Synthesis and reactivity of palladium and platinum diimine complexes containing boronate esters

Article abstract of DOI:10.1139/v02-145

Condensation of α-diketones (2,3-butanedione, benzil, and acenaphthenequinone) with 3-H₂NC₆H₄Bpin (pin = 1,2-O₂C₂Me₄) gave the corresponding boron-containing α-diimines. The addition of the

Full text of DOI:10.1139/v02-145

1217
Synthesis and reactivity of palladium and platinum
diimine complexes containing boronate esters
Arienne S. King, Liliya G. Nikolcheva, Christopher R. Graves, Anna Kaminski,
Christopher M. Vogels, Robert H.E. Hudson, Robert J. Ireland, Stephen J. Duffy,
and Stephen A. Westcott
Abstract: Condensation of ꢀ-diketones (2,3-butanedione, benzil, and acenaphthenequinone) with 3-H2NC6H4Bpin
(pin = 1,2-O2C2Me4) gave the corresponding boron-containing ꢀ-diimines. The addition of these ligands to
[MCl2(coe)]2 (coe = cis-cyclooctene, M = Pd or Pt) gave complexes of the type cis-MCl2(ꢀ-diimine) in moderate
to high yields. The platinum complexes have been examined for their ability to bind to DNA using enzyme digest
studies. These complexes were found to bind to single-stranded DNA as well as, or better than, the non-boron
containing controls, and showed binding similar to that of cisplatin (cis-PtCl2(NH3)2).
Key words: boronate esters, diazabutadienes, DNA-binding, platinum.
Résumé : La condensation d’ꢀ-dicétones (butane-2,3-dione, benzile, et acénaphtènequinone) avec le 3-H2NC6H4Bpin
(pin = 1,2-O2C2Me4) conduit à la formation d’ꢀ-diimines contenant du bore. L’addition de ces ligands au [MCl2(coe)]2
(coe = cis-cyclooctène; M = Pd, Pt) fournit des complexes du type cis-MCl2(ꢀ-diimine) avec des rendements allant de
modérés à élevés. Faisant appel à des études de digestion d’enzymes, on a évalué la capacité de ces complexes du
platine à se fixer sur l’ADN. Vis-à-vis de l’ADN à brin unique, ces complexes se fixent aussi bien, ou mieux, que les
contrôles ne contenant pas de bore et leur taux de fixation est semblable à celui du cisplatine, cis-PtCl2(NH3)2.
Mots clés : esters de l’acide boronique, diazabutadiènes, fixation de l’ADN, platine.
[Traduit par la Rédaction] King et al. 1222
Introduction
(22). Some of the unique chemical and physical properties
observed for metal diimine complexes have been attributed
to the relatively strong ꢁ-acceptor ability of the
diazabutadiene ligands, resulting from an energetically low-
lying LUMO (23). Although fluorinated ꢀ-diimines have re-
cently been prepared (24), to the best of our knowledge no
such systems containing boronate esters have been reported.
Diimines containing these electron-withdrawing groups
would be expected to possess low lying LUMOs, and conse-
quently, be strong ꢁ-acceptors. The results of our initial in-
vestigations into preparing these compounds, and the
corresponding palladium and platinum complexes, are pre-
sented herein.
Interest in compounds containing boronic acids
[RB(OH)2] or boronate esters [RB(OR>)2] arises from their
remarkable versatility in organic synthesis (1) as well as
from their potent biological activities (2–11). As part of our
ongoing program generating novel boron compounds (12),
we decided to examine the synthesis and reactivity of a se-
ries of ꢀ-diimines containing boronate esters.
1,4-Diazabutadienes (ꢀ-diimines) have both been used ex-
tensively as ligands for transition metals, owing to their ease
of preparation and ability to fine-tune both steric and elec-
tronic properties (13). The resulting coordination complexes
have been utilized in organic synthesis and catalysis (13–20)
and as luminescence labels for the detection and photochem-
ical cleavage of DNA (21). Diazabutadienes have also been
used in dehalosilylation – ring-closure reactions of SbCl3
and BiCl3 to give the corresponding 1,2,5-pnictadiazoles
Experimental
The reagents and solvents used were obtained from
Aldrich Chemicals. NMR spectra were recorded on a JEOL
JNM-GSX270 FT-NMR spectrometer. 1H NMR chemical
shifts are reported in ppm and referenced to residual protons
in deuterated solvent at 270 MHz. 11B NMR chemical shifts
are referenced to external F3B·OEt2 at 87 MHz. 13C NMR
chemical shifts are referenced to solvent carbon resonances
as internal standards at 68 MHz. Multiplicities are reported
as (s) singlet, (d) doublet, (t) triplet, (q) quartet, (m) multiplet,
(br) broad, and (ov) overlapping. Infrared spectra were
obtained using a Mattson Genesis II FT-IR spectrometer, and
are reported in cm–1. Melting points were measured
(uncorrected) with a Mel-Temp apparatus. Microanalyses for
C, H, and N were carried out at Desert Analytics (Tucson,
Received 7 June 2002. Published on the NRC Research Press
Web site at http://canjchem.nrc.ca on 30 August 2002.
A.S. King, L.G. Nikolcheva, C.R. Graves, C.M. Vogels,
S.J. Duffy, and S.A. Westcott.1 Department of Chemistry,
Mount Allison University, Sackville, NB E4L 1G8, Canada.
R.J. Ireland. Department of Biology and Biochemistry,
Mount Allison University, Sackville, NB E4L 1G7, Canada.
A. Kaminski and R.H.E. Hudson. Department of Chemistry,
The University of Western Ontario, London, ON N6A 5B7,
Canada.
1Corresponding author (e-mail: swestcott@mta.ca).
Can. J. Chem. 80: 1217–1222 (2002)
DOI: 10.1139/V02-145
© 2002 NRC Canada

1218
Can. J. Chem. Vol. 80, 2002
AZ) and CMA (Vancouver, BC). All reactions were carried
out in ambient conditions and the products were found to be
stable indefinitely under those circumstances. Polymeriza-
tion experiments were done by Dr. Marc Kristen (Basell
Polyolefin GmbH).2
1315, 1271, 1231, 1143, 1098, 1072, 1045, 964, 943, 871,
850, 783, 703. H NMR (CDCl3) ꢂ: 7.85 (d, J = 8 Hz, 2H,
1
Ar), 7.69 (d, J = 8 Hz, 2H, Ar), 7.55 (s, 2H, Ar), 7.46 (ov
dd, J = 8 Hz, 2H, Ar), 7.33 (ov dd, J = 8 Hz, 2H, Ar), 7.20
(br d, J = 8 Hz, 2H, Ar), 6.78 (d, J = 8 Hz, 2H, Ar), 1.33 (s,
24H, BO2(CH3)4). 13C NMR ꢂ: 161.2, 151.4, 141.8, 131.2,
130.7, 130 (br, C-B), 128.8 (2C), 128.7, 127.7, 124.3, 124.1,
121.2, 83.9, 25.0. 11B NMR ꢂ: 30 (br).
Synthesis
1,4-Bis[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]-2,3-dimethyl-1,4-diaza-1,3-butadiene (1a)
(1,4-Bis[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]-2,3-dimethyl-1,4-diaza-1,3-butadiene)di-
chloropalladium(II) (2a)
An EtOH solution (5 mL) of 3-H2NC6H4Bpin (3-APBpin
(pin = 1,2-O2C2Me4)) (1.67 g, 7.62 mmol) was added
dropwise to 2,3-butanedione (0.30 g, 3.48 mmol) in EtOH
(3 mL). Following the addition of formic acid (1 drop), the
reaction was heated at reflux (4 h) and then stored at 0°C,
whereupon a beige precipitate formed, which was collected
by suction filtration and washed with hexane (3 × 10 mL).
Yield: 1.10 g (65%); mp 225–227°C. IR (Nujol) (cm-1):
2937, 2912, 2856, 1637, 1599, 1570, 1483, 1464, 1417,
1358, 1321, 1265, 1201, 1140, 1076, 966, 901, 881, 849,
To a stirred CH2Cl2 solution (10 mL) of [PdCl2(coe)]2
(0.10 g, 0.17 mmol), 1a (0.18 g, 0.37 mmol) in CH2Cl2
(5 mL) was added dropwise. The reaction was allowed to
proceed for 18 h, at which point the solvent was removed
under vacuum to afford an orange solid, which was then
triturated with Et2O (3 × 10 mL). Yield: 0.19 g (84%); mp
200ꢃ202°C (decomp.). IR (Nujol) (cm-1): 2943, 2904, 2870,
1603, 1462, 1427, 1358, 1311, 1269, 1140, 1076, 964, 858,
704. 1H NMR (CDCl3) ꢂ: 7.76 (br d, J = 8 Hz, 2H, Ar), 7.54
(br ov m, 2H, Ar), 7.38 (br ov m, 4H, Ar), 2.13 (br s, 6H,
N=C(CH3)), 1.34 (s, 24H, BO2(CH3)4). 13C NMR ꢂ: 179.6,
145.0, 134.4, 129.8 (br, C-B), 128.9, 128.3, 126.1, 84.2,
25.1, 21.2. 11B NMR ꢂ: 31 (br). Anal. calcd. for
PdCl2C28H38N2B2O4: C 50.51, H 5.77, N 4.21; found: C 49.94,
H 5.87, N 4.16.
1
804, 779, 714, 706, 671. H NMR (CDCl3) ꢂ: 7.54 (d, J =
8 Hz, 2H, Ar), 7.36 (ov dd, J = 8 Hz, 2H, Ar), 7.22 (br s,
2H, Ar), 6.85 (br d, J = 8 Hz, 2H, Ar), 2.11 (s, 6H,
N=C(CH3)), 1.34 (s, 24H, BO2(CH3)4). 13C NMR ꢂ: 168.3,
150.5, 130.2, 130 (br, C-B), 128.5, 124.9, 121.6, 83.9, 25.0,
15.5. 11B NMR ꢂ: 31 (br).
1,4-Bis[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]-2,3-diphenyl-1,4-diaza-1,3-butadiene (1b)
(1,4-Bis[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]-2,3-diphenyl-1,4-diaza-1,3-butadiene)dichloro-
palladium(II) (2b)
A CH2Cl2 solution (10 mL) of 3-APBpin (1.17 g,
5.35 mmol) was added dropwise to benzil (0.50 g,
2.38 mmol) in methylene chloride (10 mL). Activated mo-
lecular sieves (10 g) were added and the reaction was heated
at reflux for 24 h. The molecular sieves were removed by
suction filtration and washed with CH2Cl2 (3 × 10 mL). Re-
moval of the solvent under vacuum gave an oil that was
triturated with cold Et2O (10 mL) to afford a yellow solid.
Yield: 0.87 g (60%); mp 224°C. IR (Nujol) (cm-1): 2915,
2856, 1620, 1461, 1376, 1315, 1268, 1142, 1071, 965, 899,
853, 785, 697. 1H NMR (CDCl3) ꢂ: 7.88 (br d, J = 8 Hz, 4H,
Ar), 7.46ꢃ7.35 (ov m, 8H, Ar), 7.06 (ov dd, J = 8 Hz, 2H,
Ar), 6.97 (br s, 2H, Ar), 6.56 (br d, J = 8 Hz, 2H, Ar), 1.26
(s, 12H, BO2(CH3)4), 1.22 (s, 12H, BO2(CH3)4). 13C NMR
ꢂ: 164.4, 148.8, 138.0, 131.0, 130.9, 130 (br, C-B), 128.7,
128.4, 127.8, 126.7, 122.9, 83.6, 24.9, 24.8. 11B NMR ꢂ: 31 (br).
A CH2Cl2 solution (5 mL) of 1b (0.12 g, 0.20 mmol) was
added dropwise to a stirred solution of [PdCl2(coe)]2 (0.05 g,
0.09 mmol) in CH2Cl2 (10 mL). The reaction was allowed to
proceed for 6 h, at which point the solvent was removed un-
der vacuum to afford an orange solid. The solid was
triturated with Et2O (3 × 10 mL). Yield: 0.11 g (77%); mp
214ꢃ216°C (decomp.). IR (Nujol) (cm-1): 2937, 2868, 1601,
1462, 1423, 1377, 1358, 1319, 1271, 1142, 1074, 999, 852,
723, 700, 561. 1H NMR (CDCl3) ꢂ: 7.52 (br d, J = 8 Hz, 4H,
Ar), 7.38 (br d, J = 8 Hz, 2H, Ar), 7.08–6.92 (br ov m, 12H,
Ar), 1.29 (s, 24H, BO2(CH3)4). 13C NMR ꢂ: 178.6, 145.4,
134.0, 132.2, 130.3, 130 (br, C-B), 129.9, 128.7, 127.9,
127.6, 127.3, 84.0, 25.0. 11B NMR ꢂ: 31 (br). Anal. calcd.
for PdCl2C38H42N2B2O4: C 57.78, H 5.37, N 3.55; found:
C 56.94, H 5.31, N 3.49.
1,4-Bis[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]-2,3-acenaphthene-1,4-diaza-1,3-butadiene (1c)
A CH2Cl2 solution (10 mL) of 3-APBpin (1.20 g,
5.49 mmol) was added dropwise to acenaphthenequinone
(0.50 g, 2.74 mmol) in CH2Cl2 (10 mL), in the presence of
activated molecular sieves (10 g). The reaction was allowed
to proceed at room temperature for 12 days, at which point
the sieves were removed by suction filtration and the solu-
tion was washed with CH2Cl2 (3 × 10 mL). Removal of the
solvent under vacuum gave an oily mixture that was
triturated with Et2O (3 × 5 mL) to afford an orange solid.
Yield: 1.11 g (70%); mp 245°C. IR (Nujol) (cm-1): 2974,
2882, 2843, 1666, 1644, 1594, 1568, 1461, 1415, 1359,
(1,4-Bis[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]-2,3-acenaphthene-1,4-diaza-1,3-butadiene)dichloro-
palladium(II) (2c)
A CH2Cl2 solution (5 mL) of 1c (0.11 g, 0.19 mmol) was
added dropwise to a stirred solution of [PdCl2(coe)]2 (0.05 g,
0.09 mmol) in CH2Cl2 (10 mL). The reaction was allowed to
proceed for 6 h, whereupon removal of the solvent under
vacuum afforded an orange solid, which was triturated with
Et2O (3 × 5 mL). Yield: 0.11 g (80%); mp 338°C (decomp.).
IR (Nujol) (cm-1): 2967, 2945, 2894, 2871, 2847, 1599,
1579, 1461, 1376, 1359, 1141, 971, 735, 701. 1H NMR
2 Supplementary material may be purchased from the Depository of Unpublished Data, Document Delivery, CISTI, National Research Coun-
cil Canada, Ottawa, ON K1A 0S2, Canada (http://www.nrc.ca/cisti/irm/unpub_e.shtml).
© 2002 NRC Canada

King et al.
1219
(CDCl3) ꢂ: 8.09 (d, J = 8 Hz, 2H, Ar), 7.93 (d, J = 8 Hz, 2H,
Ar), 7.78 (br s, 2H, Ar), 7.59 (ov dd, J = 8 Hz, 2H, Ar),
7.49–7.43 (ov m, 4H, Ar), 6.73 (d, J = 8 Hz, 2H, Ar), 1.33
(s, 24H, BO2(CH3)4). 13C NMR (in DMF) ꢂ: 177.4, 147.9,
146.1, 135.0, 133.0, 132.2, 131.0 (br, C-B), 129.7, 129.5,
129.1, 126.7, 126.1, 126.0, 84.9, 25.2. 11B NMR ꢂ: 29 (br).
Anal. calcd. for PdCl2C36H38N2B2O4: C 56.76, H 5.04,
N 3.68; found: C 56.94, H 5.08, N 3.90.
24H, BO2(CH3)4). 13C NMR ꢂ: 175.6, 147.2, 144.5, 135.6,
132.2, 131.0, 130 (br, C-B), 129.7, 129.1, 128.8, 126.3,
126.1, 124.5, 84.2, 25.0. 11B NMR ꢂ: 30 (br). Anal. calcd.
for PtCl2C36H38N2B2O4: C 50.84, H 4.51, N 3.29; found:
C 50.44, H 4.69, N 3.40.
Nuclease digest studies
Binding of the platinum complexes to DNA was investi-
gated using enzymatic degradation of the DNA to nucleo-
sides. Nucleosides were detected using reverse-phase HPLC.
The sequence of the model 20-mer DNA strand used in this
study (eq. [1]) has two predominant cisplatin-binding-sites:
TGGT on one strand and AGGA on the complementary
strand. Both the single and the double DNA strands were in-
cubated with each platinum complex, in a 1:3 DNA:Pt molar
ratio, for 24 h, in the dark. Samples (2.0 nmol of single-
stranded and 1.0 nmol of double-stranded DNA) were di-
gested in series with DNAse I (Amersham Biosciences) (36
U, 4 h), nuclease P1 (Sigma) (10 U, 18 h), and alkaline
phosphatase (Promega) (20 U, 4 h), at 37°C, to convert the
DNA strand into mononucleosides. The samples were heated
to 90°C for 2 min, centrifuged at 10 000 g for 30 s, and then
the protein pellet was discarded. The nucleoside composition
in each sample was analyzed at 254 nm on a C18 column, us-
ing a Pro-Star RP-HPLC (Varian). The isocratic solvent sys-
tem used was Et3NH–OAc (93%, 20 mM, pH 6.5) and
CH3CN (7%, 1 mL min-1). The areas under the nucleoside
peaks were integrated and the G:C ratio analyzed and com-
pared with ANOVA, followed by post-hoc multiple compari-
sons with Bonferonni’s adjustment.
(1,4-Bis[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]-2,3-dimethyl-1,4-diaza-1,3-butadiene)dichloro-
platinum(II) (3a)
A CH2Cl2 solution (5 mL) of 1a (0.14 g, 0.29 mmol) was
added dropwise to a stirred solution of [PtCl2(coe)]2 (0.10 g,
0.13 mmol) in CH2Cl2 (10 mL). The reaction was allowed to
proceed for 18 h, at which point the solvent was removed
under vacuum to give an oily solid. The mixture was
triturated with Et2O (4 × 5 mL) to afford an orange solid.
Yield: 0.15 g (76%); mp 204°C (decomp.). IR (Nujol) (cm-1):
2943, 2908, 2870, 1603, 1462, 1377, 1358, 1313, 1269,
1213, 1142, 1076, 964, 858, 806, 704, 677. 1H NMR (CDCl3)
ꢂ: 7.78 (br d, J = 8 Hz, 2H, Ar), 7.56–7.31 (br ov m, 6H, Ar),
1.76 (s, 6H, N=C(CH3)), 1.33 (s, 24H, BO2(CH3)4). 13C NMR ꢂ:
178.1, 145.1, 134.6, 130 (br, C-B), 128.4, 128.1, 126.5,
84.2, 25.1, 21.0. 11B NMR ꢂ: 31 (br). Anal. calcd. for
PtCl2C28H38N2B2O4: C 44.58, H 5.09, N 3.71; found: C 44.78,
H 5.38, N 3.63.
(1,4-Bis[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]-2,3-diphenyl-1,4-diaza-1,3-butadiene)dichloro-
platinum(II) (3b)
[1]
5> T C T C C T T C T G G T C T C T T C T C 3>
3> A G A G G A A G A C C A G A G A A G A G 5>
A CH2Cl2 solution (5 mL) of 1b (0.20 g, 0.33 mmol) was
added dropwise to a stirred solution of [PtCl2(coe)]2 (0.12 g,
0.16 mmol) in CH2Cl2 (10 mL). The reaction was allowed to
proceed for 4 h, at which point the solvent was removed un-
der vacuum to afford an oil, which was triturated with Et2O
(3 × 5 mL) and hexane (4 × 5 mL) to afford a red solid.
Yield: 0.17 g (60%); mp 278°C (decomp.). IR (Nujol) (cm-1):
2945, 2902, 2872, 1603, 1462, 1377, 1358, 1325, 1271,
Equation [1] illustrates the sequence of the DNA 20-mer
used in the binding studies. Possible platinum binding sites
are shown in bold type.
Results and discussion
1
1144, 1076, 964, 854, 700, 567. H NMR (CDCl3) ꢂ: 7.56
Diimines
(br d, J = 8 Hz, 4H, Ar), 7.41 (br ov m, 4H, Ar), 7.07–6.81
(br ov m, 10H, Ar), 1.29 (s, 24H, BO2(CH3)4). 13C NMR ꢂ:
178.3, 145.7, 134.1, 132.9, 131.3, 130 (br, C-B), 129.5,
128.1, 127.8 (2C), 127.2, 84.0, 25.0. 11B NMR ꢂ: 31 (br).
Anal. calcd. for PtCl2C38H42N2B2O4: C 51.95, H 4.83, N
3.19; found: C 51.57, H 4.61, N 3.22.
Protection of the boronic acid groups in commercially
available 3-aminophenylboronic acid (3-H2NC6H4B(OH)2),
by transesterification with pinacol (HOCMe2CMe2OH) to
prevent unwanted formation of anhydrides (25), gave quanti-
tative formation of aminoboronate ester 3-H2NC6H4Bpin
(3-APBpin (pin = O2C2Me4)) (12). Unfortunately, the addi-
tion of 3-APBpin to glyoxal gave complex product distribu-
1
(1,4-Bis[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]-2,3-acenaphthene-1,4-diaza-1,3-butadiene)dichloro-
platinum(II) (3c)
tions, as evidenced by H NMR spectroscopy, and isolation
of the corresponding boron-containing diazabutadiene
proved unsuccessful. This result is not surprising as previous
studies have shown that glyoxal reacts with electron-
deficient amines, such as 3-nitroaniline, to give high yields
of 1,2-dihydroxy-1,2-diamino compounds (26). Conversely,
we found that reactions of 3-APBpin proceeded smoothly
with substituted ꢀ-diketones, 2,3-butanedione, benzil, and
acenaphthenequinone, to give the corresponding boron-
containing ꢀ-diimines (1a–1c) in moderate yields (Fig. 1).
All diazabutadienes were characterized by multinuclear
NMR spectroscopy. A peak at ca. ꢂ 30 ppm in the 11B NMR
spectra is indicative of a three-coordinate boron atom, which
suggests that no appreciable intermolecular interaction
A CH2Cl2 solution (5 mL) of 1c (0.16 g, 0.27 mmol) was
added dropwise to a stirred solution of [PtCl2(coe)]2 (0.10 g,
0.13 mmol) in CH2Cl2 (10 mL). The reaction was allowed to
proceed for 4 h, at which point the solvent was removed un-
der vacuum. The resultant oily solid was triturated with Et2O
(3 × 10 mL) to afford a red solid. Yield: 0.17 g (77%); mp
350°C (decomp.). IR (Nujol) (cm-1): 2924, 2855, 1600,
1
1420, 1358, 1303, 1210, 1145, 967, 856, 777, 703. H NMR
(CDCl3) ꢂ: 8.24 (d, J = 8 Hz, 2H, Ar), 7.96 (d, J = 8 Hz, 2H,
Ar), 7.88 (br s, 2H, Ar), 7.67–7.57 (ov m, 4H, Ar), 7.40 (ov
dd, J = 8 Hz, 2H, Ar), 6.89 (br d, J = 8 Hz, 2H, Ar), 1.33 (s,
© 2002 NRC Canada

1220
Can. J. Chem. Vol. 80, 2002
Fig. 1. ꢀ-Diimines derived from 3-APBpin.
have shown that palladium diimine complexes also require
bulky substituents in the ortho- position of the N-aryl group
to be effective catalysts. Indeed, complexes lacking this
steric requirement are known to give oligomerization prod-
ucts (14). It appears that the boronate ester groups in 2a–2c
are too far removed from the metal center to provide the
steric requirement needed for polymerization. Future studies
will, therefore, concentrate on designing analogous diimine
catalysts derived from 2-APBpin (35).
Platinum complexes
Cisplatin (cis-PtCl2(NH3)2) is one of the most effective
chemotherapeutic agents currently used for the treatment of
ovarian, bladder, and testicular cancer (36ꢃ 44). The drug
has to be administered intravenously, however, and has dose-
limiting side effects such as severe renal toxicity,
neurotoxicity, and emesis, arising, in part, from the low solu-
bility of cisplatin in water. These problems, along with the
fact that cancer cells treated with cisplatin acquire resistance
to the drug, have resulted in considerable research focussed
on the development of a more effective platinum drug that
can be administered orally and with reduced side effects.
Cisplatin acts by making intra- and interstrand cross-links
with DNA, which result in a halt of replication and lead to
programmed cell death. Structural analogues of cisplatin,
however, react with DNA in a way similar to the parent drug
and therefore cause similar biological effects (36). In fact, to
be considered for clinical evaluation, a new platinum drug
should have an activity different from that of cisplatin and
thereby eliminate multi-factorial drug resistance. Therefore,
it is highly unlikely that future platinum drug candidates will
adhere to the classical structure-activity relationships for
cisplatin analogues. Toward this objective, we have prepared
platinum complexes (3a–3c) containing ꢀ-diimines by addi-
tion to [PtCl2(coe)]2 (45, Fig. 2). The use of bidentate lig-
ands prevents trans labilization and undesired displacement
of the ligands by sulfur and nitrogen donors in biomolecules,
interactions that are believed to be responsible for the ad-
verse side effects associated with cisplatin (42).
occurs with the basic imine functionality in solution (27).
Although one boron resonance is observed for 1b, it is inter-
esting to note that two separate peaks are observed for the
Bpin methyl groups in the 1H NMR spectra, presumably
arising from the perpendicular phenyl groups in the back-
bone. It is plausible that restricted rotation about the Bꢃ C
bond causes this loss of symmetry.
Palladium complexes
To examine the potential of these electron withdrawing
diimines to act as ligands, we have prepared palladium com-
plexes 2a–2c by the addition of 1a–1c to organic-soluble
[PdCl2(coe)]2 (28, Fig. 2). Indeed, complexes 2a–2c were
prepared in high yield and characterized using a number of
physical methods, including multinuclear NMR spectros-
copy. The boron atom appears to maintain its three-
coordinate geometry in solution, as evidenced by a peak at
30 ppm in the 11B NMR spectra. Coincidentally, only one
1
peak is observed for the Bpin methyl groups in the H NMR
spectra for 2b.
Electrophilic 1,4-diazabutadiene palladium complexes
have found extensive application as catalysts in the polymer-
ization of alkynes (29) and alkenes (14, 30ꢃ34). Unfortu-
nately, attempts to catalyze the polymerization of ethylene
using complexes 2a–2c proved unsuccessful. Although the
addition of electron-withdrawing boronate ester groups
should enhance polymerization activities, previous studies
Interactions of platinum complexes with DNA
As the efficacy of platinum-based anticancer drugs is be-
lieved to arise from the coordination of the metal to DNA
(43), we decided to examine the binding potential of plati-
Fig. 2. Preparation of metal complexes.
© 2002 NRC Canada

King et al.
1221
Fig. 3. The G:C ratio from the nuclease digests of single-
stranded 20-mer DNA. Values are mean M95%CI (n = 10). Com-
plex 4c is not significantly different from the non-platinum con-
trol at p > 0.05.
Fig. 4. The G:C ratio from the nuclease digests of double-
stranded 20-mer DNA. Values are mean M95%CI (n = 10). Com-
plexes 3b, 4b, and 4c are not significantly different from the
non-platinum control at p > 0.05.
num complexes 3a–3c using a 20-bp strand (46). This DNA
model contains one preferential binding site (a TGGT motif)
in the single strand and a second binding site (AGGA) on
the complementary strand. The degree of platinated
DNA can be quantified by enzymatically degrading the
DNA strand and separating the mononucleosides and Pt-
containing dinucleotides using reverse-phase HPLC
(47ꢃ 49). Platinum binding will result in the formation of
cis-[Pt(diimine){d(GpG)}], and the amount of free
guanosine can, therefore, be negatively correlated to the de-
gree of platinated DNA. Cytosine can be used as an internal
standard because its concentration is not affected by
platinated DNA (50–52).
As expected, the nuclease digest results showed that treat-
ment with cisplatin significantly decreased the G:C ratio
(compared to the unplatinated control) in both single-
stranded (Fig. 3) and double-stranded DNA (Fig. 4), and
confirmed that cisplatin binds well to both types of DNA.
The binding affinity for single-stranded DNA was also found
to decrease as the size of the backbone of the non-boron
diimine compounds (4aꢃ 4c, 14) increased. This result was
also evident in the double-stranded samples. It is possible
that the larger, more sterically-hindered backbones of 4b and
4c do not fit into the binding site and are therefore excluded
from the major groove of double-stranded DNA. Remark-
ably, the boron-containing compounds (3a–3c) bound to sin-
gle-stranded DNA as well as, or better than, the non-boron
controls, and exhibited binding capabilities not significantly
different from those of cisplatin. Binding among the boron
complexes could not be correlated with the size of the back-
bone. These results suggest that the boronate ester may in-
deed contribute to the increased affinity of these compounds
to bind to single-stranded DNA. Compound 3b showed sig-
nificant binding to single-, but not to double-stranded DNA;
presumably, the flexibility of the DNA single-strand was suf-
ficient to allow access to the binding site, but the complex
could not fit into the major groove of the helix in the dou-
ble-stranded DNA. This binding difference may provide
higher selectivity in rapidly dividing cancer cells, where the
DNA is replicated at a higher rate, and, as a result, is more
often in the single-stranded form. Achieving significant
binding to single-, but not to double-stranded DNA, might
provide a solution to the problems associated with current
platinum therapies. Future work in this area will examine the
cytotoxicities of compounds 3aꢃ3c, and relate these find-
ings to binding studies in an effort to design more potent
and less toxic platinum complexes for the treatment of can-
cer.
Conclusion
ꢀ-Diimines, derived from the condensation of substituted
ꢀ-diketones and aminoboronate ester 3-H2NC6H4Bpin (pin =
O2C2Me4), have been prepared in moderate yield and used
as ligands for palladium and platinum. The platinum com-
plexes have been studied for their ability to bind to DNA.
The boron-containing complexes bound to single-stranded
DNA as well as, or better than, the non-boron containing
controls, and showed binding not significantly different from
that of cisplatin.
Acknowledgements
Thanks are gratefully extended to the Research Corpora-
tion (Cottrell College Science Award), Natural Sciences and
Engineering Council of Canada (NSERC), Canada Research
Chairs program (CRC), the University of Western Ontario,
and Mount Allison University for financial support. We also
thank Dan Durant (MAU) for expert technical assistance, Dr.
Marc Ö. Kristen (Basell Polyolefine GmbH) for conducting
polymerization studies, and anonymous reviewers for helpful
comments.
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