Print version ISSN 0103-5053
J. Braz. Chem. Soc. vol.22 no.7 São Paulo July 2011
Lisandra V. Rosas; Thiago André M. Veiga; João B. Fernandes; Paulo C. Vieira; M. Fátima das G. F. da Silva*
Departamento de Química, Universidade Federal de São Carlos, CP 676, 13565-905 São Carlos-SP, Brazil
The dichloromethane extract from the stems of Raputia praetermissa afforded four new compounds, 4-deoxyraputindole C (1), raputimonoindoleA-B (2, 3), and hexadecanyl 2-hydroxy-4-methoxy-cinnamate (5), besides the alkaloids 5-(4-methoxymethylfuran-2-yl)-1H-indole (raputimonoindole C), furoquinolines maculosidine, robustine, evolitrine and dictamnine. The hexane extract yielded N-methyl-4-methoxyquinolin-2(1H)-one, skimmianine, cycloartenone, sitosterol, stigmasterol and sitostenone. The anthranilate alkaloid content indicates that the genus is strongly related to those included in Cusparieae tribe, but differs from Neoraputia by the absence of prenylindole alkaloids in the late, whose species have previously been placed in Raputia.
Keywords: Raputia praetermissa, Neoraputia, Rutaceae, prenylindole alkaloids, chemosystematics
O extrato diclorometano do caule de Raputia praetermissa levou ao isolamento de quatro compostos novos, 4-desóxi-raputindol C (1), raputimonoindol A-B (2, 3) e hexadecanil 2-hidróxi-4-metóxi-cinnamato (5), juntamente com os alcalóides 5-(4-metóxi-metilfuran-2-il)-1H-indol (raputimonoindol C), furoquinolinos maculosidine, robustine, evolitrine e dictamnine. O estudo do extrato hexano levou ao isolamento de N-metil-4-metóxi-quinolin-2(1H)-ona, skimmianina, cicloartenona, sitosterol, stigmasterol e sitostenona. Os alcalóides antranílicos isolados indicam que o gênero possui afinidade química relevante com aqueles da tribo Cusparieae, mas difere de Neoraputia devido à ausência de alcalóides prenilindois neste último, cujas espécies foram anteriormente incluídas em Raputia.
The Raputia genus was established by Aublet in 1775,1 and based on morphological characteristics of R. aromatica Aubl. Emmerich later dismembered this genus,1 placing most of the species into Neoraputia Emmerich, Sigmatanthus Huber ex Emmerich, and Raputiarana Emmerich. Following the research of Kallunki and Pirani,2-5 a total of eleven species have now been included in the Raputia genus: R. aromatica Aubl., R. maroana (R. S. Cowan) Kallunki, R. neblinensis (R. S. Cowan) Kallunki, R. ulei (K. Krause) Kallunki, R. brevipedunculata Kallunki, R. megalantha Kallunki, R. simulans Kallunki, R. amazonica (Huber) Kallunki (synonym: Ravenia amazonica Huber), R. szczerbanii (Steyerm.) Kallunki (synonym: Lubaria szczerbanii Steyerm.), R. hirsuta (Gereau) Kallunki and R. praetermissa Pirani & Kallunki. Raputia and Neoraputia are assigned to the tribe Cusparieae and are distributed from Venezuela and French Guiana to Amazonian Colombia, Peru and Brazil.5
Previous investigations of Neoraputia reported the presence of eleven polymethoxylated flavonoids, six flavones, three 5,6-(2",2"-dimethylpyrano)flavones, one 6,7-(2",2"-dimethylpyrano)flavone and one flavanone from N. alba (Engler) Emmerich;6,7 five polymethoxylated flavones and two flavanones, 2'-hydroxy-3,4,4',5,6'- pentamethoxychalcone, three 5',6'-(2",2"-dimethylpyrano)-polymethoxylated chalcones from N. magnifica var. magnifica (Engler) Emmerich;8,9 ten polymethoxylated flavonoids, six flavones, three 6,7-(2",2"-dimethylpyrano) flavones and one 6-(3"-hydroxy,3"-methyl-trans-but-1" - enyl)flavone from N. paraensis.10,11 A reinvestigation of N. paraensis searching for alkaloids afforded flindersine, skimmianine, 8-methoxyflindersine and dictamnine.12 C-glycosylflavones were also reported from N. paraensis,13 which was cited as Raputia paraensis, but this species was transferred to Neoraputia by Emmerich.1
The first investigation about the chemistry of Raputia reported the presence of cyclopentyl bisindole alkaloids raputiindoles A-D from R. simulans Kllunki.14
In this paper we report a phytochemical study on R. praetermissa Pirani & Kallunki, and the chemosystematic significance of isolated compounds is discussed in order to clarify the relationships between Raputia and Neoraputia.
Results and Discussion
The dichloromethane extract from the stems of Raputia praetermissa afforded four prenylindole alkaloids (1-4), a cinnamic acid derivative (5) (Figure 1), and furoquinoline alkaloids maculosidine, robustine, evolitrine15 and dictamnine.16 The hexane extract yielded N-methyl-4-methoxyquinolin-2(1H)-one,17 skimmianine,17 cycloartenone,18 sitosterol, stigmasterol and sitostenone.
Compound 1, C26H26N2 (HREIMS), was identified as a bisindole alkaloid. The presence of two indole nucleus was suggested by an UV absorption maximum at 328 nm, an IR band at 3426 cm -1 (NH), and 1H NMR signals for N-H protons at δ 8.00 and 8.04 (brs, no correlation in the HSQC spectrum) (Table 1), which in the COSY experiments showed cross peaks with the 1H signals at δH 7.14 (dd, 3.2, 2.5 Hz), 6.50 (ddd, 3.2, 2.5, 1.0 Hz), 7.11 (dd, 3.0, 2.5 Hz) and 6.44 (ddd, 3.0, 2.5, 1.0 Hz), respectively. These signals were then assigned to 2N-H (d 8.00 and 8.04), 2H-α (δH 7.14 and 7.11) and 2H-b (δH 6.50 and 6.44) of the indole rings, respectively. HMBC cross peaks (Figure 2) between the signals H-4' (δH 7.30)/C-3' (δC 102.3), C-6' (δC 144.3), 7'a (δC 135.5) and 40.7 (CH); H-7' (δH 7.18)/C-3'a (δC 127.3), C-5' (δC 139.4), and δC 48.5 (quaternary carbon) led to the assignment of a 5',6'-dialkylindole system. Moreover, the observed cross peaks between the 1H signals at δH 4.07 (H-6), 2.43 (H-5a) and 1.81 (H-5b), and the 13C signals for C-5', C-6' and 48.5 (quaternary carbon, C-3) suggested a 3,3,6-trisubstituted cyclopentyl fused to the indole ring at C-5' and C-6'. An isobutene group was identified from the 1H NMR signals at δH 5.22 (dsep, 9.0, 1.0), 1.82 (br s, 3H), and 1.79 (br s, 3H), assigned to olefinic proton and methyl groups, respectively. This was supported by the HMBC experiments which showed correlations from the olefinic proton at δH 5.22 to the methyl carbons at δc 25.9 and 18.3. The isobutene group was connected at C-6 due to coupling of H-6 to the olefinic proton at δH 5.22. A methyl group must be connected at C-3 due to the observed HMBC cross peaks between its 1H signal at δ3H 1.59 and the 13C signals for C-6' and C-3. This structural unit was corroborated by the MS base-peak at m/z 223.13387 (100.0%) resulting from C-3-C-2 cleavage.
The 1H NMR spectrum also showed signals for three hydrogens with ortho and meta coupling constants, δH (d, 0.7 Hz), 7.23 (dd, 8.4, 0.7 Hz) and 7.22 (d, Hz), suggesting the second indole nucleus to be monosubstituted. In adition, the presence of a trans-disubstituted double bond was evidenced by two vinylic protons at δH6.13 (δC126.8) and 6.40 (d, 16.0 Hz; δC136.0) with a vicinal coupling constant of 16.0 Hz. From HMBC experiments the observed cross peak between the signal with meta coupling constant at δH 7.50 and the 13C signal for C-3" (δC 102.7), permited the assignment of the signal at δH 7.50 to H-4" (C-4", δC 118.7). The meta coupling constant for H-4" indicatedthat C-5" was substituted. The attachment of the ethylenyl bridge to C-3 and C-5" was evidenced from HMBC correlations H-1 (δH 6.13)/C-3, C-4" and H-2 (δH 6.40)/C-3, C-6'. These spectral characteristics are in agreement with those published for raputindole C (6, Figure 3), isolated from Raputia simulans.14 The main difference observed in the 1H and 13C NMR spectra (Tables 1 and 2) of compound 1, when compared to those of 6, was the replacement of the signal for an oxymethylene by a methyl singlet (C-4, δ3H 1.59, δC27.1). The relative stereochemistry of compound 1, named as 4-deoxyraputindole C, was determined from gNOESY experiments. The nOes of H-2, H-1, and H-5a, coming from H-6, indicated that H-6 and the ethylenylindole system are on the same side of the five-membered ring, whereas nOe between H-5b and CH3-4, required the methyl group to be anti (β) to H-6, and syn to the isobutene chain.
Compounds 2-4 showed the spectral characteristic of a 5-substituted-1H-indole alkaloid (Tables 1, 2). The 13C NMR spectrum (Table 2) revealed resonances for C-2 to C-7a in close agreement with those for the corresponding carbons in the structural unit 5-substituted-1H-indole of compound 1, except for C-5 whose chemical shift was affected by a different substituent. Elemental analysis and MS indicated the molecular formula to be C18H21NO for compound 2, requiring the presence of an aliphatic chain of 10 carbons and one oxygen. A heterocyclic oxolane was identified from the 1H NMR spectrum, which showed a proton at δH 2.73 (td, 7.0, 5.6, H-3'; δC 51.6) coupled to a proton attached to carbon adjacent to an oxygen atom (δH 4.64, d, 5.6, H-2'; δC 86.6), and two doublet of doublets for an oxymethylene (δH 4.44, 4.65, J 13.1, 2.3, 2H-5'; δC 71.5). Observed HMBC cross peaks between the 1H signals at δH 2.73 (H-3') and 4.64 (H-2') with the 13C signals at δC 132.7 (C-5) and 119.1 (C-4), respectively, as well as those of H-5'a and H-5'b (δH 4.44 and 4.65) with C-3' (δC 51.6), suggested the attachment of the heterocyclic oxolane to C-5 of the indole nucleus. The presence of an isopentene group was deduced from the proton resonances at δH 5.12 (tsep, 7.0, 1.2, H-8'), 1.64 (br s, 3H-10'), 1.60 (br s, 3H-11'), 2.28 (br t, 7.0, 2H-7'), and corroborated by the HMBC correlation between the methyl and methylene protons with the olefinic carbons at δC 132.7 (C-9') and 121.7 (C-8'). This was supported by the mass spectrum which showed fragment at m/z 211 [C18H21NO - C4H8]+. The 1H-1H coupling between the methylene at δH 2.28 and H-3'(δH 2.73) indicated the linkage of the isopentene chain to C-3'. An exomethylene (δH 4.99, 4.97, J 2.3, 2H-6'; δC 103.6) must be connected at C-4' of oxolane ring on the basis of the observed cross peaks between the 1H signals at δ2H 4.99/4.97and the 13C signals for C-3' (δC51.6) and C-5' (δC 71.5). As for compound 1, the relative stereochemistry of 2 was deduced from gNOESY experiments. The nOes of the H-4 and H-6, coming from H-3', indicated that H-3' and the indole system must be on the same side of the oxolane ring. The above data confirmed the structure of 2, here named as raputimonoindole A.
As commented above compounds 2-4 showed the spectral characteristic of a 5-substituted-1H-indole alkaloid. Elemental analysis and MS indicated the molecular formula to be C14H11NO3 and C14H13NO2 for compounds 3 and 4, respectively, requiring the presence of an aliphatic chain of 6 carbons (C6H5O3 and C6H7O2, respectively) and indole nucleus (C8H6N). Their 1H NMR resonances, when compared to those of 2, showed low field shifts for the disubstituted furan ring potons. In compound 3, the existence of a cross peak between the 1H signal at δH 6.88 assigned to H-3', and the 13C signal at δC 123.0 assigned to C-5, determined the position of the furan ring at C-5 of the indole nucleus. The presence of a carbomethoxy group linked at C-4' was indicated by HMBC cross peaks between the 1H signals at δH 8.04 (H-5', δC 146.3) and 3.87 (methyl protons) with the 13C signal at δC 165.0 (C-6'). The structure of the new natural product is therefore 5-(4-carbomethoxylfuran-2-yl)-1H-indole, here named as raputimonoindole B (3). However, compound 3 was purified by column chromatography on Sephadex and eluted with MeOH-CH2Cl2, hence, 3 could be an artifact.
The 1H NMR resonances for compound 4, when compared to those of 2, showed low field shifts for the disubstituted furan ring potons. In compound 4, the main difference observed in the 1H NMR, when compared with 3, was the replacement of the resonance for a carbomethoxy group by two 1H singlets at δ2H 4.11 (δC 66.0) and δ3H 3.44 (δC 57.6) from a methoxymethylene group. This was supported by the mass spectrum which showed a fragment at m/z 197 [C14H13NO2 - H2CO]+. These signals together with the mass and 13C NMR spectral data are consistent with 4 being 5-(4-methoxymethylfuran-2yl)-1H-indole, which has previously been isolated from Raputia simulans Kallunki.19 However, the isolation of 5-(4-methoxymethylfuran-2-yl)-1H-indole was cited without spectroscopic data in an congress whose abstracts were published in Planta Medica Proceedings.19 Thus, its spectroscopic data are cite here for the first time, and it was named raputimonoindole C.
The cinnamic acid (5) derivative showed the spectral characteristic of a trans α,β-unsaturated carboxyl functional group (δHβ 7.61, d, J 15.9, δCβ 144.5; δHα 6.29, d, J 15.9, δCα 115.7; COOR 167.3). In addition, the 1H NMR showed signals for one methoxyl group at δH 3.92 (s, 3H; δC 55.9), three aromatic hydrogens at δH 7.07 (dd, 8.1, 1.7 Hz), 7.03 (d, 1.7 Hz) and 6.91 (d, 8.1 Hz), clearly indicating the aromatic ring to be 1,2,4-trisubstituted. From the HMBC experiments, the cross peaks observed between the signal of methoxyl group at δ3H 3.92 with δC 146.7, and the 1H signal at δH 7.61 (H-3') with δC 147.9 but not with δC 146.7, indicated the presence of a 2-hydroxy-4-methoxy-cinnamic acid derivative. The 13C NMR spectrum revealed resonances for an aliphatic chain of sixteen carbons, one being attached to carboxylate as indicated by the HMBC cross peak between the 1H signal at δH 4.18 and the 13C signal at δ 167.3 (C-1'). The presence of a hexadecanyl chain was corroborated by the MS spectrum, which showed an ion at m/z 279 [HCC-COO-(CH2)14-CH2]+. The new compound was therefore identified as hexadecanyl 2-hydroxy-4-methoxy-cinnamate (5). The structural assignment was also supported by comparison of its 13C NMR spectrum with that of 4-hydroxy-2- methoxy-cinnamic acid.20
A number of 3,5- and 3,6-diprenylated indoles have been reported for the Annonaceae genera Isolona,21-23 Uvaria,22 Annonidium,24 Monodora,25 Hexalobus,26 Asteranthe,27 Greenwayodendron,28 and Polyalthia.29 However, there are only a few examples of 3-, 5-, 6- and 7-and 3,7-prenylated indoles reported in the Rutaceae genera Raputia,14 Esenbeckia,30,31 Murraya,32-34 Merrillia35 and Glycosmis.36,37 Four bisindoles (6-9; Figure 3) similar to compound 1 have been isolated from Raputia simulans.14 One bisindole, yuehchukene, which may be regarded as the product of Diels-Alder-type condensation of two 3-isopentenylindoles, occurs in Murraya species.32 While several bisindoles derived from 2-prenyltryptamine have been isolated from Flindersia species (Rutaceae),38 pyrano[3,2-b]indole skeleton (koniamborine), a novel type of alkaloid was isolated from Boronella koniambiensis (Rutaceae).39
The anthranilate alkaloid content found in R. praetermissa indicates that the genus is strongly related to those included in Cusparieae tribe. As mentioned in the introduction, the polimethoxylated flavonoids form an extremely good marker for the Neoraputia. Their use in this context shows that R. praetermissa differs substantially from Neoraputia species, and reinforce its inclusion in Raputia genus. Furthermore, the prenylindole alkaloids have been reported only from Esenbeckia and Raputia in Cusparieae, thus suggesting an affinity of this tribe with subfamily Aurantioideae, where similar prenylindoles occur in Murraya,33-35 Merrillia36 and Glycosmis.37,38 It is noteworthy that Neoraputia shares with Murraya and Citrus a propensity for producing polymethoxylated flavonoids,9,12,40,41 showing also chemical affinity with Aurantioideae.
General experimental procedures
Optical rotations were measured by using a Perkin Elmer 241 spectropolarimeter; NMR: Bruker DRX 400, with TMS as internal standard; high resolution EI-MS: Fisons VG Autospec; GC-MS: low resolution on a HP-2576 instrument; IR: Bomen-FT/IR; UV: Hewlett Packard/8452A; Elemental analyses: on a EA 1108, CHNS-O (Fisons).
Raputia praetermissa was collected in the Forest Reserve Adolpho Ducke, Amazonas, Brazil, and identified by J. R. Pirani (Department of Botany, University of São Paulo). A voucher specimen (189865) is deposited in the Herbarium of the Instituto Nacional de Pesquisa da Amazônia (INPA), Manaus, AM (Brazil).
Extraction and isolation
Ground stems (4.4 kg) were extracted 3 times at room temperature using hexane, followed by CH2Cl2 and MeOH. The concentrated hexane extract (13.3 g) was subjected to silica gel (230-400 mesh) column chromatography with successive elution with hexane, CH2Cl2, EtOAc and MeOH, yielding 6 fractions. Fraction 2 was flash rechromatographed twice on silica gel with successive elution with hexane, CH2Cl2, EtOAc and MeOH, and then by preparative TLC (silica gel; hexane-acetone 9:1), yielding cycloartenone (10 mg). Fraction 3 was flash rechromatographed twice as above, and then by gel permeation column chromatography (Sephadex LH 20, CH2Cl2-MeOH 2:8) affording N-methyl-4-methoxyquinolin-2(1H)-one (30 mg). Fraction 4 was chromatographed on silica gel and Florisil (1:1) with hexane-EtOAc-MeOH gradient elution to give two fractions (A and B). Fraction A was subjected to column chromatography over silica gel and eluted with hexane-acetone gradient, yielding a mixture of sitosterol and stigmasterol. Fraction B was purified by preparative TLC (silica gel; hexane-acetone 9:1), yielding sitostenone (60 mg). Fraction 5 was chromatographed on silica gel and Florisil (1:1) with hexane-EtOAc-MeOH gradient elution to give skimmianine (50 mg).
The concentrated dichloromethane extract (30.0 g) was subjected to column chromatography over silica gel (70-230 mesh) under vacuum. Elution with hexane, CH2Cl2, EtOAc and MeOH yielded 4 fractions. Fraction 1 was flash rechromatographed on silica gel with hexane-EtOAc-MeOH gradient, yielding compound 1 (700 mg) and a new fraction C. Fraction C was flash rechromatographed twice as above, and then by preparative TLC (silica gel; hexane-acetone 6:1), yielding compound 5. Fraction 2 was chromatographed on silica gel and Florisil (1:1) with hexane-acetone-MeOH gradient elution to give new fractions D, E and F. Fractions D and E were rechromatographed over Sephadex LH 20 (MeOH) to give compounds 2 and 4, respectively. Fraction F was flash rechromatographed on silica gel with hexane-acetone-MeOH gradient elution, yielding robustine (50 mg). Fraction 3 was rechromatographed as above using hexane-CH2Cl2-MeOH gradient to yield two fractions. Both fractions were rechromatographed over Sephadex LH 20 (MeOH-CH2Cl2 2:8) affording maculosidine (80 mg), and a new fraction containing compound 3 which was purified by preparative TLC (silica gel; hexane-acetone 5:1). Fraction 4 was rechromatographed on silica gel and Florisil (1:1) with hexane-acetone-MeOH gradient elution to give evolitrine (50 mg) and dictamnine 120 mg).
4-Deoxyraputindole C (1)
Brown solid; [α]D25 + 94 (CHCl3; c 0.0012); UV (acetone) λmax/nm: 230; IR (KBr) νmax/cm-1: 3425.7; 1H NMR (400 MHz, CDCl3), see Table 1; 13C NMR (100 MHz, CDCl3), see Table 2; HREI-MS, 366.20560 (37.5; calc. for C26H26N2), 294.11201(10.0), 223.13387 (100), 167.07123 (20), 130.06388 (30).
Raputimonoindole A (2)
Yellow solid; [a]D25 -41 (CHCl3;c 0.003); UV (acetone) λmax/nm: 228; IR (KBr) νmax/cm-1: 3411.5; 1H NMR (400 MHz, CDCl3), see Table 1; 13C NMR/DEPT (100 MHz, CDCl3), see Table 2. Anal. found C 80.28%, H 7.80%, N 5.20%; calc. for C18H21NO, C 80.86%, H 7.92%, N 5.24%, O 5.98 %; MS m/z 267 [M]+ (10), 252 (5), 211 (50), 144 (100), 107 (80), 79 (70).
Raputimonoindole B (3)
Yellow solid; UV (acetone) λmax/nm: 230; IR (KBr) νmax/cm-1: 3310.2, 1770.1; 1H NMR (400 MHz, CDCl3), see Table 1; 13C NMR/DEPT (100 MHz, CDCl3), see Table 2. Anal. found C 69.76%, H 4.58%, N 5.80%; calc. for C14H11NO3, C 69.70%, H 4.60%, N 5.81%, O 19.90 %; MS m/z 241 [M]+ (100), 226 [C14H11NO3 - Me]+ (15), 210 [C14H11NO3 -OMe]+ (10), 198 (10), 154 (30), 105 (40), 77 (50).
Raputimonoindole C (4)
Yellow solid; UV (acetone) λmax/nm: 232; IR (KBr) νmax/cm-1: 3315.4; 1H NMR (400 MHz, CDCl3), see Table 1; 13C NMR/DEPT (100 MHz, CDCl3), see Table 2. Anal. found C 73.90%, H 5.80%, N 6.15%; calc. for C14H13NO2, C 73.99%, H 5.77%, N 6.16%, O 14.08 %; MS m/z 227 [M]+ (100), 197 (80), 168 (70), 98 (30).
Hexadecanyl 2-hydroxy-4-methoxy-cinnamate (5)
Amorphous white solid; 1H NMR (400 MHz, CDCl3): δ 7.61 (d, J 15.9 Hz, H-3'), 7.07 (dd, J 8.1, 1.7 Hz, H-5), 7.03 (d, J 1.7 Hz, H-3), 6.91 (d, J 8.1 Hz, H-6), 6.29 (d, J 15.9, H-2'), 3.92 (s, OMe), 4.18 (t, J 6.8 Hz, H-1"), 1.69 (quint, J 6.8 Hz, H-2"), 1.25 (br s, 3"-15") and 0.88 (t, J 6.6 Hz, H-16); 13C NMR (100 MHz, CDCl3): δ 167.3 (C-1'), 147.9 (C-2), 146.7 (C-4), 144.5 (C-3'), 127.0 (C-1), 123.0 (C-5), 115.7 (C-2'), 114.6 (C-6), 109.3 (C-3), 64.5 (C-1"), 55.9 (OMe), 29.6-28.7 (C-3"-C-15"), 14.0 (C-16"); MS m/z 418 [M]+ (5), 279 (10), 207 [279 - C5H12]+ (10), 167 (50), 149 (100), 71 (40), 57 (45).
Note from the Editor
During the edition of the present paper, the spectroscopic data of compound 4 have been published online on March 7, 2011 by Planta Medica, in the entitled Letter "Simple Indole Alkaloids from the Neotropical Rutaceous Tree Raputia simulans" by K. Vougogiannopoulou,N.Fokialakis,N.Aligiannis, C. Cantrel, A-L Skaltsounis.
1H and 13C NMR spectra of compounds 1-5 are available free of charge at http://jbcs.sbq.org.br as PDF file.
The authors thank the Brazilian agencies, Institutos Nacionais de Ciência e Tecnologia -Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq/MCT), Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP), Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES) and Financiadora de Estudos e Projetos (FINEP) for their financial support.
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Submitted: October 4, 2010
Published online: March 24, 2011
FAPESP has sponsored the publication of this article.