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Dinor Casearin X, a New Cytotoxic Clerodane Diterpene from Casearia sylvestris

Abstract

A new clerodane-type diterpene, named dinor casearin X, and four known casearins (A, B, G and J) were isolated from leaves of Casearia sylvestris(Salicaceae). These compounds were evaluated for cytotoxic activity against five human cancer cell lines (A2058, HL-60, HCT, MCF-7 and HeLa) as well as against a murine melanoma cell line (B16F10-Nex2). Among these compounds, dinor casearin X exhibited the highest cytotoxic activity against HL-60 cells with IC50 of 0.51 ± 0.11 µg mL-1, whereas casearin A exhibited the highest cytotoxic activity against HCT cells (IC50 1.84 ± 0.14 µg mL-1).

Keywords
Casearia sylvestris; cytotoxic activity; dinor casearin X


Introduction

Introduction

Casearia sylvestris Swartz (Salicaceae), popularly known as “guaçatonga”, is geographically distributed throughout Latin America,1Lorenzi, H.; Matos, F. J. A.; Plantas Medicinais do Brasil: Nativas e Exóticas; Instituto Plantarum: Nova Odessa, 2002. where it has been used by native communities to treat several diseases.2Tininis, A. G.; Assonuma, M. M.; Telascrea, M.; Perez, C. C.; Silva, M. R. S. R. M.; Favoreto, R.; Cavalheiro, A. J.; Rev. Bras. Plant. Med. 2006, 8, 132. The use of this plant in traditional medicine and subsequent scientific investigations have highlighted the importance of C. sylvestris extracts due to their antiulcer, antiinflammatory, antiophidian and antitumor properties.3Ferreira, P. M. P.; Costa-Lotufo, L. V.; Moraes, M. O.; Barros, F. W. A.; Martins, A. M. A.; Cavalheiro, A. J.; Bolzani, V. S.; Santos, A. G.; Pessoa, C. O.; An. Acad. Bras. Cienc. 2011, 83, 1373. Chemically, C. sylvestrisextracts are rich in clerodane-type diterpenes, known as casearins and casearvestrins.3Ferreira, P. M. P.; Costa-Lotufo, L. V.; Moraes, M. O.; Barros, F. W. A.; Martins, A. M. A.; Cavalheiro, A. J.; Bolzani, V. S.; Santos, A. G.; Pessoa, C. O.; An. Acad. Bras. Cienc. 2011, 83, 1373.,4Oberlies, N. H.; Burgess, J. P.; Navarro, H. A.; Pinos, R. E.; Fairchild, C. R.; Peterson, R. W.; Soejarto, D. D.; Farnsworth, N. R.; Douglas, K. A.; Wani, M. C.; Wall, M. E.; J. Nat. Prod. 2002, 65, 95. Casearins A-F have been described as antitumor compounds, with casearin C exhibiting the highest cytotoxicity against V-79 cells in vitro.5Itokawa, H.; Totsuka, N.; Morita, H.; Takeya, K.; Litaka, Y.; Schenkel, E. P.; Motidome, M.; Chem. Pharm. Bull. 1990, 38, 3384. Moreover, casearin B exhibited chemoprotective effect against DNA damage.6Prieto, A. M.; dos Santos, A. G.; Oliveira, A. P.; Cavalheiro, A. J.; Silva, D. H.; Bolzani, V. S.; Varanda, E. A.; Soares, C. P.; Food Chem. Toxicol. 2013, 53, 153. Other studies reported the occurrence of antitumoral casearins G-R,7Morita, H.; Nakayama, M.; Kojima, H.; Takeya, K.; Itokawa, H.; Ichenkel, E. P.; Motidome, M.; Chem. Pharm. Bull. 1991, 39, 693. DNA-damaging casearins S and T,8Carvalho, P. R. F.; Furlan, M.; Young, M. C. M.; Kingston, D. G. I.; Bolzani, V. S.; Phytochemistry 1998, 49, 1659. and cytotoxic casearins U and V.9Wang, W.; Zhao, J.; Wang, Y. H.; Smillie, T. A.; Li, X. C.; Khan, I. A.; Planta Med. 2009, 75, 1436. Cytotoxic effects of casearin X were demonstrated in leukemia cells where it triggered apoptosis.1010 Santos, A. G.; Ferreira, P. M.; Vieira Jr., G. M.; Perez, C. C.; Tininis, A. G.; Silva, G. H.; Bolzani, V. S.; Costa-Lotufo, L. V.; Pessoa, C. O.; Cavalheiro, A. J.; Chem. Biodiversity 2010, 7, 205.,1111 Ferreira, P. M. P.; Santos, A. G.; Tininis, A. G.; Costa, P. M.; Cavalheiro, A. J.; Bolzani, V. S.; Moraes, M. O.; Costa-Lotufo, L. V.; Montenegro, R. C.; Pessoa, C.; Chem.-Biol. Interact. 2010, 188, 497.Furthermore, cytotoxic casearvestrins A-C have also been isolated in C. sylvestris.4Oberlies, N. H.; Burgess, J. P.; Navarro, H. A.; Pinos, R. E.; Fairchild, C. R.; Peterson, R. W.; Soejarto, D. D.; Farnsworth, N. R.; Douglas, K. A.; Wani, M. C.; Wall, M. E.; J. Nat. Prod. 2002, 65, 95.

As a part of our continuous study aiming at the discovery of novel bioactive compounds from C. sylvestris,1212 Bou, D. D.; Lago, J. H. G.; Figueiredo, C. R.; Matsuo, A. L.; Guadagnin, R. C.; Soares, M. G.; Sartorelli, P.; Molecules 2013, 18, 9477.,1313 Bou, D. D.; Tempone, A. G.; Pinto, E. G.; Lago, J. H. G.; Sartorelli, P.; Phytomedicine 2014, 21, 676. this work reports the isolation and characterization of casearins A, B, G and J, as well as a new derivative named dinor casearin X, which displayed cytotoxic activity against the human leukemia cell line HL-60.

Experimental

General experimental procedures

1H and 13C nuclear magnetic resonance (NMR) spectra of compounds 1-4 were recorded at 300 and 75 MHz, respectively, in a Bruker Ultrashield 300 Avance III spectrometer. 1H and 13C NMR spectra of compound5 were recorded in a Bruker AIII-500 (500 MHz for 1H) spectrometer and in a Bruker Avance III Ultrashield Plus spectrometer (150 MHz for 13C) with cryo-probe of 5 mm. CD3OD (Aldrich) was the solvent and the residual resonance peaks at dH 3.3 (1H ) and dC 49.0 (13C) were used as internal standard. Optical rotation was recorded in a Schmidt+Haensch polartronic H100 (automatic high resolution circular). Fourier transform infrared (FTIR) spectrum was recorded on a Shimadzu Prestige-21 FTIR spectrometer. High resolution electrospray ionization mass spectra (HRESIMS) were obtained in a Bruker Daltonics ultrOTOFq (ESI/time-of-flight (TOF), positive mode). High performance liquid chromatography (HPLC) analysis was performed in a Dionex Ultimate 3000 chromatograph, using a Luna Phenomenex RP-18 column (3 µm, 150 × 5 mm) and an UV-diode array detector (DAD). Silica gel (Merck, 230-400 mesh) and Sephadex LH-20 (Sigma-Aldrich) were used for the column chromatographic (CC) separation, while silica gel 60 PF254 (Merck) was used for analytical and preparative thin-layer chromatography (TLC).

Plant material

Leaves of Casearia sylvestris were collected from a single tree in the Atlantic Forest area of São Paulo City, SP, Brazil (coordinates 23º53’08.86’’ S, 46º40’10.45’’ W), in October 2012. Botanical identification was carried out by PhD Roseli Buzanelli Torres from Instituto Agronômico de Campinas (IAC), Campinas-SP, Brazil. A voucher specimen (IAC 55272) has been deposited in the IAC herbarium.

Extraction and isolation

Leaves of C. sylvestris (290 g) were dried, powdered and exhaustively extracted with MeOH to obtain 11.1 g of crude extract. After cytotoxic evaluation, the active MeOH extract was ressuspended in MeOH:H2O (2:1) and partitioned using hexane, CH2Cl2 and EtOAc. Part of active hexane phase (6.4 g) was subjected to separation over silica gel CC and eluted with increasing amounts of EtOAc in hexane (9:1 to 1:9) to obtain 23 fractions (A1-A23), in which A11-A13 displayed cytotoxic activity. Fraction A11 (380 mg) was chromatographed over Sephadex LH-20, eluted with MeOH and purified by preparative TLC on SiO2 (hexane:EtOAc, 4:1) to afford 3 (77 mg) and 4 (51 mg). Compound 5 (1 mg) was purified by semi-preparative RP-18 HPLC, eluted with MeCN:H2O (64:36, flow rates 3.7 mL min-1, UV 218 nm) from the active fraction A11‑3‑4 (20 mg). Fraction A12 (300 mg) was also subjected to CC over Sephadex LH-20, eluted with MeOH to yield 2 (12 mg). Fractionation of A13 (526 mg) over Sephadex LH-20 (MeOH as eluent) followed by preparative TLC on SiO2(hexane:EtOAc, 7:3) afforded 1 (43 mg).

Dinor casearin X ((1R*,3S*,5S*,6aR*,7S*,8S*,10R*,10aR*)-1-(acetyloxy)-3,5,6,6a,7,8,9,10-octahydro-10-hydroxy-7,8-dimethyl-7-[(1E)-butenone]naphtho[1,8a-c]furan-3,5-diyl dibutanoate) (5)

Amorphous white solid; [a]D2020 Kanokmedhakul, S.; Kanokmedhakul, K.; Buayairaksa, M.; J. Nat. Prod. 2007, 70, 1122.+0.20º (c 0.02, MeOH); HRESIMS [M + Na]+ calcd.: 543.2570; found: 543.2564; IR (KBr) νmax / cm-1 3445, 2955, 2918, 2918, 2850, 1723, 1617; 1H and 13C NMR see Table 1.

Table 1
1H and 13C NMR (δ, CD3OD, 500 and 150 MHz, respectively) data of dinor casearin X (5)

Cytotoxicity assays

The murine melanoma cell line B16F10 was originally obtained from the Ludwig Institute for Cancer Research (São Paulo, Brazil). The melanotic B16F10-Nex2 subline, which is characterized by low immunogenicity and moderate virulence, was identified at the Experimental Oncology Unit (UNIFESP). Human melanoma (A2058), leukemia (HL-60), colon cancer (HCT) and breast cancer (MCF-7) cell lines were obtained from the Ludwig Institute for Cancer Research. Human cervical carcinoma (HeLa) was acquired from PhD Hugo Pequeno Monteiro (UNIFESP).

Purified casearins 1-5 were resuspended in dimethyl sulfoxide (DMSO) at a final concentration of 10 mg mL-1, and next diluted in Roswell Park Memorial Institute-1640 (RPMI-1640) medium (Invitrogen) containing 10% fetal calf serum at concentrations ranging from 100 to 0 µg mL-1. The media were then incubated with 1 × 104Oberlies, N. H.; Burgess, J. P.; Navarro, H. A.; Pinos, R. E.; Fairchild, C. R.; Peterson, R. W.; Soejarto, D. D.; Farnsworth, N. R.; Douglas, K. A.; Wani, M. C.; Wall, M. E.; J. Nat. Prod. 2002, 65, 95.cells in a 96-well plate. After 18 h of incubation, cell viability was measured using the cell proliferation kit 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT; thiazol blue) (Sigma).1414 Mosmann, T.; J. Immunol. Methods 1983, 65, 55. Readings were made on a plate reader at 570 nm. All experiments were performed in triplicate. Doxorubicin (positive control) was purchased from Sigma.

Results and Discussion

Bioactivity guided chromatographic fractionation of the hexane phase obtained from the MeOH extract of C. sylvestris leaves led to the isolation of known casearins A (1),5Itokawa, H.; Totsuka, N.; Morita, H.; Takeya, K.; Litaka, Y.; Schenkel, E. P.; Motidome, M.; Chem. Pharm. Bull. 1990, 38, 3384. B (2),5Itokawa, H.; Totsuka, N.; Morita, H.; Takeya, K.; Litaka, Y.; Schenkel, E. P.; Motidome, M.; Chem. Pharm. Bull. 1990, 38, 3384.,1515 Santos, A. G.; Perez, C. C.; Tininis, A. G.; Bolzani, V. S.; Cavalheiro, A. J.; Quim. Nova 2007, 30, 1100. G (3)7Morita, H.; Nakayama, M.; Kojima, H.; Takeya, K.; Itokawa, H.; Ichenkel, E. P.; Motidome, M.; Chem. Pharm. Bull. 1991, 39, 693.,8Carvalho, P. R. F.; Furlan, M.; Young, M. C. M.; Kingston, D. G. I.; Bolzani, V. S.; Phytochemistry 1998, 49, 1659. and J (4)7Morita, H.; Nakayama, M.; Kojima, H.; Takeya, K.; Itokawa, H.; Ichenkel, E. P.; Motidome, M.; Chem. Pharm. Bull. 1991, 39, 693. as well as one new derivative named dinor casearin X (5) (Figure 1). Identification was carried out by analysis of their spectral data and comparison with those reported in the literature.5Itokawa, H.; Totsuka, N.; Morita, H.; Takeya, K.; Litaka, Y.; Schenkel, E. P.; Motidome, M.; Chem. Pharm. Bull. 1990, 38, 3384.,7Morita, H.; Nakayama, M.; Kojima, H.; Takeya, K.; Itokawa, H.; Ichenkel, E. P.; Motidome, M.; Chem. Pharm. Bull. 1991, 39, 693.,8Carvalho, P. R. F.; Furlan, M.; Young, M. C. M.; Kingston, D. G. I.; Bolzani, V. S.; Phytochemistry 1998, 49, 1659.,1515 Santos, A. G.; Perez, C. C.; Tininis, A. G.; Bolzani, V. S.; Cavalheiro, A. J.; Quim. Nova 2007, 30, 1100.

Figure 1
Structures of casearins isolated from C. sylvestris.

Dinor casearin X (5) was isolated as an amorphous white solid, with a molecular formula C28H40O9, as determined from the HRESIMS (positive mode) adduct ion [M + Na]+ at m/z543.2564 (calcd. 543.2570). The IR spectrum showed the presence of one carbonyl ketone conjugated to a double bound at 1617 cm-1 and one hydroxyl broad band at 3445 cm1. The 13C NMR spectrum exhibited 28 signals (Table 1), several of which were similar to casearins 1-4, suggesting a substructure containing the decalinic system (rings A and B) and diacetalic ring C. Analysis of the heteronuclear multiple-bond correlation (HMBC) spectrum indicated the partial structure formed by the side chain containing one α,β-unsaturated system (double bond at C-11 and carbonyl group at C-13) attached at C-9. The proposed structure was confirmed by correlations of the hydrogen signal at δH 7.05 (H-11) with carbon resonances at δC 41.5 (C-8), 41.0 (C‑9), 25.8 (C‑18), 35.7 (C-10) and 200.1 (C-13). Additional cross peaks between the signal at δH 6.15 (H-12) with those at δC41.0 (C-9) and δC 200.1 (C-13), and between the signal at δH2.20 (H-14) with the resonance of the carbonyl group at δC 200.1 (C-13), confirmed the connectivity of the carbon side chain at C-9 (Figure 2). Trans configuration of the double bond at C-11 was confirmed by the coupling constant of doublets assigned to H-11 and H-12 (J 16.5 Hz) (Table 1).1616 Borges-Argaez, R.; Medina-Baizabal, L.; May-Pat, F.; Waterman, P. G.; Pena-Rodriguez, L. M.; J. Nat. Prod. 2001, 64, 228. Additionally, the 13C NMR spectrum displayed signals at δC 169.9, 173.0 and 173.3, which were assigned to one acetate and two butanoate groups, respectively.1010 Santos, A. G.; Ferreira, P. M.; Vieira Jr., G. M.; Perez, C. C.; Tininis, A. G.; Silva, G. H.; Bolzani, V. S.; Costa-Lotufo, L. V.; Pessoa, C. O.; Cavalheiro, A. J.; Chem. Biodiversity 2010, 7, 205. The acetate group was attached to C-17 of the diacetalic ring C, as deduced from the HMBC correlations between the signal at δH 6.31 (H‑17) and that at δC 169.9 (C-1’’’). Furthermore, the signal at δH6.31 (H-17) exhibited correlations with those at δC145.7 (C-4), 53.4 (C-5), 71.5 (C-6) and 95.0 (C-16) (Figure 2). The assignment of the structure was straightforward with exception of the butyrate groups, since HMBC correlations between H-2, or H-16, and the carbonyl groups were not observed, in accordance with previously reported data.1717 Williams, R. B.; Norris, A.; Miller, J. S.; Birkinshaw, C.; Ratovoson, F.; Andriantsiferana, R.; Rasamison, V. E.; Kingston, D. G. I.; J. Nat. Prod. 2007, 70, 206.,1818 Gibbons, S.; Gray, A. I.; Waterman, P. G.; Phytochemistry 1996, 41, 565. However, the downfield chemical shift of C-2 (δC 66.3) and C-16 (δC 95.9) indicated that the butanoate groups were attached at C-2 and C-16 of the A ring.1010 Santos, A. G.; Ferreira, P. M.; Vieira Jr., G. M.; Perez, C. C.; Tininis, A. G.; Silva, G. H.; Bolzani, V. S.; Costa-Lotufo, L. V.; Pessoa, C. O.; Cavalheiro, A. J.; Chem. Biodiversity 2010, 7, 205.,1717 Williams, R. B.; Norris, A.; Miller, J. S.; Birkinshaw, C.; Ratovoson, F.; Andriantsiferana, R.; Rasamison, V. E.; Kingston, D. G. I.; J. Nat. Prod. 2007, 70, 206. Spectral analysis of heteronuclear single quantum coherence (HSQC) indicated the correlations δH 7.05 (H-11)/δC153.3 (C-11), δH 6.15 (H-12)/δC 130.6 (C‑12), and δH 2.2 (H-14)/δC 23.5 (C-14), which confirmed the partial structure of the side chain. An additional cross peak between the signal at δH 1.17 (H-7) with that at δC36.2 (C-7) suggested that there was no substituent in this carbon, a similar pattern previously observed for casearin X,1010 Santos, A. G.; Ferreira, P. M.; Vieira Jr., G. M.; Perez, C. C.; Tininis, A. G.; Silva, G. H.; Bolzani, V. S.; Costa-Lotufo, L. V.; Pessoa, C. O.; Cavalheiro, A. J.; Chem. Biodiversity 2010, 7, 205. caseanigrescen D,1717 Williams, R. B.; Norris, A.; Miller, J. S.; Birkinshaw, C.; Ratovoson, F.; Andriantsiferana, R.; Rasamison, V. E.; Kingston, D. G. I.; J. Nat. Prod. 2007, 70, 206. and argutin A.1919 Whitson, E. L.; Thomas, C. L.; Henrich, C. J.; Sayers, T. J.; McMahon, J. B.; McKee, T. C.; J. Nat. Prod. 2010, 73, 2013. Thus, considering that the structure of 5 differs from that of casearin X with regards to its C-9 side chain, which is shortened by two carbons, the name dinor casearin X was proposed for this substance.

Figure 2
Key HMBC correlations (H → C) observed for compound 5.

The relative configuration at the stereogenic centers of 5 was suggested from the comparison of its 13C NMR spectral data and hydrogen coupling constants with those reported in the literature.2020 Kanokmedhakul, S.; Kanokmedhakul, K.; Buayairaksa, M.; J. Nat. Prod. 2007, 70, 1122.

21 Vieira-Júnior, G. M.; Gonçalves, T. O.; Regasini, L. O.; Ferreira, P. M. P.; Pessoa, C. O.; Lotufo, L. V. C.; Torres, R. B.; Boralle, N.; Bolzani, V. S.; Cavalheiro, A. J.; J. Nat. Prod. 2009, 72, 1847.
-2222 Vieira-Júnior, G. M.; Dutra, L. A.; Ferreira, P. M. P.; Moraes, M. O.; Lotufo, L. V. C.; Pessoa, C. O.; Torres, R. B.; Boralle, N.; Bolzani, V. S.; Cavalheiro, A. J.; J. Nat. Prod. 2011, 74, 776. The cis configuration of the A/B ring junction was deduced from chemical shift of Me-18 (dC25.8).1010 Santos, A. G.; Ferreira, P. M.; Vieira Jr., G. M.; Perez, C. C.; Tininis, A. G.; Silva, G. H.; Bolzani, V. S.; Costa-Lotufo, L. V.; Pessoa, C. O.; Cavalheiro, A. J.; Chem. Biodiversity 2010, 7, 205.,2121 Vieira-Júnior, G. M.; Gonçalves, T. O.; Regasini, L. O.; Ferreira, P. M. P.; Pessoa, C. O.; Lotufo, L. V. C.; Torres, R. B.; Boralle, N.; Bolzani, V. S.; Cavalheiro, A. J.; J. Nat. Prod. 2009, 72, 1847. Cis clerodane diterpenes that are not substituted at C-7 show chemical shifts around dC 15 and 26 for Me-17 and Me-20, respectively, when these groups are in a trans relationship,5Itokawa, H.; Totsuka, N.; Morita, H.; Takeya, K.; Litaka, Y.; Schenkel, E. P.; Motidome, M.; Chem. Pharm. Bull. 1990, 38, 3384. whereas values around dC 16 and 18 for Me-17 and Me-20, respectively, characterize a cis relationship.7Morita, H.; Nakayama, M.; Kojima, H.; Takeya, K.; Itokawa, H.; Ichenkel, E. P.; Motidome, M.; Chem. Pharm. Bull. 1991, 39, 693.,1010 Santos, A. G.; Ferreira, P. M.; Vieira Jr., G. M.; Perez, C. C.; Tininis, A. G.; Silva, G. H.; Bolzani, V. S.; Costa-Lotufo, L. V.; Pessoa, C. O.; Cavalheiro, A. J.; Chem. Biodiversity 2010, 7, 205. Considering that in the structure of dinor casearin X there is no substituent at C-7, the carbon resonances of Me-15, and Me-18 indicated their trans relationship. The carbon chemical shift for C-2 was determined to be dC 66.3, which is consistent with a C-2 substituent having an α-orientation. When the substituent has β-orientation the chemical shift is around dC 70.1717 Williams, R. B.; Norris, A.; Miller, J. S.; Birkinshaw, C.; Ratovoson, F.; Andriantsiferana, R.; Rasamison, V. E.; Kingston, D. G. I.; J. Nat. Prod. 2007, 70, 206.,1919 Whitson, E. L.; Thomas, C. L.; Henrich, C. J.; Sayers, T. J.; McMahon, J. B.; McKee, T. C.; J. Nat. Prod. 2010, 73, 2013.,2020 Kanokmedhakul, S.; Kanokmedhakul, K.; Buayairaksa, M.; J. Nat. Prod. 2007, 70, 1122.,2323 Beutler, J. A.; McCall, K. L.; Herbert, K.; Herald, D. L.; Pettit, G. R.; Johnson, T.; Shoemaker, R. H.; Boyd, M. R.; J. Nat. Prod. 2000, 63, 657.,2424 Kanokmedhakul, S.; Kanokmedhakul, K.; Kanarsa, T.; Buayairaksa, M.; J. Nat. Prod. 2005, 68, 183. Moreover, the J values of 7.5 and 14.0 Hz for the coupling H-10/H-1 revealed that H-10 has an axial orientation.2121 Vieira-Júnior, G. M.; Gonçalves, T. O.; Regasini, L. O.; Ferreira, P. M. P.; Pessoa, C. O.; Lotufo, L. V. C.; Torres, R. B.; Boralle, N.; Bolzani, V. S.; Cavalheiro, A. J.; J. Nat. Prod. 2009, 72, 1847.

The crude MeOH extract from the leaves of C. sylvestris and its respective hexane partition phase displayed cytotoxic effects on B16F10-Nex2, A2058, HL-60, HCT, MCF-7, and HeLa tumor cell lines. Bioguided fractionation afforded compounds 1-5 as being responsible for the activity (Table 2). Based on the IC50 values casearins 1, 2 and 4 showed cytotoxic activities for all tested cell lines, while casearin G (3) exhibited cytotoxic activity only for HL-60, HeLa and HCT. Dinor casearin X (5) was the less active compound against the tested cell lines in comparison with casearins 1-4, except for the HL-60 cell line, thus indicating a probable selective activity of this compound. Therefore, studies upon the mechanism of action of this new compound on HL-60 cells must be addressed in order to eventually propose dinor casearin X as a lead anti-leukemic agent.

Table 2
Cytotoxic activity of compounds 1-5 against human tumor cell lines

Conclusions

One novel clerodane diterpene, named dinor casearin X, was isolated from leaves of Casearia sylvestris. Dinor casearin X reduced cell viability of the HL-60 tumor cell line, indicating a selective cytotoxic activity of this compound when compared to that displayed against other cells lines (A2058, HCT, MCF-7 and HeLa). These findings suggest that dinor casearin X could be considered as a lead anti-leukemic agent.

  • Supplementary Information
    Supplementary data are available free of charge at http://jbcs.sbq.org.br as PDF file.
  • FAPESP has sponsored the publication of this article.

Acknowledgments

The authors wish to thank PhD Roseli Buzanelli Torres for the identification of Casearia sylvestris. This work was supported by grants from FAPESP (2011/51739-0 and 2013/16320-4) and CNPq. D. D. B. obtained a fellowship from CAPES, P. S. and J. H. G. L. received a scientific research award from CNPq. We are greatful to Prof João Batista Fernandes for use of nanoprobe NMR and to Prof Ari J. S. Ferreira for revision.

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Data availability

Publication Dates

  • Publication in this collection
    Aug 2015

History

  • Received
    19 Mar 2015
  • Accepted
    19 May 2015
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