Marchantin A, a macrocyclic bisbibenzyl ether, isolated from the liverwort Marchantia polymorpha, inhibits protozoal growth in vitro.
In vitro anti-plasmodial activity-guided fractionation of a diethyl ether extract of the liverwort species Marchantia polymorpha, collected in Iceland, led to isolation of the bisbibenzyl ether, marchantin A. The structure of marchantin A (1) was confirmed by NMR and HREIMS. Marchantin A inhibited proliferation of the Plasmodium falciparum strains, NF54 ([IC.sub.50] = 3.41 [micro]M) and K1 ([IC.sub.50] = 2.02 [micro]M) and showed activity against other protozoan species Trypanosoma brucei rhodesiense, T. cruzi and Leishmania donovani with IC50 values 2.09, 14.90 and 1.59 [micro]M, respectively. Marchantin A was tested against three recombinant enzymes (PfFabI, PfFabG and PfrabZ) of the PfFAS-II pathway of P. falciparum for malaria prophylactic potential and showed moderate inhibitory activity against PfFabZ ([IC.sub.50] = 18.18 [micro]M). In addition the cytotoxic effect of marchantin A was evaluated. This is the first report describing the inhibitory effects of the liverwort metabolite rnarchantin A against these parasites in vitro.
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Diseases caused by unicellular protozoal parasites are a major public health concern for about one billion people worldwide, particularly in tropical countries. Trypanosoma (African sleeping sickness and Chagas disease), Leishmania (leishmaniasis) and Plasmodium (malaria) are genera responsible for considerable medical morbidity and, in the case of malaria, high mortality (Astelbauer and Walochnik 2011; Fidalgo and Gille 2011). Despite years of effort to eradicate these diseases, the treatment options today are few, costly or with adverse effects and in addition parasite resistance against the limited number of drugs available is increasing. With the absence of functional, safe and widely available vaccines (Fidalgo and Gille 2011; Kaye and Aebischer 2011; The RTS 2011), the adequate treatment of these infections is becoming increasingly difficult. This underlines the importance and urgent need to discover new and effective drug candidates and identify novel potential chemotherapeutic targets (Astelbauer and Walochnik 2011; Pradines et al. 2002). The FAS-II pathway of P. falciparum has become an interesting target for malaria prophylaxis, as it is crucial for the liver stage, the first of the two infection stages in human host, of malaria parasites. Deletion or inhibition of critical FAS-II elongation enzymes such as PfFabl (enoyl-ACP reductase), PfFabZ ([beta]-hydroxyacyl-ACP dehydratase) and pfFabG ([beta]-ketoacyl-ACP reductase) prevents the proceeding of the subsequent blood stage infection, thus the clinical symptoms of the disease (Min et al. 2008; Vaughan et al. 2009).
Despite a decline of natural products research in pharmaceutical industry during the past several years, a vast majority of the existing chemotherapeutic agents, particularly those used in the control of malaria, are still based on natural product scaffolds. Hence the identification of natural product leads from diverse natural sources will critically augment the search in anti-parasitic drug discovery (Bero and Quetin-Leclercq 2011; Li and Vederas 2009; Newman and Cragg 2012).
Liverworts are primitive terrestrial plants that grow worldwide. They contain cellular membrane-bound oil bodies which elaborate mainly ethereal terpenoids and lipophilic aromatics, as their major chemical constituents. Several biological activities are triggered from these secondary metabolites and various liverwort species have been used in traditional oriental medicine, generally to treat various topical disorders and bacterial infections (Asakawa 2001; Asakawa et al. 2009; Huang et al. 2010). Macrocyclic bisbibenzyls are a family of phenolic compounds belonging to the stilbenoids. They are produced exclusively in liverworts and are attracting increasing attention due to their broad range of interesting pharmacological activities (Asakawa et at. 2009).
Marchantia polymorpha L. (Marchantiaceae) is a common thallus liverwort species known to produce a wide array of distinctive compounds and several bisbibenzyls, including marchantin A (1, Fig. 1). Marchantin A has been found to possess diverse biological and pharmacological activities i.e. anti-bacterial, anti-tumour and antileukaemia, anti-oxidant, 5-LOX-, COX- and calmodulin-inhibitory activity (Asakawa et al. 2009; Huang et al. 2010; Iwai et al. 2011; Keser and Nogradi 1995; Schwartner et al. 1995). M. polyrnor-pha therefore represented an interesting candidate in a random screening for anti-plasmodial activity of Icelandic lower plants. This liverwort thrives in moist and enclolithic areas of Iceland and although it is widely distributed and easily accessible (Johannsson 2002), no records of traditional uses in Iceland were found. In the present study, the in vitro effects of marchantin A were evaluated against four parasitic protozoa and against three different enzymes (PfFabl, PfFabG and PlFabZ) involved in the FAS-II pathway of P. fal-ciparuni. The cytotoxicity against primary mammalian L6 cells was also determined and compared to the corresponding anti-parasitic activities.
Materials and methods
General experimental procedures
Analytical grade solvents for extraction and HPLC grade solvents for chromatography were purchased from Sigma-Aldrich (St. Louis, MO, USA). HPLC grade water was obtained by a Millipore Milli-Q Academic water purification system. 1D and 2D NMR spectra using CDCI3 as a solvent were recorded on a Bruker 400 spectrometer (5 mm BB-1HID probe-head) at 25 C, using TMS as an internal standard. HREIMS analysis was performed on an Agilent 1100 system (Supplementary data, Si). Silica gel 60H (Merck) was used for VLC and silica gel 60 F254 (Merck) was used for TLC. Further purification was performed by preparative HPLC (Dionex 3000 Ultimate; pump, UV-VIS detector).
The whole plant of Marchantia polymorpha L. (Marchantiaceae) WS collected in July 2007 in Thverdalur in Adalvik (N66 20.32 W23 03.37), in North-Western Iceland and in September 2009 in mountain Esja close to Reykjavik (N64 12.64 W21 42.81), in South-Western Iceland. The liverwort was identified by biologist Groa Ingimundardottir at the Icelandic Institute of Natural History, and botanist Agust H. Bjarnason. Voucher speciemens (ICEL, catalogue nr. BR-44839 and BR-45237) are deposited at the Icelandic Institute of Natural History, Reykjavik, Iceland. The extracts of the plants from the two collection sites showed uniform chemical contents according to TLC and were pooled.
Extraction and isolation of marchantin A
The air-dried and powdered liverwort material (300g) was extracted with diethyl ether for one week to obtain a crude extract (7.9g). The extract was fractionated by VLC on silica gel with an n-hexane-Et0Ac gradient (100:0 to 0:100, followed by pure Me0H) to yield twenty-three 250 ml fractions. Fraction 15 (70:30, 0.5g) was partitioned by liquid-liquid extraction using petroleum ether and 80% aqueous methanol to obtain two fractions (Mp-15-MH and Mp-15-P). The more active fraction, Mp-15-MH, was purified by preparative HPLC (C-18 column, 250 mm x 21.1 mm, 5 [micro]m, Phe-nomenex Luna), eluting with MeCN-[H.sub.2]0 (50:50), a now rate of 10 ml/min, detection at 210 and 254 nm at room temperature. The active component ([t.sub.R] = 38 min) was identified as the known compound, marchantin A (1). Purity of marchantin A was analysed by analytical HPLC on a RP column (G.L Sciences, Inc., Herbal medicine, C-18, 4.6 mm x 250 min), a solvent system of MeOH: [H.sub.2]0 (70:30), flow rate of 1 ml/mm, UV-detection at 210 nm at 25 C and injection volume 10 [micro]l.
In vitro P. falciparum assays
Anti-plasmodial activity of M. polymorpha extract and fractions was determined against erythrocytic stages of chloroquine-sensitive 3D7 strain of P. falciparum (Ziegler et al. 2002) whereas in vitro activity of marchantin A against erythrocytic stages of P. falciparum was determined by a modified [3H ]-hypoxa nthine incorporation assay (Scala et al. 2010) using the chloroquine sensitive strain NF54 and the chloroquine- and pyrimethamine-resistant strain k1. The standard drug used as a positive control was chloro-quine.
Anti-protozoal activity assays
All cells were cultured on 96-well micro-titre plates and incubated at 37 [degrees]C under a 5% [CO.sub.2] atmosphere. The parasites tested were Trypanosoma brucei rhodesiense STIB 900 strain, Trypanosoma cruzi Tulahuen strain C2C4 containing the [beta]-galactosidase (Lac Z) gene and Leishmania donovani strain MHOMJET/67/L82. Bioassays were run as described by Scala et al. (20W). Experiments included untreated controls, serial compound dilutions covering a range from 90 to 0.123 [micro]g/ml and positive control drugs melarsoprol, benznidazole and miltefosine respectively. The [IC.sub.50] values were calculated from sigmoidal inhibition dose-response curves and each [IC.sub.50] value obtained is the mean of at least two separate experiments performed in duplicate (the variation is maximum 20%).
Cytotoxicity against L6-cells
The cytotoxicity assay was performed as described (Scala et al. 2010). Briefly, L-6 cells (a primary cell line derived from rat skeletal myoblasts) were incubated on 96-well micro-titre plates for 72 h with drug dilutions ranging from 90 to 0.123 [micro]g/ml The cell viability was assessed by resazurin staining and absorbance was read with a Spectramax Gemini XS microplate fluorometer using wavelengths 536 and 588 nm. Data were analysed using the microplate reader software Softmax Pro. Each CC50 value obtained is the mean of at least two separate experiments performed in duplicate and the standard drug used was podophyllotoxin.
PfFAS-11 enzyme inhibition assays
Expression and purification of the PfFab enzymes as well as the inhibition assays were performed as described (Tasdemir et al. 2006b). The enzyme inhibition was monitored using a Pericin Elmer Lambda 25 UV/VIS spectrophotometer. Marchantin A was dissolved in DMSO and a dilution series of 10-0.001 mg/m1 of the dissolved compound was measured. Triclosan and (-)-epigallocatechin gallate (EGCG) were used as reference standards and were analysed in the same way. IC50 values were estimated from graphically plotted dose-response curves. Each IC50 value obtained is the mean of at least two separate experiments performed in duplicate.
Results and discussion
The liverworts are a great source of exclusive biologically active secondary metabolites which could prove interesting in antiparasitic drug research, especially given the recognised biocidal and insecticidal activity of many liverwort extracts (Saxena and Harinder 2004). As part of a random anti-plasmodial screening assay of Icelandic lower plants, the liverwort Marchantia poly-morpha was tested in an assay described by Ziegler et al. (2002) and showed activity against Plasmodium falciparum strain 3D7 ([IC.sub.50] = 18 [micro]g/m1). A diethyl ether extract of M. polymorpha was prepared according to Asakawa et al. (1983) and fractionated with increasing polarity by vacuum liquid chromatography (VLC), to yield 23 fractions. The most active fraction (#15, 70:30) was subjected to solvent-solvent partition between petroleum ether and aqueous Me0H. The aqueous methanol fraction (Mp-15-MH) showed activity with IC50 less than 12.5 [micro]g/ml. Further purification of fraction Mp-15-MH by preparative HPLC on a reversed-phase column afforded the bioactive compound marchantin A ([C.sub.28][H.sub.24][O.sub.5], [[M+H].sup.+] at m/z 441.1689, Supplementary data, Si). The structure of marchantin A was confirmed by 1H and 13C NMR spectroscopy (Supplementary data, S2) and reference chemical shifts (Asakawa et al. 2000; Kodama et al. 1988). The purity was determined to be >96% according to the relative peak area on HPLC (Supplementary data, S3).
Marchantin A exhibited activity against two erythrocytic stage strains of Plasmodium falciparum, chloroquine-sensitive NF54 strain ([IC.sub.50] = 3.41 [micro]M) and chloroquine- and pyrimethamine-resistant K1 strain ([IC.sub.50] = 2.02 [micro]M). In the development of new anti-malarial strategies and chemotherapies two approaches is currently being pursued to limit the emergence and spreading of drug resistant parasites. The first is the discovery or development of novel compounds targeting new chemotherapeutic targets and second is to reverse or evade drug resistance by combined chemotherapy (Pradines et al. 2002; Zishiri etal. 2011). Recently published results on the cytotoxic effects of marchantin A against breast cancer cells in vitro, describe the synergism of this compound in combination with compounds addressing different targets in these cells (Jensen et al. 2012). Accordingly, although the mechanism of action in the parasites is not known, marchantin A and derivatives could be considered as candidates for studies on synergistic effects in drug resistant malaria parasites. The anti-plasmodial activity of marchantin A is to our knowledge for the first time described here.
The species selectivity of marchantin A was also evaluated in vitro against the mammalian stages of three parasitic protozoa; Trypanosoma brucei rhodesiense (bloodstream forms, [IC.sub.50] = 2.09 [micro]M), T. cruzi (intracellular amastigotes in L6 rat skeletal myoblasts, [IC.sub.50] = 14.90 [micro]M) and Leishmania donovani (axenic amastigotes, [IC.sub.50] = 1.59 [micro]M). The least susceptibility was observed against T. cruzi (Table 1). These results are in accordance with a recent report on remarkable anti-trypanosomal activity of marchantin A against the cattle pathogen T. brucei brucei, with an [IC.sub.50] of 0.27 [micro]g/ml (0.61 [micro]M) (Otoguro et al. 2011). Besides marchantin A, the same authors tested several other bisbibenzyl compounds against this parasite and evaluated their selectivity. The results show that most of the bisbibenzyl derivatives strongly inhibit T. brucei brucei. Although the selectivity index (SI) is relatively low, small structural changes appear to increase the anti-trypanocidal activity considerably (Otoguro et al. 2011), which encourages the search for favourable analogues for anti-parasitic drug candidates against these devastating diseases. To our knowledge this is the first report of inhibiting activity of marchantin A against human pathogens T. brucei rhodesiense and T. cruzi, as well as Leishmania don ovani.
Table 1 In vitro anti-protozoal and cytotoxic effects of marchantin A (MA) and reference drugs. The [IC.sub.50] values are in [micro]M and represent the average of at least two independent experiments performed in duplicates. [IC.sub.50]-values SI (f) ([micro]M) MA Ref drug P. falciparum [3D7] 3.41 0.045 (d) 2.0 P. falciparum [K1] 2.02 0.38 (a) 3.3 T. brucei rhodesiense 2.09 0.0075 (b) 3.2 T. cruzi 14.9 1.46 (c) 0.5 L donovani 1.59 0.49 (d) 4.2 [CC.sub.50] L6-cells 6.64 0.019 (e) Reference drugs: (a.) Chloroquine. (b.) Melarsoprol. (c.) Benznidazole. (d.) Miltefosine. (e.) Podophyllotoxin. (f.) SI = selectivity index ([CC.sub.50]/[IC.sub.50]) for marchantin A.
In addition the malaria prophylactic potential of marchantin A was evaluated against three key elongation enzymes involved in the fatty acid biosynthesis pathway (FAS-II) of P. falciparum. Marchantin A did not inhibit the reductases Pffabl (enoyl-ACP reductase) or PfFabG ([brta]-ketoacyl-ACP reductase) enzymes ([IC.sub.50] values > 100 [micro]M). However, a moderate activity ([IC.sub.50] = 18.18 [micro]M) was observed against the dehydratase type enzyme, PfFabZ ([brta]-hydroxyacyl-ACP dehydratase, Table 2). Other polyphenolic compounds, mainly of a flavonoid nature, have been studied for their anti-protozoal activities and for their potential to inhibit FAS-II enzymes of P. falciparum (Maity et al. 2011; Tasdemir et al. 2006a,b). Docking studies using a PjFabZ model indicate that these flavonoids, including the positive reference drug (-)-EGCG, bind differently to PfrabZ in comparison to small molecule inhibitors. Due to their large size they cannot enter the narrow active site tunnel of the enzyme (Fig. 2a), but instead they seem to block the entrance of the tunnel and inhibit the substrate from reaching the active site (Maity et al. 2011). With respect to the bulky structure of marchantin A in comparison to other polyphenolic compounds discussed (Fig. 2b and c) it could be expected to act in this non-direct inhibitory manner by blocking the entrance rather than entering the active site tunnel of PfFabZ.
Table 2 In vitro inhibition of P.falciparum FAS-Il enzymes FabZ, Fahi and FabG by marchantin A (MA). The [IC.sub.50] values are in [mu]M and represent the average of at least two independent experiments performed in duplicates. Enzyme [IC.sub.50]-values ([mu]M) MA Ref. drug PfFabZ 18.18 0.07 (a) PfFabG >100 0.44 (a) PfFabI >100 0.05 (b) Reference drugs: (a.) (-)-EGCG. (b.) Triclosan.
Marchantin A exerted inhibitory activity against several different protozoan species; but also showed some cytotoxicity against primary L6 rat cells with a [CC.sub.50] value of 6.64 [micro]M. These results show that marchantin A has a low selectivity index (SI) in the range of 2-4 with respect to the tested parasites (Table 1) and consequently indicates a rather narrow therapeutic window. In comparison, the reported SI values for marchantin A (1) and the similar bisbibenzyl marchantin C (2), assessed against the MRC-5 human cells and Ttypanosoma brucei brucei are 13 and 3, respectively (Otoguro et at. 2011). Thus, marchantin C has a relatively low SI for Trypanosoma brucei brucei, which is similar to the SI values obtained for marchantin A in the present study using different parasites and L6 rat cells. In spite of this low St in vitro, marchantin C (2) has been shown to cause low toxicity in vivo (Shi et at. 2009). This demonstrates the importance to consider the influence of structural differences, species and cell types on selectivity and promote continued investigation of bisbibenzyls and their analogues as drug candidates for parasitic infections. The cytotoxicity of marchantin A against cancer cells is known (Huang et al. 2010; Jensen et al. 2012; Keser and Nogradi 1995) and its microtubule depolymerising effect has been established (Gao et al. 2009; Jensen et at. 2012). Compounds that interfere with microtubule dynamics are currently among the most effective drugs to treat many different medical conditions such as cancer, gout and helminth infections (Desta et al. 2011). In a recent report (Desta et at. 2011), the tubulin depolymerising anti-cancer compound combretastatin A-4 (3) and its derivatives were tested for their anti-protozoal activity. Some of the analogues demonstrated low cytotoxicity against mammalian cells and good potency against the parasites (Desta et al. 2011). The bisbibenzyl marchantin A (1) and the bibenzyl combretastatin A-4 (3) are structurally related (Fig. 1) and both belong to the stilbenoids. Considering the similarities and differences of these two molecules the degree of cyclisation of the bibenzyl skeleton as well as the substitution pattern of the hydroxy- and methoxy groups may play an important role in the mechanism involved in their microtubule depolymerising activity and influence the cytotoxic and anti-protozoal potential. These structural characteristics were also pointed out as key factors for the anti-oxidant and anti-inflammatory properties determined for several marchantins and related compounds in earlier structure-activity relationship studies (Panossian et al. 1996; Schwartner et al. 1995).
Although the exact mechanism of action for the parasitocidal effect of marchantin A observed in this study is unclear, it can be suggested that it might target the parasites through two different pathways. That is by binding tubulin and causing microtubule depolymerisation in the blood stages of the parasites, and in the specific case of P. falciparum by inhibiting the FAS-II pathway in the liver stage. In addition the previously described anti-oxidant activity could be considered to be involved (Panossian et al. 1996; Schwartner et al. 1995). Consequently, marchantin A (1) is certainly worthy of further evaluation for its anti-parasitic activity and potential in malaria prophylaxis.
The marchantins represent an interesting class of secondary liverwort metabolites. Based on the results obtained for marchantin A, they potentially constitute an interesting chemical scaffold for further investigation and development to improve the selectivity and activity against protozoa and against enzymes of the P. falci-parum FAS-II pathway. The potential of these compounds as potent lead candidates will therefore depend on the success to design derivatives with increased affinity, selectivity and a favourable pharmacokinetic profile.
HPLC-HREIMS, H and 13C NMR spectra of marchantin A (1), analytical HPLC chromatogram of marchantin A.
Conflict of interest
None of the authors have financial relationship with a commercial entity that has an interest in the content of this study.
The authors are grateful to Sigridur Jonsdottir, Science Institute, University of Iceland, for recording the NMR spectra, Dr. Nils Nyberg and Dorte Brix, Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, for HREIMS and anti-plasmodial measurements. Financial support by The Icelandic Research Fund, The University of Iceland Research Fund--Doctoral grant, Bergthora and Thorsteinn Scheving Thorsteinsson Fund are gratefully acknowledged. Angela Gono Bwalya thanks the Commonwealth Scholarship Commission for financial support.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.phymed.2012.07.011.
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Abbreviations: VLC, vacuum liquid chromatography; MA, marchantin A; SI, selectivity index; EGCG, (-)-epigallocatechin gallate; HPLC, high performance liquid chromatography; HREIMS, high resolution electron ionisation mass spectrometry: 5-LOX, 5-lipoxygenase; COX, cyclooxygenase.
* Corresponding author. Tel.: +354 525 5804; fax: +354 525 4071.
E-mail address: email@example.com (E.S. Olafsdottir).
(1) Current address: School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland.
Sophie Jensen (a), Sesselja Omarsdottir (a), Angela Gono Bwalya (b), Morten Agertoug Nielsen (c), Deniz Tasdemir (b), (1), Elin Soffia Olafsdottir (a), *
(a) Faculty of Pharmaceutical Sciences, School of Health Sciences, University of Iceland, Hagi, Hofsvallagata 53, I5-107 Reykjavik, Iceland
(b) Department of Biological and Pharmaceutical Chemistry, University College of London, School of Pharmacy, London WC1N IAX, United Kingdom
(c) Department of International Health, Immunology and Microbiology, University of Copenhagen, Oster Farimagsgade 5, 1014 Copenhagen, Denmark
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|Author:||Jensen, Sophie; Omarsdottir, Sesselja; Bwalya, Angela Gono; Nielsen, Morten, Agertoug; Tasdemir, Den|
|Publication:||Phytomedicine: International Journal of Phytotherapy & Phytopharmacology|
|Date:||Oct 15, 2012|
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