microliters of the incubation mixture was mixed with 100 µL of the Malstat™ reagent (Flow Inc.) and incubated at room temperature for 30 min followed by the addition of 20 µL of a 1 : 1 mixture of nitroblue tetrazolium salt and phenazine ethosulfate (NBT/PES; Sigma) and incubation in the dark for 1 h. The reaction was then stopped by the addition of 100 µL of 5% acetic acid solution (v/v), at which point the plate was read at 650 nm. Percent growth inhibition was calculated compared to vehicle control, and IC50 values were computed from the dose-response curves. Artemisinin and chloroquine were included in each assay as the drug controls. These compounds were purchased from Sigma-Aldrich and are > 98% pure.

Cytotoxicity assay To determine the selectivity index of antimalarial activity of the samples in vitro, cytotoxicity to mammalian (Vero) cells was also determined. The assay was performed in 96-well tissue culturetreated plates as described earlier [44]. Vero cells were seeded to the wells of 96-well plate at a density of 25 000 cells/well and incubated for 24 h. Samples at different concentrations were added, and plates were again incubated for 48 h. The number of viable cells was determined by neutral red assay, and percent growth inhibition was calculated. IC50 values were obtained from doseresponse curves. Doxorubicin was used as a positive control.

Acknowledgements !

The authors would like to thank Chris Rollins from the Fruit and Spice Park (Homestead, FL) for providing samples used in this research and Margaret J. Basile for her help in collecting plant material.

Conflict of Interest !

The authors declare no conflict of interest.

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In vitro antiplasmodial activity of benzophenones and xanthones from edible fruits of Garcinia species.

Species of Garcinia have been used to combat malaria in traditional African and Asian medicines, including Ayurveda. In the current study, we have ide...
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