Palladium salicylaldimine complexes containing boronate esters

Springer 2005

Transition Metal Chemistry (2005) 30: 63–68

Palladium salicylaldimine complexes containing boronate esters Haiwen Zhang, David W. Norman, Tracey M. Wentzell, Alison M. Irving, Janet P. Edwards, Susan L. Wheaton, Christopher M. Vogels and Stephen A. Westcott* Department of Chemistry, Mount Allison University, Sackville, NB E4L 1G8, Canada Felix J. Baerlocher Department of Biology and Biochemistry, Mount Allison University, Sackville, NB E4L 1G7, Canada Andreas Decken Department of Chemistry, University of New Brunswick, Fredericton, NB E3B 5A3, Canada Received 13 July 2004; accepted 5 August 2004

Abstract

4: 3-Bpin, 5: 4-Bpin a: R = H, b : R = NO2, c : R = naphthalene

Reactions of salicylaldehydes with boronate ester derivatives of aniline have been examined. Addition of these Schiff base ligands to palladium acetate or Na2PdCl4 afforded novel boron-containing trans-bis(N-arylsalicylaldiminato) palladium complexes. Condensation of salicylaldehyde (2-HOC6H4C(O)H) with H2NC6H4Bpin (pin ¼ 1,2-O2C2Me4) afforded the boron-containing Schiff bases, 2-HOC6H4C(H)@NC6H4Bpin (1–3a). Similar reactivity with 2-hydroxy-5-nitrobenzaldehyde and 2-hydroxy-1-naphthaldehyde gave the corresponding Schiff bases (1-3b) and (1-3c), respectively. Reaction of Schiff bases (2) and (3) with palladium acetate or Na2PdCl4 afforded complexes of the type PdL2 (4,5), where L ¼ deprotonated Schiff base. The molecular structure of the nitro-salicylaldehyde 4-Bpin palladium complex (5b) was characterized by an X-ray diffraction study. All new palladium compounds have been characterized fully and tested for their antifungal activity against Aspergillus niger and Aspergillus flavus. Introduction Compounds containing boronic acids [RB(OH)2] or boronate esters [RB(OR¢)2] have been used extensively as intermediates in Suzuki–Miyaura cross-coupling reactions for a variety of applications [1–11]. Interest in these boron compounds also arises from their potent biological activities [12–26]. For instance, aminoboronic acids are potent inhibitors of serine proteases, a diverse group of proteolytic enzymes responsible for the generation of most disease processes [13–18]. The boronic *

Author for correspondence

acid containing inhibitor 2(S)-amino-6-boronohexanoic acid has also recently been shown to enhance erectile function in male rats [25]. Likewise, simple aminoboronic acid derivatives are also being examined for application in boron neutron capture therapy, a binary form of cancer treatment that relies on delivering a compound containing boron-10 selectively to tumour tissues prior to irradiation by neutrons [26]. With the wealth of medicinal properties associated with boron compounds, we decided to examine the ability of Schiff bases derived from salicylaldehydes and boronate ester aniline compounds, (4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenylamine, to act as ligands with

64 biologically active metals. Results of our study are presented herein.

Experimental Materials and measurements Reagents and solvents used were obtained from Aldrich Chemicals and Strem Chemicals. Palladium(II) acetate was purchased from Precious Metals Online Ltd. 2-(4,4,5,5-Tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenylamine [27] and 3-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)phenylamine [28] were prepared as described in the literature. Schiff bases were prepared as described elsewhere [29, 30]. N.m.r. spectra were recorded on a JEOL JNM-GSX270 FT n.m.r. spectrometer. 1H-n.m.r. chemical shifts are reported in p.p.m. and referenced to residual protons in deuterated solvent at 270 MHz. 11B-n.m.r. chemical shifts are referenced to external BF3 Æ OEt2 at 87 MHz. 13 C-n.m.r. chemical shifts are referenced to solvent carbon resonances as internal standards at 68 MHz. Multiplicities are reported as singlet (s), doublet (d), triplet (t), multiplet (m), broad (br), and overlapping (ov). I.r. spectra were obtained using a Mattson Genesis II f.t.-i.r. spectrometer and reported in cm)1. Melting points were measured uncorrected with a Mel-Temp apparatus. Elemental analyses for C, H, and N were carried out at Guelph Chemical Laboratories Inc. (Guelph, ON). All reactions were carried out in the air and products are stable indefinitely under such conditions. Preparation of compounds Synthesis of (4a) To a warm MeOH (2 cm3) solution of palladium(II) acetate (17 mg, 0.08 mmol) was added a MeOH (3 cm3) solution of 3-[3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenylimino]methylphenol (50 mg, 0.16 mmol). Upon heating at reflux for 4 h, the solution was stored at 5 C for 18 h and the resultant precipitate was collected by suction filtration and washed with MeOH (3 · 5 cm3). Yield: 18 mg (30%) of a green solid; m.p. 238 C (dec). Spectroscopic n.m.r. data (in CDCl3): 1H d: 7.80–7.70 (ov m, 6H, CH@N and Ar), 7.44 (m, 4H, Ar), 7.15 (d, J ¼ 8 Hz, 2H, Ar), 7.08 (t, J ¼ 8 Hz, 2H, Ar), 6.48 (t, J ¼ 8 Hz, 2H, Ar), 6.12 (d, J ¼ 8 Hz, 2H, Ar), 1.35 (s, 24H, O2C2(CH3)4); 11B d: 30.5 (br); 13C{1H} d: 165.2, 162.9, 148.9, 135.1, 134.5, 133.0, 132 (br, C-B), 129.9, 128.5, 127.3, 120.9, 120.2, 115.1, 84.1, 25.0. I.r. (nujol): 2951, 2926, 2854, 1608, 1535, 1464, 1444, 1360, 1306, 1149, 966, 860, 756, 702. [Found: C, 60.6; H, 5.4; N, 3.9. C38H42N2B2O6Pd calcd.: C, 60.8; H, 5.7; N, 3.7%.] Synthesis of (4b) 5-Nitro-3-[3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2yl)-phenylimino]methylphenol (52 mg, 0.14 mmol) in

MeOH (3 cm3) was added to a warm MeOH (2 cm3) solution of palladium(II) acetate (15 mg, 0.07 mmol). After heating the mixture at reflux for 4 h, the reaction was allowed to cool to room temperature and the resultant precipitate was collected by suction filtration and washed with MeOH (3 · 5 cm3). Yield: 19 mg (32%) of a green solid; m.p. 338 C (dec). Spectroscopic n.m.r. data (in CDCl3): 1H d: 8.26 (d, J ¼ 3 Hz, 2H, Ar), 7.92 (d of d, J ¼ 8, 3 Hz, 2H, Ar), 7.87–7.82 (ov m, 4H, Ar), 7.68 (s, 2H, CH@N), 7.48–7.37 (ov m, 4H, Ar), 6.07 (d, J ¼ 8 Hz, 2H, Ar), 1.36 (s, 24H, O2C2(CH3)4); 11B d: 31.0 (br); 13C{1H} d: 169.2, 162.8, 147.6, 137.0, 133.9, 132.4, 130 (br, C-B), 129.8, 129.5, 127.8, 127.5, 121.4, 119.2, 84.3, 25.0. I.r. (nujol): 2935, 2912, 2856, 1604, 1549, 1464, 1421, 1387, 1358, 1315, 1144, 1101, 966, 714. [Found: C, 53.9; H, 4.7; N, 6.8. C38H40N4B2O10Pd requires C, 54.3; H, 4.8; N, 6.7%.]

Synthesis of (4c) To a warm MeOH (5 cm3) solution of palladium(II) acetate (54 mg, 0.24 mmol), 3-[3-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)-phenylimino]methylnaphthalen-2-ol (180 mg, 0.48 mmol) in MeOH (5 cm3) was added. After heating the solution at reflux for 4 h, the reaction was allowed to cool to room temperature and the resultant precipitate was collected by suction filtration and washed with MeOH (3 · 5 cm3). Yield: 78 mg (38%) of a green solid; m.p. 326–328 C (dec). Spectroscopic n.m.r. data (in CDCl3): 1H d: 8.54 (s, 2H, CH@N), 7.84–7.81 (ov m, 6H, Ar), 7.59–7.36 (ov m, 10H, Ar), 7.19 (t, J ¼ 8 Hz, 2H, Ar), 6.34 (d, J ¼ 8 Hz, 2H, Ar), 1.37 (s, 24H, O2C2(CH3)4); 11B d: 30.3 (br); 13 C{1H} d: 166.2, 156.7, 149.8, 135.3, 134.4, 134.3, 132.8, 130.7, 129 (br, C-B), 128.9, 128.5, 127.6, 126.9, 123.7, 122.4, 119.5, 110.6, 84.1, 25.0. I.r. (nujol): 2924, 2854, 1616, 1603, 1585, 1535, 1504, 1452, 1427, 1402, 1356, 1323, 1254, 1182, 1161, 1142, 1099, 962, 856, 822, 754, 706, 567. [Found: C 63.3; H 5.3; N 3.3. C46H46N2B2O6Pd Æ MeOH requires C, 63.9; H, 5.7; N, 3.2%.] Synthesis of (5a) To a warm MeOH (2 cm3) solution of palladium(II) acetate (17 mg, 0.08 mmol), 4-[3-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)-phenylimino]methylphenol (50 mg, 0.16 mmol) in MeOH (3 cm3) was added. After heating the solution at reflux for 4 h, the reaction was allowed to cool to room temperature and the resultant precipitate was collected by suction filtration and washed with MeOH (3 · 5 cm3). Yield: 45 mg (75%) of a green solid; m.p. 264 C (dec). Spectroscopic n.m.r. data (in CDCl3): 1H d: 7.84 (d, J ¼ 8 Hz, 4H, Ar), 7.67 (s, 2H, CH@N), 7.32 (d, J ¼ 8 Hz, 4H, Ar), 7.14–7.08 (ov m, 4H, Ar), 6.49 (t, J ¼ 8 Hz, 2H, Ar), 6.14 (d, J ¼ 8 Hz, 2H, Ar), 1.38 (s, 24H, O2C2(CH3)4); 11B d: 30.5 (br); 13C{1H} d: 165.3, 162.9, 152.1, 135.4, 134.9, 134.6, 134 (br, C-B), 124.1, 121.1, 120.2, 115.2, 84.0, 25.0. I.r. (nujol): 2922, 2854, 1608, 1533, 1462, 1443, 1398, 1362, 1311, 1271,

65 1184, 1146, 1092, 862, 833, 752, 658. [Found: C, 60.2; H, 5.4; N, 3.9. C38H42N2B2O6Pd requires C, 60.8; H, 5.7; N, 3.7%.] Synthesis of (5b) To a warm MeOH (2 cm3) solution of palladium(II) acetate (15 mg, 0.07 mmol), 5-nitro-4-[3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenylimino]methylphenol (52 mg, 0.14 mmol) in MeOH (3 cm3) was added. After heating the reaction at reflux for 4 h, the solution was allowed to cool to room temperature and the resultant precipitate was collected by suction filtration and washed with MeOH (3 · 5 cm3). Yield: 25 mg (43%) of a green solid; m.p. 350 C (dec). Spectroscopic n.m.r. data (in CDCl3): 1H d: 8.25 (d, J ¼ 3 Hz, 2H, Ar), 7.96 (d of d, J ¼ 8, 3 Hz, 2H, Ar), 7.89 (d, J ¼ 8 Hz, 4H, Ar), 7.77 (s, 2H, CH@N), 7.29 (d, J ¼ 8 Hz, 4H, Ar), 6.06 (d, J ¼ 8 Hz, 2H, Ar), 1.39 (s, 24H, O2C2(CH3)4); 11B d: 32.0 (br); 13C{1H} d: 169.2, 162.7, 150.8, 137.1, 135.2, 132.4, 130 (br, C-B), 129.7, 123.6, 121.6, 119.1, 84.3, 25.0. I.r. (nujol): 2922, 2854, 1603, 1547, 1487, 1458, 1396, 1375, 1362, 1321, 1146, 1103, 1016, 833, 704. [Found: C, 54.3; H, 4.6; N, 6.8. C38H40N4B2O10Pd requires C, 54.3; H, 4.8; N, 6.7%.] Synthesis of (5c) 4-[3-(4,4,5,5-Tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenyli mino]methylnaphthalen-2-ol (134 mg, 0.36 mmol) in MeOH (3 cm3) was added to a warm MeOH (2 cm3) solution of palladium(II) acetate (40 mg, 0.18 mmol). Upon heating at reflux for 4 h, the solution was allowed to cool to room temperature and the resulting precipitate was collected by suction filtration and washed with MeOH (3 · 5 cm3). Yield: 54 mg (35%) of a green solid; m.p. 296–298 C (dec). Spectroscopic n.m.r. data (in CDCl3): 1H d: 8.49 (s, 2H, CH@N), 7.90 (d, J ¼ 8 Hz, 4H, Ar), 7.78 (d, J ¼ 8 Hz, 2H, Ar), 7.59 (d, J ¼ 8 Hz, 2H, Ar), 7.51–7.43 (ov m, 6H, Ar), 7.39 (t, J ¼ 8 Hz, 2H, Ar), 7.19 (t, J ¼ 8 Hz, 2H, Ar), 6.33 (d, J ¼ 8 Hz, 2H, Ar), 1.40 (s, 24H, O2C2(CH3)4); 11B d: 32.0 (br); 13C{1H} d: 166.3, 156.7, 153.1, 135.7, 135.1, 134.4, 132 (br, C-B), 129.0, 127.7, 127.0, 124.6, 123.7, 122.5, 119.3, 110.8, 84.0, 25.0. I.r. (nujol): 3030, 2976, 2924, 2856, 1601, 1579, 1535, 1502, 1452, 1429, 1394, 1360, 1321, 1269, 1186, 1142, 1090, 1018, 983, 960, 825, 764, 746, 661, 573. [Found: C, 62.7; H, 5.0; N, 3.3. C46H46N2B2O6Pd
2CH3OH requires C, 63.0; H, 5.9; N, 3.1%.] Antifungal testing Compounds were tested for antifungal activity against pure cultures of Aspergillus niger and Aspergillus flavus supplied by Ward’s Natural Science Ltd. (St. Catharines, Ontario, Canada). Cultures were maintained on Sabouraud dextrose agar. Six agar plugs (10 mm diameter) were cut from a 5–8-day old colony and homogenized in distilled, sterilized water (3 cm3). From this suspension, 0.5 cm3 was transferred aseptically to a Petri plate with Sabouraud dextrose agar (15 cm3) and

spread evenly over the entire surface. Each plate was provided with four evenly spaced paper disks (6 mm Fisherbrand P8 filter paper) containing the compound (200 lg, respectively). Each compound was applied to the disks as a solution (5 mg compound per 1 cm3 of acetone or chloroform) where control disks were treated with neat acetone or chloroform (20 ll). Amphotericin B acted as a standard (100 lg). Test plates with fungal homogenates were incubated at 20 C for 48 h. Four replicate plates were used for each test. Antifungal activity was taken by the diameter of the clear zone surrounding the disk. X-ray crystallography Crystals of (5b Æ 2THF) were grown from a THF solution at 5 C. Single crystals were mounted using a glass fibre and Paratone-N oil and frozen in the cold stream of the goniometer. Data were collected on a Bruker AXS P4/SMART 1000 diffractometer using x and / scans with a scan width of 0.3 and 40 s exposure times. The detector distance was 5 cm. The data were reduced (SAINT) [31] and corrected for absorption (SADABS) [32]. The structure was solved by direct methods and refined by full-matrix least squares on F2 (SHELXTL) [33]. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were located in Fourier difference maps and refined isotropically. Crystallographic information has been deposited with the Cambridge Crystallographic Data Centre (CCDC 223548). Copies of the data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +441223-336033; [email protected]).

Results and discussion Salicylaldimines are versatile intermediates in organic synthesis and have been used to prepare numerous pharmacologically important compounds [34–40]. For instance, Whiting and co-workers have used imines containing boronate esters to make enantio-enriched cphenyl-c-amino alcohols [34] and Ho¨pfl has prepared air-stable cyclophane-type macrocycles from salicylideneaminoaryl alcohols and arylboronic acids [40]. In this study, we have found that pinacol-protected boronic acid derivatives of aniline {(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenylamine} add to salicylaldehydes to give compounds having spectroscopic data consistent with the salicylaldimines 1–3 (Figure 1). As Schiff bases are ubiquitous in transition metal chemistry, we decided to investigate the use of salicylaldimines 1–3 as novel boron-containing ligands. Our initial investigations have been directed at making diamagnetic palladium(II) complexes owing to their ease of synthesis and known biological activities. For instance, related Pd(II) complexes of the general empirical formula, [M(NS)2] (NS ¼ anion of acetone

66

Fig. 1. Schiff bases and palladium complexes containing boronate ester groups.

Schiff bases of S-methyl- and S-benzyldithiocarbazate), have recently been prepared and characterized by a variety of techniques [41]. Antimicrobial tests indicate that these Schiff base complexes exhibit strong activities against a variety of pathogenic bacteria and fungi. In this study, we have found that addition of salicylaldimines containing an ortho Bpin group (1) to either Pd(OAc)2 or Na2PdCl4 resulted in degradation of the boron-containing ligand to give a number of different metal complexes. Unfortunately, all attempts to generate the palladium Schiff base complexes proved unsuccessful. This result is not surprising as the orthoboronate ester would be brought into close proximity to the metal center upon coordination to palladium, where cleavage of the BAC bond presumably leads to degradation of the boron fragment. Indeed, a peak at d 21 p.p.m. in the 11B-n.m.r. spectra for these reactions signifies the degradation product B2pin3, arising from a redistribution of pinacolate groups [29,42]. However, we have found that (2) and (3) add cleanly to methanolic solutions of either Pd(OAc)2 or Na2PdCl4 to afford square planar bis(N-arylsalicylaldiminato)palladium(II) complexes in low to moderate yields (30– 75%). Complexes (4) and (5) have been characterized by a number of physical methods, including multinuclear n.m.r. spectroscopy. A significant upfield shift in the 1H-n.m.r. spectra is observed for the imine methine proton upon coordination of the ligand to the metal centre. For instance, the singlet at d 8.62 p.p.m. for the free ligand (3a) shifts to 7.67 p.p.m. in complex (5a). Of note, however, is the absence of the broad OH stretch in the f.t.-i.r. spectra when the ligands are coordinated to palladium. The 11B-n.m.r. data show broad peaks at ca. 30 p.p.m., suggesting that the boron atoms remain three coordinate in solution. Complex (5b
2THF) has also been characterized by a X-ray diffraction study (Figure 2). Crystallographic data are given in Table 1 and bond distances and angles are shown in Table 2. The palladium atom lies on an inversion centre and assumes a slightly distorted square planar configuration with trans-bis(salicylaldiminato) groups. The PdAO and PdAN distances of 1.970(4) and 2.017(4) A˚, respectively, are similar to those seen in related complexes [43–45]. For instance, distances of 1.966(8) and 2.067(10) A˚ for the PdAO and PdAN bonds are found in a related bis(salicylideneaminato)palladium complex derived from 2-hydroxy-4(n-hexyloxy)benzaldehyde and 4-n-hexylaniline [45]. The

Fig. 2. The molecular structure of (5b Æ 2THF) with ellipsoids drawn at 30% probability level. Hydrogen atoms and solvent molecules omitted for clarity.

Table 1. Crystallographic data collection parameters for (5b Æ 2THF) Formula C38H40B2N4O10Pd Æ 2THF fw 984.97 Crystal system Monoclinic Space group P2(1)/n a (A˚) 6.4532(6) b (A˚) 37.573(3) c (A˚) 10.0745(9) b deg 102.462(1) V (A˚)3 2385.2(4) Z 2 qcalcd (mg m)3) 1.371 0.025 · 0.3 · 0.35 Crystal size (mm3) Temperature (K) 198(1) Radiation MoKa (k = 0.71073) l (mm)1) 0.453 Total reflections 11772 Total unique Relections 4047 Number of variables 299 Rint 0.0291 Theta range, deg 2.14–24.99 Largest difference peak/hole, (e A˚))3 0.586/)0.532 GoF on F2 1.206 R1a (I > 2r(I)) 0.0659 wR2b (all data) 0.1403 P P P P a R1 ¼ jjFO j  jFC jj= jFO j: b wR2 ¼ ð ½wðFO2  FC2 Þ2 = ½wFO4 Þ1=2 , 2 2 2 where w ¼ 1=½r ðFO Þ þ ð0:0273  P Þ þ ð8:7312  P Þ and P ¼ ðmaxðFO2 ; 0Þ þ 2  FC2 Þ=3.

67 Table 2. Selected bond lengths [A˚] and angles [] for (5b Æ 2THF) Bond lengths PdAO(18) PdAN(15) BAO(1) BAO(4) BAC(9) O(1)AC(2) C(2)AC(6) C(2)AC(3) C(2)AC(5) C(3)AO(4) N(23)AO(24) N(23)AO(25)

Bond angles 1.970(4) 2.017(4) 1.348(7) 1.360(7) 1.539(8) 1.449(7) 1.465(13) 1.530(9) 1.534(13) 1.448(7) 1.218(6) 1.225(6)

O(18)#1APdAO(18) O(18)#1APdAN(15) O(18)APdAN(15) O(18)#1APdAN(15)#1 O(1)ABAO(4) O(1)ABAC(9) O(4)ABAC(9) BAO(1)AC(2) O(1)AC(2)AC(6) O(1)AC(2)AC(3) C(16)AN(15)APd C(12)AN(15)APd O(24)AN(23)AO(25)

180.0(2) 88.94(16) 91.06(16) 91.06(16) 113.0(5) 122.9(5) 124.1(5) 108.0(5) 105.3(7) 103.8(5) 123.0(3) 118.8(3) 123.6(5)

Table 3. Antifungal testing Compound

Dose (lg/disk)

A. niger clear zone/mm

A. flavus clear zone/mm

4a 4b 4c 5a 5b 5c Amphotericin B

200 200 200 200 200 200 100

6 6 6 6 6 3 15

6 6 6 6 0 5 9

BAO bond distances of 1.354(7) A˚ (avg.) are also typical for three coordinate Bpin groups and are significantly shorter than those observed in Schiff base chelate complexes with phenylboronic acid (ca. 1.45 A˚), where the boron is four coordinate [40]. This result confirms that no appreciable intermolecular interactions exist in the solid state with the Lewis acidic boron atom. Four coordinate boron complexes have been invoked as intermediates in Suzuki–Miyaura cross-coupling reactions that utilize organic boronate esters and a palladium catalyst [1]. The Bpin is roughly coplanar with the aniline ring (12), as expected if dative bonding is occurring with the aromatic pp electrons and the empty p orbital on boron. Similar palladium amine complexes containing pendant boronate esters have been reported [46,47]. As mentioned previously, related Schiff base palladium compounds are known to display considerable antimicrobial activities [41]. In this study, all new palladium compounds have been tested as potential antifungal agents against A. niger and A. flavus using Amphotericin B [48] as an antifungal control (Table 3). Unfortunately, the corresponding palladium complexes only displayed minimal levels of activity against both A. niger and A. flavus even at double the dose of the control. In order to understand the structure activity relationships in these complexes, further work is required in an effort to design more potent fungicidal palladium complexes containing biologically active aminoboron groups.

Conclusion We have prepared new Schiff bases containing boronate ester groups via condensation reactions with pinacolprotected boronic acid derivatives of aniline and salicylaldehydes. Addition of these Schiff bases to palladium(II) salts lead to the formation of novel boron-containing trans-bis(N-arylsalicylaldiminato)palladium(II) complexes. These complexes showed only negligible antifungal activity against both A. niger and A. flavus. Acknowledgements Thanks are gratefully extended to the Research Corporation (Cottrell College Science Award), NSERC, AIF the University of New Brunswick, Mount Allison University for financial support. We also thank the Canadian Liver Foundation for a Summer Studentship Award (JPE) and Dan Shrubby Durant and Roger Smith for their expert technical assistance.

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