Prostratin and 12-O-Tetradecanoylphorbol 13 ... - ACS Publications

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Prostratin and 12‑O‑Tetradecanoylphorbol 13-Acetate Are Potent and Selective Inhibitors of Chikungunya Virus Replication Mélanie Bourjot,† Leen Delang,‡ Van Hung Nguyen,§ Johan Neyts,‡ Françoise Guéritte,† Pieter Leyssen,‡ and Marc Litaudon*,† †

Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles (ICSN), CNRS, Labex LERMIT, 1, Avenue de la Terrasse, 91198 Gif sur Yvette Cedex, France ‡ Rega Institute for Medical Research (KULeuven), Minderbroedersstraat, B3000, Leuven, Belgium § Institute of Marine Biochemistry of the Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet Road, Cau Giay, Hanoï, Vietnam S Supporting Information *

ABSTRACT: A chemical study of the Vietnamese plant species Trigonostemon howii led to the isolation of a new tigliane-type diterpenoid, trigowiin A (1), along with several known coumarins and phenylpropanoids. The planar structure and the relative configuration of compound 1 were elucidated based on spectroscopic analysis, including 1D- and 2D-NMR experiments, mass spectrometry, and comparison with literature data. Trigowiin A (1) exhibited moderate antiviral activity in a virus-cell-based assay for Chikungunya virus (CHIKV). Since the structure of compound 1 is closely related to those of well-known tigliane diterpenoids such as prostratin (2), phorbol (3), 12-O-tetradecanoylphorbol 13-acetate (TPA) (4), and 4α-TPA (5), the antiviral activity of the latter compounds was also evaluated against CHIKV, as well as in virus-cell-based assays of two additional members of the genus Alphavirus (Sindbis virus, SINV, and Semliki forest virus, SFV). Whereas prostratin inhibited CHIKV replication with a moderate EC50 of 2.6 μM and a selectivity index (SI) approximating 30, compound 4 proved to be an extremely potent inhibitor, with an EC50 of ∼3 nM and a SI near 2000. Interestingly, no or very little activity was observed on the replication of SINV and SFV.

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selective inhibitors of CHIKV replication.4,5 Phytochemical investigation of the genus Trigonostemon was first conducted twenty years ago, resulting in the isolation of trigonostemone, a phenanthrene derivative, from T. redioides.6 Since then, approximately 80 secondary metabolites have been isolated from seven species, namely, T. cherrieri, T. chinensis, T. howii, T. lii, T. reidioides, T. thyrsoideum, and T. xyphophylloides. Many of the compounds obtained are diterpenoids possessing a daphnane skeleton with an orthoester moiety.7 This type of compound is known for antiviral activity against HIV. For example, highly oxygenated daphnane diterpenoids exhibiting potent antiviral activity against HIV-1 were isolated from T. thyrsoideum8 and also from Daphne spp.9,10

hikungunya virus (CHIKV) is an alphavirus that is transmitted to humans mainly by Aedes aegypti and A. albopictus mosquitoes. CHIKV has recently re-emerged, causing massive epidemics that have moved from Africa throughout the Indian Ocean to India and Southeast Asia.1 In 2007, the first Chikungunya virus outbreak ever occurring in a temperate area of the Northern Hemisphere was reported in Italy, and the number of infections is expected to rise in the near future.2 In humans, the virus is responsible for an acute disease, characterized by a triad of fever, arthralgia, and maculopapular rash.3 Currently, no specific antiviral therapy nor a vaccine is available for the treatment or prevention of this disease. Recently, trigocherrins A−F and trigocherriolides A−D, compounds possessing a daphnane carbon skeleton, were isolated from Trigonostemon cherrieri (Euphorbiaceae), a species originating from New Caledonia, and were shown to be © XXXX American Chemical Society and American Society of Pharmacognosy

Received: September 17, 2012

A

dx.doi.org/10.1021/np300637t | J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products

Article

groups and 1723 and 1680 cm−1 for carbonyl groups. The 1H NMR spectrum of 1 in methanol-d4 revealed the presence of five methyl signals [δH 0.89 (d, J = 6.5 Hz, H3-18), 1.13 (s, H317), 1.16 (s, H3-16), 1.75 (dd, J = 2.7, 1.3 Hz, H3-19), and 2.02 (s, H3-22)], five methine signals (two oxygenated) [δH 1.72 (d, J = 5.5 Hz, H-14), 2.23 (m, H-11), 3.05 (q, J = 2.7 Hz, H-10), 3.76 (d, J = 5.5 Hz, H-8), and 5.37 (d, J = 10.5 Hz, H-12)], one oxymethylene (δH 4.18 and 4.21, dd, J = 14.5, 1.5 Hz, H2-20), two olefin signals [δH 6.90 (t, J = 1.5 Hz, H-5) and 7.56 (d, J = 1.3 Hz, H-1)], and signals for a fatty acid moiety at δH 0.84 (3H, t, J = 7.0 Hz, H3-12′), 1.24−1.30 (16H, m, H2-4′ to H211′), 1.58 (2H, m, H2-3′), and 2.30 (2H, brt, J = 7.4 Hz, H2-2′). Considering the aforementioned data, the tigliane-type carbon skeleton nature of 1 and its relative configuration were established by comprehensive 1D- and 2D-NMR data analysis (Figure 1).

With the objective of identifying novel daphnane diterpenoids with potent and selective antiviral activity against CHIKV, the bark of Trigonostemon howii Merrill & Chun (Euphorbiaceae), collected in central Vietnam, was selected for a chemical and biological study. So far, from the twigs of another variant of this species, 13 daphnane-type diterpenoids, i.e., trigohownins A−I and trigoxyphins A and D−F, have been isolated, of which trigohownins A and D showed moderate cytotoxic activity against the human promyelocytic leukemia HL-60 cell line.11 Unexpectedly, chemical investigation of an extract of T. howii bark did not yield any daphnane diterpenoids. However, a new tigliane diterpenoid, named trigowiin A (1), was isolated instead. In addition, four coumarins (scopoletin,12 isoscopoletin,12 6-hydroxy-7,8-dimethoxycoumarin,13 and fraxinol14) and two phenylpropanoids (3,4-dimethoxycinnamyl alcohol15 and sinapaldehyde16) were obtained from an inactive fraction and identified by comparison with literature spectroscopic data. In the present paper, the isolation, characterization, and antiCHIKV activity of trigowiin A (1) are reported. Furthermore, the scope of this study was broadened by including four wellknown and structurally closely related tigliane diterpenes, i.e., prostratin (2), phorbol (3), 12-O-tetradecanoylphorbol 13acetate (TPA) (4), and 4α-12-O-tetradecanoylphorbol 13acetate (5) (4α-TPA). The range of viruses against which the antiviral activity of the compound class is studied was expanded to two additional members of the genus alphavirus (Sindbis virus:, SINV, and Semliki forest virus, SFV).

Figure 1. Selected COSY (bold), HMBC (blue arrows, left), and NOESY (red arrows, right) correlations for structural elucidation of 1.

The presence of a 2-methylcyclopentenone ring A was deduced from the CH−CHC−CH3 spin system deduced from the COSY spectrum and HMBC correlations from CH319 to C-1, C-2, and the carbonyl C-3 (δC 159.1, 137.0 and 205.8, respectively) and from H-1 to the methine C-10 and the oxy-quaternary C-4 (δC 60.5 and 74.0, respectively). The construction of ring B and the junction of rings A and B were determined from the 1H−1H COSY correlations between H220 and H-5 and HMBC correlations from H2-20 to C-5, C-6, and the carbonyl C-7 (δC 138.7, 149.8, and 202.5, respectively), from H-8 to C-7 and the oxy-quaternary C-9 (δC 77.2), and from H-5 to C-10. The dimethylcyclopropane ring fused to the cyclohexane ring C and the junction between rings B and C were deduced from the following observations: the presence of CH3−CH−CHO− and −CH−CH− spin systems observed in the COSY spectrum and HMBC correlations from the secondary CH3-18 to C-9, C-11 (δC 46.0), and C-12 (δC 78.2), from H-12 to C-11, C-13 (δC 67.4), and C-15 (δC 26.8), from H-8 to C-9, C-14 (δC 30.6), and C-15, and from CH3-16 and CH3-17 to C-13 and C-14. HMBC correlations from H-12 and CH3-22 to the carbonyl C-21 (δC 172.9) allowed the acetyl group to be located at C-13. The attachment of a fatty acid moiety at C-12, via an ester linkage, was supported by the HMBC correlation from H-12 to C-1′ (δC 173.2). Thus, the remaining hydroxy groups could be positioned at C-4, C-9, and C-20. The NMR data of 1 were closely comparable to those of another tigliane diterpene, 12-O-hexadecanoyl-7-oxo-5-enephorbol-13-acetate, isolated from the leaves of Aleurites fordii (Euphorbiaceae).17 The only noticeable structural difference between trigowiin A (1) and the aforementioned compound resulted from the length of the long carbon chains, 12 and 16 carbons, respectively, located at C-12. The relative configuration of compound 1 was deduced from NOESY correlations and comparison with data reported in the

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RESULTS AND DISCUSSION The air-dried powder of the bark of T. howii was first extracted with n-heptane and then with EtOAc to yield crude extracts after evaporation of solvent. The EtOAc extract showed antiviral activity against CHIKV with an EC50 of 8.7 μg/mL. The CHIKV-cell-based assay was used to conduct bioassayguided purification on this extract, which was subjected to silica gel column chromatography and semipreparative HPLC to yield trigowiin A (1) in a trace quantity. Compound 1 possesses the molecular formula C34H50O9, based on its deprotonated molecular ion peak at m/z 601.3372 [M − H]− obtained by HRESIMS (calcd for 601.3377), thus requiring 10 degrees of unsaturation. Its IR spectrum showed characteristics absorption bands at 3380 cm−1 for hydroxy B



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is the fourth example of a phorbol derivative possessing a 5-en7-one functionality. However, this compound could be an artifact formed by autoxidation during the isolation step, as it has been reported for some phorbol esters.19 A biogenetic scheme for this unusual tigliane carbon skeleton has been proposed by Hohmann et al.18 Trigowiin A (1) and the four coumarins and the two phenylpropanoids isolated were evaluated for antiviral activity in a CHIKV virus-cell-based assay. Only trigowiin A (1) showed weak antiviral activity against CHIKV, with an EC50 of 43.5 ± 12.8 μM. Since its structure is very similar to that of some well-known tigliane diterpenoids such prostratin (2), phorbol (3), 12-O-tetradecanoylphorbol 13-acetate (TPA) (4), and 4α-TPA (5), and taking into account that prostratin (2) is considered as a promising adjuvant for anti-HIV therapy,20 the antiviral potential of these related compounds was also evaluated on the replication of Chikungunya virus, as well as on that of two other members of the genus Alphavirus, i.e., Sindbis virus (SINV) and Semliki forest virus (SFV). In the CHIKV assay, and compared to the reference compound chloroquine, TPA (4) and prostratin (2) proved to be the most potent inhibitors, as apparent from their lower EC50 values and higher selectivity indices (SI calculated as CC50 Vero/EC50 CHIKV, a value that is representative for the window of antiviral selectivity). Furthermore, TPA (4) proved to be on average 65 times more potent than prostratin (2) (SI of 1965 and 30.3, respectively) and 1000 times more potent than its 4α-epimer (5) (SI of 1.9), while phorbol (3) was found to be completely inactive. Interestingly, none of the compounds were active against SFV, while only TPA (4) exhibited antiviral activity against SINV, although it was far less potent compared to the effect observed on the replication of CHIKV. Taking into account that the antiviral assays are performed on the same cell line and using the same methodology, it is proposed that the compounds elicit their antiviral activity on CHIKV through a CHIKV-specific mechanism. This mechanism could be associated with the activation of the signal transduction enzyme protein kinace C (PKC), similar to the mechanism of inhibition of HIV replication proposed for TPA.21 From the results obtained, it can be deduced that the presence of an α,β-unsaturated carbonyl function at C-7 on ring B proves deleterious for the anti-CHIKV activity [trigowiin A (1) versus TPA (4)], as well as the presence of two hydroxy groups at C-12 and C-13 [phorbol (3) versus prostratin (2)]. In addition, for compounds having a trans A/B ring junction, the presence of an ester group at C-12 with a C13-chain fatty acid appears to be important for strong anti-CHIKV activity [TPA (4) versus prostratin (2)]. Since trigowiin A (1), which showed a weak anti-CHIKV activity, might be an artifact isolated in trace quantity, and considering its close structural

Table 1. NMR Spectroscopic Data (600 MHz, methanol-d4) for Trigowiin A (1) position

δ Ca

1

159.1

2 3 4 5

137.0 205.8 74.0 138.7

6 7 8

149.8 202.5 55.9

9 10

77.2 60.5

11 12

46.0 78.2

13 14

67.4 30.6

15 16 17 18

26.8 17.2 23.9 15.0

19

10.5

20

62.5

21 22

172.9 21.0

a

δH (J in Hz) 7.56, d (1.3)

6.90, t (1.5)

3.76, d (5.5) 3.05, q (2.7) 2.23, m 5.37, d (10.5)

position 1′

δ Ca

δH (J in Hz)

173.2

2′ 3′ 4′ 5′

35.3 25.9 30.3 29.8−31.5

2.30, brt (7.4) 1.58, m 1.25, m 1.26−1.30, m

6′ 7′ 8′

29.8−31.5 29.8−31.5 29.8−31.5

1.26−1.30, m 1.26−1.30, m 1.26−1.30, m

9′ 10′

29.8−31.5 33.3

1.26−1.30, m 1.24, m

11′ 12′

23.9 14.6

1.26, m 0.84, t (7.0)

1.72, d (5.5) 1.16, s 1.13, s 0.89, d (6.5) 1.75, dd (2.7, 1.3) 4.18, dd (14.5, 1.5) 4.21 dd (14.5, 1.5) 2.02, s

Chemical shifts based on 2D-NMR spectra.

literature. Cross-peaks of H-8/H-11, H-11/H-16, and H-16/H8 indicated that they are all cofacial, arbitrarily assigned as βoriented. The correlation between H3-18 and H-12 suggested that the fatty acid moiety is also β-oriented. Although no other NOESY correlation could support the trans A/B ring junction with H-10α and OH-4β and the 13-acyl group in an α-position, their orientations were based on biogenetic considerations from all phorbol-type diterpenes characterized so far and because the carbon chemical shift values of 1 were in good agreement with those of structurally related compounds.17,18 Trigowiin A (1), identified as 12-O-dodecanoyl-7-oxo-5-ene-phorbol-13-acetate, Table 2. Antiviral Activity of Compounds 1−5 in μM (n ≥ 3) compound 1 2 3 4 5 chloroquine a

CC50 Vero cells

EC50 CHIKV

SI

EC50 SINV

EC50 SFV

>100 79.0 ± 17.4 >343 5.7 ± 1.7 5.3 ± 0.6

43.5 ± 12.8 2.6 ± 1.5 >343 0.0029 ± 0.0003 2.8 ± 0.5

>2.3 30.3 >1 1965 1.9

n.d.a >256 >274 2.2 n.d.

n.d. >256 >274 >162 n.d.

89 ± 28

11 ± 7

8.1

11 ± 2

14 ± 2

n.d. = not determined. C



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MeOH−H2O (50:50 to 100:0 + 0.1% formic acid) at 3 mL·min−1 in 35 min to yield scopoletin (2.8 mg), isoscopoletin (1.5 mg), 6hydroxy-7,8-dimethoxycoumarin (3.2 mg), fraxinol (0.9 mg), 3,4dimethoxycinnamyl alcohol (0.9 mg), and synapaldehyde (1.9 mg). The active fraction F14 (1.5 g, CE50 = 9.9 μg/mL) was subjected to C18 flash chromatography using a gradient of H2O−MeOH−EtOAc (1:0:0 to 0:8:2), leading to 17 fractions (F14-1 to F14-17). The active fraction F14-11 (65 mg, CE50 = 2.4 μg/mL) was purified on a semipreparative C18 HPLC using H2O−ACN (20:80 + 0.1% formic acid) at 3 mL·min−1, leading to nine fractions (F14-11-1 to F14-11-9). F14-11-6 (4 mg) was purified on a semipreparative C18 column using H2O−ACN (10:90 + 0.1% formic acid) at 3 mL·min−1 to yield trigowiin A (1, 0.7 mg). Trigowiin A (1). 12-O-Dodecanoyl-7-oxo-5-ene-phorbol-13-acetate: white, amorphous powder; [α]25D +113 (c 0.015, MeOH); UV (MeOH) λmax (log ε) 213 (3.45) nm; IR νmax 3380, 1723, 1680, 1624, 1462 cm−1; 1H NMR (MeOD, 600 MHz) and 13C NMR (MeOD, 150 MHz), see Table 1; HRESIMS m/z 601.3372 ([M − H]−; calcd for C34H49O9, 601.3377). Virus Cell-Based Antiviral Assay. Throughout the experiments, Vero (African green monkey kidney) cells were used. The following viruses were used: Chikungunya virus strain 899, Sindbis virus strain HRsp, and Semliki forest virus strain. Serial dilutions of the plant extract, fractions, or compounds, as well as the reference compound chloroquine, were prepared in assay medium [MEM Rega3 (cat. no. 19993013; Invitrogen), 2% FCS (Integro), 5 mL of 200 mM Lglutamine, and 5 mL of 7.5% sodium bicarbonate] added to empty wells of a 96-well microtiter plate (Falcon, BD). Subsequently, 50 μL of a 4× virus dilution in assay medium was added, followed by 50 μL of a cell suspension. This suspension, with a cell density of 25 000 cells/50 μL, was prepared from a Vero cell line subcultured in cell growth medium (MEM Rega3 supplemented with 10% FCS, 5 mL of L-glutamine, and 5 mL of sodium bicarbonate) at a ratio of 1:4 and grown for 7 days in 150 cm2 tissue culture flasks (Techno Plastic Products). The assay plates were returned to the incubator for 6−7 days (37 °C, 5% CO2, 95−99% relative humidity), a time at which maximal virus-induced cell death or cytopathic effect (CPE) is observed in untreated, infected controls. Subsequently, the assay medium was aspirated, replaced with 75 μL of a 5% MTS (Promega) solution in phenol red-free medium, and incubated for 1.5 h. Absorbance was measured at a wavelength of 498 nm (Safire2, Tecan); optical densities (OD values) reached 0.6−0.8 for the untreated, uninfected controls). Raw data were converted to percentage of controls, and the EC50 (50% effective concentration or concentration that is calculated to inhibit virus-induced cell death by 50%) and CC50 (50% antimetabolic concentration or concentration that is calculated to inhibit the overall cell metabolism by 50%) were derived from the dose−response curves. All assay conditions producing an antiviral effect exceeding 50% were checked microscopically for minor signs of a cytopathic effect or adverse effects on the host cell (i.e., altered cell morphology). A compound is only considered to elicit a selective antiviral effect on virus replication when, following microscopic quality control, at least at one concentration of compound no CPE nor any adverse effect is observed (image resembling untreated, uninfected cells). Multiple, independent experiments were performed.

analogy with TPA (4), we hypothesized that the anti-CHIK activity of the crude extract could be due to the presence of a parent compound, such as 12-O-dodecanoylphorbol-13-acetate, exhibiting activity of similar magnitude to that of TPA (4). TPA (4) currently is one of the most potent and wellcharacterized tumor-promoting agents known to date.22 Even though prostratin (2) is less active than TPA, showing a moderate EC50 of 2.6 μM and a selectivity index (SI) approximating 30, its potent and selective inhibitory activity on CHIKV replication and the absence of proven tumorpromoting activity23 may make this compound a potential candidate for further study and development. On the basis of the preliminary structure−activity relationship derived from this study, and taking into account results obtained by Muñoz et al., it would be very interesting to evaluate compounds possessing the basic phorbol carbon skeleton esterified at position 13 with carbon chains of variable length and leaving free the OH group at position 12.24 In conclusion, the search for new inhibitors with selective antiviral activity against CHIKV from species of the genus Trigonostemon has led to the characterization of a new tigliane diterpenoid named trigowiin A (1), which showed moderate antiviral activity. Furthermore, prostratin (2) and TPA (4), two tigliane-type diterpenoids structurally related to 1, also exhibited potent and selective anti-CHIKV activity. The biological activity observed for 2 as well as the relevant previous literature may stimulate the further investigation of this class of compounds as selective inhibitors of CHIKV replication and of alphaviruses in general. Currently, studies to determine the precise mechanism of action by which the compound inhibits CHIKV replication are in progress.

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EXPERIMENTAL SECTION

General Experimental Procedures. Optical rotations were determined at 24 °C with a JASCO P1010 polarimeter. UV spectra were recorded using a Perkin-Elmer Lamba 5 spectrophotometer. IR spectra were acquired on a Nicolet FT-IR 205 spectrophotometer. NMR spectra were recorded in methanol-d4 on a Bruker 600 MHz instrument (Avance 600) with TMS as internal standard, using a 1.7 mm microprobe. HRESIMS data were acquired on a Thermoquest TLM LCQ Deca ion-trap spectrometer. Silica gel 60 (6−35 μm) and analytical plates (Si gel 60F 254) were purchased from SDS (France). Kromasil analytical and semipreparative C18 columns (250 × 4.5 mm, 250 × 10 mm, and 250 × 21.2 mm; i.d. 5 μm, Thermo) were used for HPLC separations using a Dionex autopurification system equipped with a binary pump (P580), a UV−vis array detector (200−600 nm, Dionex UVD340U), and a PL-ELS 1000 ELSD detector (Polymer Laboratory). A prepacked C18 Versapak cartridge was used for flash chromatography using a Combiflash-Companion apparatus (Serlabo). All other solvents were purchased from SDS (France). Prostratin (2) (>99% pure), phorbol (3) (>99% pure), 12-O-tetradecanoylphorbol 13-acetate (4) (>99.5% pure), and 4α-12-O-tetradecanoylphorbol 13acetate (5) were purchased from LC Laboratories. Plant Material. The bark of T. howii was collected in January 2005 from Dakrong, Quang Tri Province, Vietnam, and authenticated by Dr. Q. B. Nguyen by comparison with an authentic specimen. A voucher specimen (VN-1452) was deposited at the Herbarium of Vietnam Academy of Science and Technology (VAST). Extraction and Isolation. The dried plant material (1.8 kg) was successively extracted with n-heptane (2 × 5 L) and EtOAc (3 × 5 L) at room temperature to afford 0.9 and 5.2 g of each extract, respectively. After concentration in vacuo, the EtOAc extract (5.2 g) was subjected to silica gel column chromatography using a gradient of heptane−dichloromethane−MeOH (1:0:0 to 0:8:2) of increasing polarity, leading to 21 fractions on the basis of TLC. Fraction 11 (43 mg) was subjected to passage over a semipreparative C18 column using

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ASSOCIATED CONTENT

S Supporting Information *

NMR spectra for compound 1 are available free of charge via the Internet at http://pubs.acs.org

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AUTHOR INFORMATION

Corresponding Author

*Tel: 33 1 69 82 30 85. Fax: 33 1 69 07 72 47. E-mail: [email protected]. Notes

The authors declare no competing financial interest. D



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Article

ACKNOWLEDGMENTS We are grateful to Museum National d'Histoire Naturelle for a fellowship (M.B.). We thank Mr. Q. B. Nguyen (VAST, Vietnam) for the identification of the plant material. We also would like to acknowledge S. Delmotte, T. Bellon, M. Flament, C. Collard, and A. De Ceulaer for their excellent assistance in the acquisition of the data in the CHIK virus-cell-based assay.

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REFERENCES

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