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PHYTOTHERAPY RESEARCH Phytother. Res. 19, 136–140 (2005) Published online in Wiley InterScience (www.interscience.wiley.com). DOI: J. F. RIVERO-CRUZ ET AL.10.1002/ptr.1642
Cytotoxic Constituents of the Twigs of Simarouba glauca Collected from a Plot in Southern Florida J. Fausto Rivero-Cruz1, Raphael Lezutekong1,2, Tatiana Lobo-Echeverri1, Aiko Ito1, Qiuwen Mi1, Hee-Byung Chai1, Djaja D. Soejarto1, Geoffrey A. Cordell1, John M. Pezzuto1,†, Steven M. Swanson1, Ivano Morelli2 and A. Douglas Kinghorn*,1,‡ 1
Program for Collaborative Research in the Pharmaceutical Sciences and Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA 2 Dipartimento di Chimica Bioorganica e Biofarmacia, Universitá di Pisa, Pisa, 56126, Italy
Activity-guided fractionation of a chloroform-soluble extract of Simarouba glauca twigs collected from a plot in southern Florida, and monitored with a human epidermoid (KB) tumor cell line, afforded six canthin6-one type alkaloid derivatives, canthin-6-one (1), 2-methoxycanthin-6-one (2), 9-methoxycanthin-6-one (3), 2-hydroxycanthin-6-one (4), 4,5-dimethoxycanthin-6-one (5) and 4,5-dihydroxycanthin-6-one (6), a limonoid, melianodiol (7), an acyclic squalene-type triterpenoid, 14-deacetyleurylene (8), two coumarins, scopoletin (9) and fraxidin (10), and two triglycerides, triolein (11) and trilinolein (12). Among these isolates, compounds 1–4, 7 and 8 exhibited cytotoxic activity against several human cancer cell lines. 14-Deacetyleurylene (8) was selectively active against the Lu1 human lung cancer cell line, but was inactive in an in vivo hollow fiber assay using this same cell type. Copyright © 2005 John Wiley & Sons, Ltd. Keywords: Simarouba glauca; canthin-6-one alkaloids; melandiol; 14-deacetyleurylene; cytotoxicity; in vivo hollow fiber assay.
INTRODUCTION Simarouba glauca DC. (Simaroubaceae), indigenous to southern Florida, the West Indies and Brazil, is a large shrub or small tree (Cronquist, 1944; 1981), commonly called the ‘paradise tree’ (Yamamoto and Shepherd, 1999). Decoctions of various species of Simarouba have been used as antimalarials, but have a narrow therapeutic window (Franssen et al., 1997). Extracts of S. glauca have been used in Guatemala for the treatment of gastrointestinal disorders (Cáceres et al., 1990; Lidia et al., 1991). The seeds of S. glauca are rich in an edible fat (nearly 60% w/w) that has been used for cooking in tropical countries. The cake obtained from the extraction for the oil contains proteins used for cattle feed after the removal of the toxic and bitter constituents (Monseur and Motte, 1983). In previous work, the seeds of S. glauca have afforded quassinoids (Ham et al., 1954; Polonsky et al., 1978; Waterman and Ampofo, 1984; Dou et al., 1996), fatty acids (Lognay et al., 1981a; 1981b; Bhatnagar et al., 1984; Jeyarani and * Correspondence to: Prof. A. D. Kinghorn, Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy. The Ohio State University, 500 W. 12th Avenue, Columbus, OH 43210, USA. E-mail:
[email protected] † Present address: Heine Pharmacy Building, Purdue University, West Lafayette, IN 47907. ‡ Present address: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy. The Ohio State University, 500 W. 12th Avenue, Columbus, OH 43210, USA. Contract/grant sponsor: National Cancer Institute, NIH, Bethesda; Contract/grant number: U19 CA 52956. Plant material collected under permit 0014 (1999–2003) from Miami-Dade County Parks and Recreation Department. Copyright © 2005 John Wiley & Sons, Ltd. Copyright © 2005 John Wiley & Sons, Ltd.
Reddy, 2001) and an alkaloid, 8-hydroxycanthin-6-one (Waterman and Ampofo, 1984). A dichloromethane extract of the bark of S. glauca was found to be toxic in the brine shrimp test and a potent inhibitor of the growth of Plasmodium falciparum. The quassinoids, glaucarubin, along with glaucarubinone and glaucarubol, from the seeds of S. glauca, showed promising activity against Plasmodium falciparum in culture (Franssen et al., 1997; Valeriote et al., 1998). Glaucarubin was shown to have amoebicidal properties by both an in vitro method and in experimental animals (Del Pozo, 1956; Cucker et al., 1958). Several quassinoid S. glauca seed constituents have exhibited cytotoxic activity in vitro against KB cells (human oral epidermoid carcinoma), including glaucarubin, glaucarubinone, glaucarubol and glaucarubolone (Polonsky et al., 1978; Valeriote et al., 1998). Two esters of glaucarubolone, ailanthinone and glaucarubinone, exhibited significant activity in vivo in the P388 lymphocytic leukemia model (Kupchan et al., 1976; Monseur and Motte, 1983). The present investigation of S. glauca twigs collected in the United States was part of an ongoing collaborative search for novel anticancer agents of plant origin (Kinghorn et al., 1999). A plot-based collection strategy was utilized for the present investigation (Calderon et al., 2000; Soejarto, 2000). The plant was selected for fractionation after its chloroform-soluble extract exhibited significant cytotoxicity against several human cancer cell lines (Likhitwitayawuid et al., 1993, Seo et al., 2001). Bioassay-guided phytochemical investigation of this extract, using the KB cell line as a monitor, led to the isolation and identification of canthin-6-one (1), 2-methoxycanthin-6-one (2), 9-methoxycanthin6-one (3), 2-hydroxycanthin-6-one (4), melianodiol Received October(2005) 2004 Phytother. Res. 19,11 136–140 Accepted 14 December 2004
CYTOTOXIC CONSTITUENTS OF SIMAROUBA GLAUCA
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Figure 1. Structures of the cytotoxic compounds isolated from twigs of S. glauca.
(7) and 14-deacetyleurylene (8) as cytotoxic principles, together with two further canthin-6-one alkaloid derivatives, 4,5-dimethoxycanthin-6-one (5) and 4,5dihydroxycanthin-6-one (6), two coumarins, scopoletin (9) and fraxidin (10), and two triglycerides, triolein (11) and trilinolein (12) as inactive constituents. The structures of the active isolates obtained are shown in Fig. 1.
MATERIALS AND METHODS Plant material. The twigs of S. glauca were collected from an established plot by T.L.-E. in Matheson Hammock, Dade County, Florida, USA, in November 2000. A voucher specimen representing this collection has been deposited at the Fairchild Tropical Garden Herbarium, Coral Gables, FL, and at the Field Museum of Natural History, Chicago, IL, under the accession number No. TL-12. Instrumentation. TLC for monitoring the fractions obtained by CC was performed on Merck silica gel 60 F254 aluminum sheets. Preparative TLC was carried out on Merck silica gel 60 F254 glass plates (2.0 mm layer thickness). The TLC plates were sprayed with 1% vanillin/sulphuric acid and heated (110 °C) or dipped in Dragendorff’s reagent. TLC spots were visualized by inspection of the plates under UV light (254 and 366 nm) on a Chromato-vue C-70G UV viewing system. All CC were performed with Whatman silica gel K6F 200–400 mesh, 60 Å pore size. A YMC-pack ODC-AQ column (5 µm, 15 × 2 cm i.d., YMC Co., Wilmington, NC) and YMC-guard pack ODC-AQ guard column (5 µm, 5 × 2 cm i.d.) were used for preparative HPLC, Copyright © 2005 John Wiley & Sons, Ltd.
along with two Waters 515 HPLC pumps and a Waters 996 photo-diode array detector (Waters, Millford, MA). Melting points of the isolates were determined using a Fisher-Johns melting point apparatus, and are uncorrected. Optical rotations were obtained on a Perkin-Elmer model 241 polarimeter. UV spectra were measured on a Beckman DU-7 spectrometer. IR spectra were taken on a Genesis Series ST IR ATI Mattson spectrometer. 1H-NMR, 13C-NMR (including DEPT), HMQC, HMBC and 1H-1H COSY spectra were measured on Bruker DRX-500 and -300 instruments. Compounds were analysed in CDCl3, with tetramethylsilane (TMS) as internal standard. 13C NMR multiplicities were determined using APT and DEPT experiments. EIMS were recorded on a Finnigan MAT-90/95 sector field mass spectrometer. Activity-guided compound isolation. The air-dried, milled twigs of S. glauca (1,805 g) were extracted with MeOH (3 × 3 L) at room temperature (24 h each) and the combined MeOH extracts were evaporated under reduced pressure, yielding a residue (67.3 g), which was partitioned with petroleum ether, chloroform and ethyl acetate. Water was added to the MeOH extract to afford a 50% aqueous MeOH solution before partitioning with chloroform. The resulting four crude extracts (petroleum ether, chloroform, ethyl acetate and aqueous) were submitted for cytotoxicity testing against a small panel of human cancer cell lines, as described subsequently. The crude CHCl3-soluble extract (20.8 g) was found to exhibit strong activity against KB cells (ED50 1.7 µg/mL). Hence, the CHCl3-soluble extract (20.8 g) was subjected to Si gel column chromatography and eluted with gradient mixtures of petroleum ether-ethyl acetate and then chloroform–methanol of Phytother. Res. 19, 136–140 (2005)
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increasing polarity to give 12 pooled fractions. Fractions 5, 7 and 8 were active in the KB cytotoxicity assay (ED50 2.3, 6.4 and 0.3 µg/mL, respectively). Active fraction 7 was purified by semipreparative HPLC, by elution with a gradient starting with CH3CN–H2O–CH3COOH (30:70:0.1) to CH3CN–H2O–CH3COOH (70:30:0.1) in 30 min, to afford pure compounds 1 (tR = 24.4 min, 4 mg), 2 (tR = 18.5 min, 9 mg), 3 (tR = 17.8, 6 mg), 4 (tR = 12.3 min, 3 mg), 5 (tR = 21.6 min, 4 mg), 6 (tR = 8.90 min, 2.9 mg), 9 (tR = 30.5 min, 4 mg) and 10 (tR = 32.8 min, 14 mg). Additional chromatograpic separation of active fraction 8 over Si gel with CHCl3–MeOH of increasing polarity yielded five subfractions (8A–8E). Compound 4 (2.7 mg) was obtained from subfraction 8C of the CHCl3-soluble extract by reversed-phase silica gel column chromatography eluted with MeOH–H2O (3:1). Further chromatographic purification of fraction 8A over Si gel using mixtures of CHCl3–MeOH (increasing polarity) afforded compound 7 (30 mg). The active fraction 5, eluted with hexane–acetone (95:5), was chromatographed over a silica gel column eluted with hexane–acetone (increasing polarity) to afford 14deacethyleurylene (8, 187 mg). From the inactive fraction 4A, triolein (9.7 mg, 11) and trilinolein (13.4 mg, 12) were obtained. Canthin-6-one (1). Yellow needles (CHCl3–MeOH). MP 152°–153 °C (lit. 155 °–156 °C) (Fish et al., 1975). This alkaloid exhibited closely comparable spectral data (UV, IR, 1H NMR, 13C NMR and EIMS) to published values (Fish et al., 1975; Koike and Ohmoto, 1985). 2-Methoxycanthin-6-one (2). Yellow needles (CHCl3); MP 247 °C (lit. 250 °C) (Ohmoto et al., 1981). This alkaloid exhibited closely comparable spectral data (UV, IR, 1H NMR, 13C NMR and EIMS) to published values (Ohmoto et al., 1981). 9-Methoxycanthin-6-one (3). Yellow solid (CHCl3). MP 177°–179 °C (lit. 178°–179 °C) (Polonsky et al., 1982). This alkaloid exhibited closely comparable spectral data (UV, IR, 1H NMR, 13C NMR and EIMS) to published values (Polonsky et al., 1982). 2-Hydroxycanthin-6-one (4). Yellow amorphous solid (CHCl3). MP > 300 °C (lit. 388°–390 °C) (Pettit et al., 1998). This alkaloid exhibited closely comparable spectral data (UV, IR, 1H NMR, 13C NMR and EIMS) to published values (Pettit et al., 1998). 4,5-Dimethoxycanthin-6-one (5). Needles (CHCl3– isopropanol); MP 144°–145 °C (lit. 146 °C) (Inamoto et al., 1961; Koike and Ohmoto, 1985). This alkaloid exhibited closely comparable UV, IR, 1H NMR, 13C NMR and EIMS data to published values (Koike and Ohmoto, 1985). 4,5-Dihydroxycanthin-6-one (6). Needles (acetone); MP 174°–175°C. This alkaloid exhibited closely comparable UV, IR and EIMS data to published values (Kimura et al., 1967). Melianodiol (7). Yellow needles (MeOH). MP 225°– 226 °C (lit. 222°–224 °C). [α]24D –42° (c 1.0, CHCl3) (lit. −46.1° (c 0.1 CHCl3)) (Puripattanavong et al., 2000). Copyright © 2005 John Wiley & Sons, Ltd.
This compound exhibited closely comparable spectral data (UV, IR, 1H NMR, 13C NMR and EIMS) to literature values (Puripattanavong et al., 2000). 14-Deacetyleurylene (8). Colorless needles (MeOH); MP 61°–63 °C (lit. 63°–65 °C); [α]D +10.8° (c 2.5, CHCl3) (lit. +6° (c 1.03 CHCl3)) (Morita et al., 1993). This compound exhibited closely comparable spectral data (UV, IR, 1H NMR, 13C NMR and EIMS) to published values (Morita et al., 1993). Scopoletin (9). Needles (acetone); MP 202°–203 °C (lit. 203°–305 °C) (Tanaka et al., 1995). This compound exhibited closely comparable 1H NMR, 13C NMR and EIMS data to published values (Tanaka et al., 1995). Fraxidin (10). Needles (acetone); MP 199°–200 °C (lit. 198°–200 °C) (Tsukamoto et al., 1985). This compound exhibited closely comparable 1H NMR, 13C NMR and EIMS data to published values (Tsukamoto et al., 1985). Triolein (11). Colorless oil. This compound exhibited closely comparable spectral data (UV, IR, 1H NMR, 13 C NMR and EIMS) to published values (Guillén and Ruíz, 2003). Trilinolein (12). Colorless oil. This compound exhibited closely comparable spectral data (UV, IR, 1H NMR, 13 C NMR and EIMS) to published values (Guillén and Ruíz, 2003). Evaluation of cytotoxic activity. The crude extract, fractions and isolates obtained were evaluated for cytotoxicity against a panel of human cancer cell lines, according to established protocols (Likhitwitayawuid et al., 1993; Seo et al., 2001). The results are expressed either as IC50 values in µg/mL (extracts) or in nm (pure compounds). IC50 values of pure compounds of >1 µm are regarded as inactive. In vivo evaluation of compound 8. 14-Deacetyleurylene (8) was evaluated for anticancer potential with the in vivo hollow fiber model, conducted as described previously (Hollingshead et al., 1995; Mi et al., 2002).
RESULTS AND DISCUSSION All of the compounds isolated from S. glauca in the present investigation were previously reported from species in the family Simaroubaceae, and their structures were identified by physical data measurement and spectral data interpretation and comparison with literature values (see Materials and Methods). Six of the 12 compounds isolated in this investigation are alkaloids (1–6) belonging to the canthin-6-one alkaloid type. The other constituents obtained were the limonoid, melianodiol (7), an acyclic squalene-type triterpenoid, 14-deacetyleurylene (8), two coumarins, scopoletin (9) and fraxidin (10), and two triglycerides, triolein (11) and trilinolein (12). This is the first phytochemical study on a plant part other than the seeds of S. glauca. The results of the present chemical study of S. glauca were in general agreement with the expected chemotaxonomic pattern for a member of the Simaroubaceae, but Phytother. Res. 19, 136–140 (2005)
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Table 1. Cytotoxic activity of compounds isolated from Simarouba glaucaa,c Cell lineb Compound name and code
Col2
HUVEC
KB
LCNaP
Lu1
hTERT-RPE1
Canthin-6-one (1) 2-Methoxycanthin-6-one (2) 9-Methoxycanthin-6-one (3) 2-Hydroxycanthin-6-one (4) Melianodiol (7) 14-Deacetyleurylene (8) Paclitaxeld Camptothecind
389 543 609 567 892 >1000 46 57
431 503 609 506 945 >1000 105 258
347 642 674 568 781 >1000 0.4 22
>1000 725 564 524 956 >1000 5 28
510 654 478 565 1000 72 2 29
210 583 509 506 910 1000 23 230
a
Results are expressed as ED50 values (nM). Key to cell lines used: Col2, human colon cancer; HUVEC, human umbilical vein endothelial; KB, human oral epidermoid carcinoma; LNCaP, human hormone-dependent prostate cancer; Lu1, human lung cancer; hTERT-RPE1, human telomerase reverse transcriptase-retinal pigment epithelial. c The known compounds 4,5-dihydroxycanthin-6-one, 4,5-dimethylcanthin-6-one, scopoletin, fraxidin, triolein and trilinolein were inactive (ED50 values >1 µM). d Positive control substance. b
it is of interest that no simaroubalides were isolated in this investigation. After their purification, six canthin-6-one alkaloids (1–6), melianodiol (7), 14-deacetyleurylene (8), scopoletin (9), fraxidin (10), triolein (11) and trilinolein (12), isolated from the twigs of Simarouba glauca, were tested for cytotoxicity against a panel of human cell lines. The results are summarized in Table 1. Canthin6-one (1) showed broad cytotoxicity against all of the cell lines in which it was tested, except for LNCaP (hormone-dependent prostate cancer) cells. Previously, canthin-6-one was reported to exhibit activity against guinea-pig ear keratinocyte epithelial cells (ED50 1.1 µg/mL), although it was not active against the KB cell line (Anderson et al., 1983). In contrast to 1, 4,5dimethoxycanthin-6-one (5) did not show cytotoxicity against any of the cell lines tested. Accordingly, the presence of the H-4 and H-5 protons in 1 may be important for the mediation of cytotoxic activity (Fukamiya et al., 1987; Pettit et al., 1998). Melianodiol (7) also exhibited broad, but weak, cytotoxicity against most of the cell lines in which it was tested (Table 1). Although there do not appear to be any reports on the cytotoxicity of melianodiol (7) with cancer cell lines, this compound was found to exhibit strong antifeedant activity against the cabbage worm, Pieris rapae (Wang
et al., 1994). However, the most potent activity among the four S. simarauoba isolates obtained in this investigation was shown by 14-deacetyleurylene (8) against the Lu1 human lung cancer cell line (ED50 72 nm), and significant selectivity was evident. Accordingly, 14deacetyleurylene (8) was evaluated with the in vivo hollow fiber test (Hollingshead et al., 1995; Mi et al., 2002). Doses of 6.25, 12.5 and 25.0 mg/kg body weight/ injection (i.p.) were administrated daily for 4 days, using the Lu1 human lung cancer cell line for evaluation. It was found that compound 8 did not mediate significant growth inhibition with cells implanted at either the i.p. or s.c. sites of the mice. However, using these regimens, no significant weight loss was observed during the test period, nor was the substance overtly toxic. Acknowledgements We thank Dr K. Fagerquist, Mass Spectrometry Facility, Department of Chemistry, University of Minnesota, Minneapolis, MN for the mass spectral data. We are grateful to the Nuclear Magnetic Resonance Laboratory of the Research Resources Center, University of Illinois at Chicago, for the provision of certain NMR spectral facilities used in investigation, the staff of Fairchild Tropical Garden, Coral Gables, FL for their herbarium facilities, and the staff of Miami-Dade County Parks and Recreation Department (Department of Environmental Protection) for granting collection permits.
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