Effect of charge and surface area on the cytotoxicity of cationic metallointercalation reagents

Article abstract of DOI:10.1139/v05-110

Reaction of a series of nitrogen donor ligands (1-phenylpyrazoles, 2-phenylpyridine, benzo[h]quinoline, 1-(2′-pyridyl)indole, 1-phenylindazole, and 2-phenylindazole) with palladium(II) and platinum(II) salts gave complexes where ortho-metallation had occurred resulting in bidentate binding to the metal centres through N and C atoms. These cyclometallated products were isolated as μ-chloro dimers. Subsequent treatment of these μ-chloro dimers with chelating diamines such as 1,2-ethanediamine converted them into 14 cationic (1+) complexes. Analogous coordination mixed ligand complexes (charge 2+) were prepared by reaction of dichloro(1,2-ethanediamine-N, N′)palladium(II) with aromatic diamines such as 2-(1′-pyrazolyl) pyridine, 2,2′-bipyridine, and 1,10-phenanthroline. The complexes exhibited growth inhibitory activity against L1210 mouse leukaemia cells in vitro over a wide concentration range; in general, the cyclometallated complexes were more active than the mixed ligand complexes, although one cyclometallated organoplatinum complex was less active than the mixed ligand analogue. Substitution around the periphery of the aromatic ligands also resulted in increased activity. One complex, derived from 1-(2′-pyridyl) indole, was tested in vivo and showed no significant antitumour inhibition against P388 leukaemia at doses below toxic levels.

Full text of DOI:10.1139/v05-110

969
Effect of charge and surface area on the
cytotoxicity of cationic metallointercalation
reagents1
Gavin L. Edwards, David St.C. Black, Glen B. Deacon, and Laurence P.G. Wakelin
Abstract: Reaction of a series of nitrogen donor ligands (1-phenylpyrazoles, 2-phenylpyridine, benzo[h]quinoline, 1-
(2′-pyridyl)indole, 1-phenylindazole, and 2-phenylindazole) with palladium(II) and platinum(II) salts gave complexes
where ortho-metallation had occurred resulting in bidentate binding to the metal centres through N and C atoms. These
cyclometallated products were isolated as µ-chloro dimers. Subsequent treatment of these µ-chloro dimers with chelat-
ing diamines such as 1,2-ethanediamine converted them into 14 cationic (1+) complexes. Analogous coordination mixed
ligand complexes (charge 2+) were prepared by reaction of dichloro(1,2-ethanediamine-N,N′)palladium(II) with aro-
matic diamines such as 2-(1′-pyrazolyl)pyridine, 2,2′-bipyridine, and 1,10-phenanthroline. The complexes exhibited
growth inhibitory activity against L1210 mouse leukæmia cells in vitro over a wide concentration range; in general, the
cyclometallated complexes were more active than the mixed ligand complexes, although one cyclometallated organo-
platinum complex was less active than the mixed ligand analogue. Substitution around the periphery of the aromatic
ligands also resulted in increased activity. One complex, derived from 1-(2′-pyridyl)indole, was tested in vivo and
showed no significant antitumour inhibition against P388 leukæmia at doses below toxic levels.
Key words: anticancer, metallointercalator, cyclometallation, palladium, platinum, cytotoxicity.
Résumé : La réaction d’une série de ligands donneurs d’azote (1-phénylpyrazoles, 2-phénylpyridine, benzo[h]quino-
léine, 1-(2′-pyridyl)indole, 1-phénylindazole et 2-phénylindazole) avec des sels de palladium(II) et de platine(II)
conduit à la formation de complexes dans lesquels il s’est produit une ortho-métallation qui résulte en une liaison bi-
dentate avec les centres métalliques par le biais des atomes de N et de C. On a isolé ces produits sous la forme de di-
mères µ-chloro et un traitement subséquent de ces dimères avec des diamines qui peuvent agir comme agent chélatant,
telles l’éthane-1,2-diamine, a permis de les transformer en quatorze complexes cationiques (1+). On a préparé des
complexes analogues avec des ligands à coordination mixte (charge 2+) en faisant réagir du dichloro(éthane-1,2-
diamine-N,N′)palladium(II) avec des diamines aromatiques, telle la 2-(1′-pyrazolyl)pyridine, la 2,2′-bipyridine et la
1,10-phénanthroline. Dans des essais in vitro, ces complexes présentent, sur large plage de concentration, une activité
inhibitrice de la croissance des cellules de la lignée L1210 de la leucémie de la souris; en général, les complexes cy-
clométallés sont plus actifs que les complexes de ligands mixtes, même si un complexe organique cyclométallé du pla-
tine est moins actif que l’analogue avec un ligand mixte. Une substitution autour de la périphérie des ligands
aromatiques conduit aussi à une augmentation de l’activité. Un complexe, celui dérivé du 1-(2′-pyridyl)indole, a été
évalué in vivo et, à des doses inférieures aux niveaux toxiques, il ne présente aucune activité d’inhibition antitumorale
contre la leucémie P388.
Mots clés : anticancéreux, intercalation métallique, cyclométallation, palladium, platine, cytotoxicité.
[Traduit par la Rédaction] Edwards et al. 979
Introduction
chemotherapeutic agents to combat cancers has led to tre-
mendous activity; however, until relatively recently, the use
of heavy metals has attracted only sporadic interest. The ser-
endipitous discovery by Rosenberg et al. (1) that cis-
Cancer, as a group of diseases, ultimately kills one-quarter
of the human population. The quest for new and effective
Received 7 December 2004. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 25 August 2005.
It is a pleasure to honour Howard Alper’s very significant contributions both to chemistry and to the chemical profession.
G.L. Edwards and D.St.C. Black.2 School of Chemistry, University of New South Wales, Sydney, New South Wales, Australia,
2052.
G.B. Deacon. School of Chemistry, Monash University, Victoria, Australia, 3800.
L.P.G. Wakelin. Department of Physiology and Pharmacology, School of Medical Sciences, University of New South Wales,
Sydney, New South Wales, Australia, 2052.
1This article is part of a Special Issue dedicated to Professor Howard Alper.
2Corresponding author (e-mail: d.black@unsw.edu.au).
Can. J. Chem. 83: 969–979 (2005)
doi: 10.1139/V05-110
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970
Can. J. Chem. Vol. 83, 2005
Table 1. Products of cyclometallation reactions.
Ligand
Abbreviation
Metal
Complex
Yield (%)
1-Phenylpyrazole (1)
2-Phenylpyridine (2)
2-Phenylpyridine (2)
1-(2′-pyridyl)indole (6)
1-Phenyl-1H-indazole (7)
2-Phenyl-2H-indazole (8)
Benzo[h]quinoline (9)
Hpzph
Hpyph
Hpyph
Hpyin
H-1phiz
H-2phiz
Hbq
Pd
Pd
Pt
Pd
Pd
Pd
Pd
Pd
3
4
5
10
11
12
13
15
99
96
65
97
99
98
92
45
3,5-Dimethyl-1-phenylpyrazole (14)
Hdmpzph
diamminedichloroplatinum(II) (cisplatin) inhibited cell divi-
sion in Escherichia coli, and the subsequent establishment
that a range of platinum complexes inhibited the develop-
ment of sarcoma 180 and leukæmia L1210 in mice (2), led
not only to the introduction of cisplatin as a clinically effica-
cious agent against testicular and ovarian cancers in 1978
(3), but also to the rekindling of interest in metal-based ther-
apies (4, 5). While the clinical effectiveness of cisplatin
against human malignancies, both as a single agent and in
combination therapy, has had a major impact on cancer
treatment, its therapeutic usefulness has been offset by a
range of toxic side effects. The combination of good activ-
ity, dose-limiting side effects, and the disadvantage that some
tumours acquire resistance to the drug, has stimulated re-
search into second and third generation platinum drugs (6,
7).
activity are based on platinum, and to date analogous palla-
dium complexes have shown marginal in vivo activity at
best. While some palladium complexes have shown promis-
ing activity in vitro (12) or in animal models (6), they have
not made a successful transition to clinical usefulness; the
poor activity could be attributed to the higher reactivity of
palladium species towards ligand displacement reactions. In
this study drugs were designed where covalent binding to
DNA is not expected and, as the coordination chemistries of
platinum(II) and palladium(II) are similar, both metals
should provide suitable frameworks upon which to build
intercalating complexes. In a following paper we report the
activity of a range of monofunctional cyclometallated plati-
num(II) and palladium(II) complexes (14).
Results and discussion
While the anticancer activity of cisplatin has been attrib-
uted to the formation of bifunctional adducts with DNA, es-
pecially guanine–guanine crosslinks (6), pioneering work
initiated by Lippard and co-workers (8) utilized another as-
pect of the chemistry of platinum(II) — its ability to act as a
square-planar template to impart planarity on ligands such as
2,2′-bipyridine (bpy). While these complexes would have
been predicted to have negligible anticancer activity based
on observations gleaned from cisplatin and its analogues, the
synthesis of planar, kinetically inert metal complexes pro-
vided a new mechanism of action namely, intercalation. In
particular, Lippard used platinum(II) as a framework to force
the aromatic rings of ligands such as bpy and 2,2′:6′,2′′-
terpyridine (terpy) into a coplanar arrangement, providing a
flat aromatic surface capable of intercalation into DNA.
However, despite extensive studies on the interactions of
these materials with isolated nucleic acids or synthetic poly-
nucleotides (9, 10), until recently there have been relatively
few reports of the biological activity of square-planar plati-
num(II) or palladium(II) metallointercalators (11, 12).
The work initiated by Lippard and co-workers (8) pro-
vided the basis for the design of a range of complexes as
potential new anticancer agents. Based on the metallo-
intercalation model, a potential intercalator (13) should in-
corporate a kinetically inert metal with square-planar
geometry, and it should fix aromatic, multidentate ligands in
a coplanar array. Central to our strategy was the use of
bidentate, nonlabile cyclometallated ligands to stabilize the
complex and suppress dissociation of the intercalating aro-
matic ligand from the metal centre in vivo. Analogous mixed
ligand coordination compounds with nitrogen donor ligands
would provide contrasts to determine the importance of
intercalator charge. Most metal complexes with anticancer
Cyclometallation reactions
Reactions of nitrogen donor ligands such as 1-
phenylpyrazole (Hpzph) (1) (15) and 2-phenylpyridine
(Hpyph) (2) (16) with palladium(II) salts to give cyclo-
metallated complexes (referred to herein as cyclopalladated
complexes) have been well-documented. While we have pre-
viously shown that the cyclopalladation of these ligands oc-
curs readily providing products 3 and 4 in near-quantitative
yields (Table 1), the analogous reaction of 2 with a plati-
num(II) salt (cycloplatination) requires more forcing condi-
tions and gives only a moderate (65%) yield of the µ-chloro
dimer 5 (17) (Fig. 1). Although the dimeric complexes are
insoluble or very sparingly soluble in most solvents, they
dissolve with reaction in dimethyl sulfoxide. An examina-
1
tion of the H NMR spectra recorded in ( 2H6)dimethyl sulf-
oxide ((CD3)2SO) indicated the loss of one aryl proton, in
agreement with the cyclometallated structures. An alterna-
tive confirmation that cyclometallation had taken place was
obtained in many cases by addition of one drop of
( 2H5)pyridine (py-d5) to a suspension of the dimers in
CDCl3; the complexes dissolved with reaction to give mono-
mers where loss of one proton was evident and shielding of
the proton ortho to the site of metallation was observed as a
result of its proximity to the pyridine ligand (Fig. 1) (17).
Variation of the aromatic ligand could provide increased
surface area for the planar intercalator possibly resulting in
enhanced DNA binding, and it was shown that 1-(2′-
pyridyl)indole (Hpyin) (6), 1-phenylindazole (H-1phiz) (7),
2-phenylindazole (H-2phiz) (8) (18), and benzo[h]quinoline
(Hbq) (9) (19) could be cyclopalladated with Na2[PdCl4] in
near-quantitative yields giving µ-chloro dimers 10–13 on
heating of the reaction mixtures for up to 24 h (Table 1,
© 2005 NRC Canada

Edwards et al.
971
Fig. 1. Cyclometallation reaction and product of bridge cleavage with py-d5.
Fig. 2. Ligands and abbreviations with positions of metallation indicated.
Fig. 2). Nonoyama and Nakajima (20) have recently
reported the cyclometallation of 6 in moderate yield with
palladium(II) acetate in boiling acetonitrile. Attempted
cyclometallation of 6 with Na2[PdCl4] at room temperature
gave a mixture of the cyclometallated dimer 10 and a non-
metallated coordination complex, as shown by a complex 1H
NMR spectrum in (CD3)2SO, where evidence for non-
metallated ligand (indole H3 was noted as a doublet at
δ 6.76 ppm, J = 3.5 Hz) was observed. A terminal ν(Pd–Cl)
corresponding to the coordination complex was also ob-
served at 343 cm–1 in the far-IR region, suggesting trans
stereochemistry. No attempt was made to separate the mix-
ture into its components. In several cases throughout this
work, metathesis of the complexes with LiBr in acetone or
dimethyl sulfoxide assisted interpretation of the far-IR spec-
tra (17).
achieved quantitatively. Extended heating only increased the
yield of the desired product 15 marginally. The products
could be separated by extraction of coordination complex 16
into boiling dichloromethane. While the insoluble cyclo-
metallated dimer 15 was contaminated with a small amount
of palladium metal, it was of sufficient purity for further
use. Analytically pure material could be obtained by precipi-
tation of the dimer from a filtered solution of N,N-
dimethylformamide (DMF) by the addition of methanol. Co-
ordination complex 16 was identified as the cis stereoisomer
by observation of two terminal ν(Pd–Cl) bands in the far-IR
spectrum at 362 and 321 cm–1; while approximately 10% of
a second component was observed in the 1H NMR spectrum,
it was not determined whether this was due to a small
amount of the trans isomer, or restricted rotation of the
pyrazole ligands within the complex on the 1H NMR
timescale resulting in detection of syn and anti rotamers of
complex 16. All attempts to convert coordination complex
16 into cyclometallated dimer 15 were unsuccessful.
Cyclometallation of 3,5-dimethyl-1-phenylpyrazole (Hdmpzph)
(14) using K2[PdCl4] in boiling aqueous methanol gave a
mixture of cyclometallated product 15 and coordination
complex 16 (Fig. 3), at variance with earlier reports by
Trofimenko and Vaughan (21) that cyclometallation was
The ligand 1-methyl-3,5-diphenylpyrazole (17) is poten-
tially able to form a five-membered chelate ring by metal-
© 2005 NRC Canada

972
Can. J. Chem. Vol. 83, 2005
Fig. 3. Products from cyclometallation of 3,5-dimethyl-1-phenylpyrazole (14).
Fig. 4. Attempt to cyclometallate 1-methyl-3,5-diphenylpyrazole (17).
lation onto an ortho carbon of the 3-phenyl ring; this would
provide an intercalator of comparable size but different ge-
ometry to other phenylpyrazoles (Fig. 4). Heating the ligand
with Na2[PdCl4] in methanol only gave the coordination
complex PdCl2L2 (18) (22); a single ν(Pd–Cl) was observed
in the far-IR spectrum at 349 cm–1 suggesting formation of
Table 2. Cationic cyclometallated complexes.
Cyclometallated
ligand
Yield
(%)
Metal
Diamine
Compound
pzph
pzph
pzph
pyph
pyph
pyph
pyph
pyph
dmpzph
dmpzph
bq
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pt
Pd
Pd
Pd
Pd
Pd
Pd
en
cis-chxn
trans-chxn
en
19
20
21
22
23
24
25
26
27
28
29
30
31
32
59
65
67
85
79
62
80
75
70
74
69
67
80
78
1
the trans stereoisomer, and the H NMR spectrum indicated
that the product was a 15:1 mixture of two components,
which Alonso et al. (22) have suggested results from re-
stricted rotation about the Pd—N bonds. It is noteworthy
that pyrazole 17 gives the trans stereoisomer 18, whereas
pyrazole 14 gives mainly the cis isomer 16, despite both re-
action mixtures being heated for comparable periods.
tn
cis-chxn
trans-chxn
en
en
tn
en
en
en
en
Preparation of cationic complexes
pyin
1phiz
2phiz
Addition of a bidentate diamine to the appropriate µ-chloro
dimers gave the desired cationic complexes as water- and al-
cohol-soluble products (Table 2), which could be purified by
precipitation of the complexes from alcoholic or aqueous al-
coholic solution by the addition of ether. Diamine ligands
chosen for study included 1,2-ethanediamine (en), 1,3-
propanediamine (trimethylenediamine, tn), and cis- and
trans-cyclohexanediamine (chxn). Biological and clinical
studies of platinum complexes of chxn have been extensive
(6, 7); in general, complexes of trans-chxn are more active
than their cis-chxn analogues (6, 23), and complexes pre-
pared from R,R-chxn are more active than those containing
S,S-chxn (23). The oxalate-containing complex oxaliplatin
(Pt(C2O4)(R,R-chxn)) in combination with 5-fluorouracil is
emerging as a major therapy for colorectal cancer (24). In
© 2005 NRC Canada

Edwards et al.
973
Fig. 5. Mixed ligand complexes isolated as dichloride salts.
this study, complexes of cis- and racemic trans-chxn were
prepared for biological testing.
resulting cationic complexes is therefore one less than the
corresponding Pt(II) complexes [Pt(en)(bpy)]2+ and
[Pt(en)(phen)]2+. A range of nonmetallated, cationic com-
plexes analogous to these classical coordination compounds
was also prepared to determine the relationship of inter-
calator charge to biological activity. Comparison of the ac-
tivities of the palladium(II) complexes with those reported
for the corresponding platinum(II) complexes could allow an
assessment of the relationship between metal and activity.
Several of the complexes were isolated as hydrates; at-
tempted drying at elevated temperature led to partial decom-
position and drying at ambient temperature failed to remove
the water of crystallization. In general, while the IR spectra
of the complexes usually showed several absorptions of me-
dium to strong intensity in the range 3000–3300 cm–1, which
could be attributed to the N–H stretching frequencies of the
coordinated diamine ligands; absorptions at higher frequen-
cies (3300–3500 cm–1) were only observed for the hydrated
complexes and were assigned to water of crystallization. Ex-
amination of the far-IR spectra of the complexes supported
the assigned chelate structures as no strong absorptions be-
tween 240 and 360 cm–1, which might be attributed to ν(M-
Cl), were observed.
Synthesis of the mixed complexes was achieved by reac-
tion of PdCl2(en) 33 with the appropriate bidentate aromatic
ligand (pyrazolylpyridines 34 and 35, bpy, and phen) by an
adaptation of the method of Watt and Carter (25); the mixed
ligand complexes 36–39 (Fig. 5) were isolated in moderate
to good yields. The alternative approach, where en was
added to Pd complexes of the bidentate aromatic ligands, led
to partial displacement of the ligand from the metal with
[Pd(en)2]Cl2 being isolated instead. Some hydration of the
mixed ligand complexes was evident from the micro-
analytical data, and this was confirmed by observation of
ν(O-H) in the range 3300–3500 cm–1, as described previ-
1
In the H NMR spectra of the complexes, two distinct
NH2 signals were observed that can be attributed to a
nonequivalence of the NH2 groups as a result of the different
trans carbon and nitrogen ligands. It is interesting that, for
the platinum complex 26, 2JPt,H was only resolved in the sig-
nal for the downfield (6.15 ppm) NH2 group; mere broaden-
ing of the other signal (5.44 ppm) was observed. The
poly(methylene) bridges in the en and tn complexes were
observed as broad signals. Coordination of chxn to a metal
constrains the ligand to adopt specific conformations and, as
a result, further resolution of the cyclohexyl amine protons
was observed. The rigidity of the chelate ring constrains the
protons on each nitrogen to lie in pseudoaxial and pseudo-
equatorial environments; as a result, up to four distinct ex-
changeable signals were observed for the chxn complexes.
1
ously. The H NMR spectra of the complexes were unre-
markable; whereas two signals for the coordinated NH2
groups were observed for the cyclometallated complexes, the
symmetry or pseudosymmetry of the coordination com-
plexes caused the NH2 groups to be chemical-shift equiva-
lent.
In vitro and in vivo testing
The complexes were subjected to an in vitro screen for
growth inhibitory activity against the murine leukæmia cell
line L1210. While these tests do not discriminate between
cytotoxic and cytostatic activity, they provide valuable infor-
The cyclometallation reaction gives complexes with an-
ionic carbon σ-donor ligands and the overall charge on the
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974
Can. J. Chem. Vol. 83, 2005
Table 4. Antitumour testing for complex 30
Table 3. Growth inhibition of L1210 cells in culture.
against P388 leukæmia.
Aromatic
Complex ligand
IC50
Metal Charge (µmol/L)
Diamine
Dose (mg/kg/injection)
%T/C
63
24
43
34
18
11.5
20.5
300
11
14
0 (control)
2
4
8
16
32
19
20
21
22
23
24
25
26
27
28
29
30
31
32
36
37
38
39
pzph
pzph
pzph
pyph
pyph
pyph
pyph
pyph
dmpzph
dmpzph
bq
en
cis-chxn
trans-chxn Pd
en
Pd
Pd
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
100
110
111
110
0
Pd
Pd
Pd
tn
cis-chxn
trans-chxn Pd
en
en
tn
en
en
en
en
en
en
en
en
en
en
0
158
50 (5-fluorouracil: standard)
Pt
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pt
In this study, a single organoplatinum cyclometallated
complex [Pt(pyph)(en)]+ (26) was prepared and its biological
activity was measured (IC50 = 300 µmol/L); somewhat sur-
prisingly it was almost an order of magnitude less active
than [Pt(en)(bpy)]2+ (IC50 = 33 µmol/L) (11). This suggests
that there might be no firm correlation between platinum and
palladium metallointercalators as the analogous organo-
palladium complex 22 [Pd(pyph)(en)]+ (IC50 = 34 µmol/L)
was more active than the coordination analogue 38
[Pd(en)(bpy)]2+ (IC50 = 60 µmol/L).
16
14
18
17
pyin
1phiz
2phiz
pzpy
dmpzpy
bpy
phen
bpy
phen
230
>200
60
13
33 (11)
2 (11)
Increased biological activity is observed with increased
substitution on the planar organometallic ligand. Substitution
with methyl groups or fusion of an extra benzene ring onto
the planar aromatic structure, led to lower IC50 values. The
Pt
mation about whether the complexes can affect the rate at
which cells grow and divide. The complexes (drugs) were
dissolved in sterile water or ethanol (for the chxn com-
plexes) and growth inhibition experiments were conducted
for a 48 h period against L1210 cell cultures, providing drug
concentrations that caused a 50% inhibition of cell growth
(IC50) (Table 3). For comparison, it should be noted that
cisplatin has an IC50 of 0.9 µmol/L under similar conditions.
methyl substituents may provide
a steric barrier to
dislodgement of an intercalated drug, accounting for the in-
creased activity. The position of fusion of an extra aromatic
ring did not seem to affect the activity greatly (compare:
1phiz 31 (18 µmol/L) and 2phiz 32 (17 µmol/L) complexes).
Additional aromatic rings give a larger surface area to inter-
calate between the base pairs in a drug–DNA complex, and
the extra aromatic ring could lead to a more stable complex
as a result of an enhanced π-orbital overlap. The weakest
drug–DNA complexes would be expected for complexes
such as the 2-(2-pyridyl)phenyl and 1-(pyrazolyl)phenyl
complexes, which have only two coplanar aromatic rings,
and stronger drug–DNA adducts would be expected for larger
cationic complexes. However, it is noteworthy that McFadyen
et al. (11) found that a series of structurally related, cationic
complexes exerted their biological activities in different
ways, and it is possible that structurally similar complexes
here might likewise be inhibiting cell growth by different
mechanisms.
Variation of the diamine ligand also resulted in a change
in biological activity. Increased bulk (chxn vs. en or tn)
tended to give more active complexes, and a consistent ef-
fect was noted for the chxn complexes, where lower IC50
values for the cis-chxn complexes 20 and 24 than their trans
analogues 21 and 25 were measured.
One of the more active complexes (the 1-(2-pyridyl)indolyl
complex 30) was selected for further study. Potential anti-
tumour activity against P388 leukæmia in mice was evalu-
ated over a range of dose levels up to a maximum tolerated
dose, with results expressed (%T/C) as a ratio of mean sur-
vival times of treated animals (T) relative to control animals
(C); significant antitumour activity requires %T/C values
greater than 125%, and values of 0% indicate that no treated
animals survived the drug regime at these dose levels. Re-
sults obtained in this screening (Table 4) indicated that the
The cationic planar complexes reported in this study
caused 50% growth inhibition over a wide range of concen-
trations. The cyclometallated complexes (formal charge 1+)
generally were more active than the dipositive coordination
analogues (compare 19 with 36, 27 with 37, and 22 with
38), but it should be noted that the phenanthroline complex
39 had a similar IC50 value (13 µmol/L) to that of the
benzo[h]quinolinyl complex 29 (16 µmol/L). Although a
variation of the intercalator charge might influence the bio-
logical activity, especially in electrostatic stabilization of an
initial drug–DNA complex, the relative stabilities of the
organometallic drugs in the presence of a wide range of bio-
logical ligands could also explain the observed differences.
As described above, in the preparation of the cationic com-
plexes, addition of diamines to the cyclometallated µ-chloro
dimers gave the desired products cleanly, whereas addition
of en to palladium complexes of bidentate heterocyclic lig-
ands resulted in at least partial displacement of the aromatic
ligand. Thus, it is proposed that the presence of the palla-
dium–carbon σ bond appears to increase the stability of the
complexes, and therefore the cyclometallated complexes
would be more likely to reach their biological target intact.
It is possible that the increased stability of the phenanthro-
line complex with respect to displacement of the ligand from
the metal centre meant that its stability was similar to that of
the benzo[h]quinolinyl complex under biological conditions,
hence its activity was likewise similar.
© 2005 NRC Canada

Edwards et al.
975
metallointercalator showed no significant antitumour activity
in vivo at doses below toxic levels.
1253, 1185, 745, 734, 418, 319 (Pd–Cl), 290, 240 (Pd–Cl).
1H NMR (90 MHz, CDCl3 – one drop of py-d5) δ: 9.22 (dd,
J = 5.9, 1.2 Hz, 1H, pyridyl H6), 7.91–7.07 (m, 6H, aryl),
6.89 (ddd, J = 7.4, 5.9, 1.4 Hz, 1H, pyridyl H5), 5.58 (d, J =
0.5 Hz, 1H, indolyl H3). Elemental anal. calcd. for
C26H18Cl2N4Pd2 (%): C 46.6, H 2.7, N 8.4; found: C 46.6, H
2.55, N 8.2.
Experimental
General procedure
Elemental analyses were performed by the Microanaly-
tical Service, School of Chemistry, University of New South
Wales. IR spectra were measured with a PerkinElmer 180
Grating IR spectrophotometer with a far-IR option, and refer
to paraffin mulls of solids, measured between KBr plates
(4200–380 cm–1) and between polyethylene discs (550–
100 cm–1). Only absorptions of strong to medium intensity
are reported herein. 1H NMR spectra were recorded at
90 MHz (Bruker WH90 spectrometer), 200 MHz (Bruker
AC200 spectrometer), or 300 MHz (Bruker AM300 spec-
trometer). Chemical shifts are reported in parts per million
(ppm) downfield from tetramethylsilane (δ 0.00 ppm, refer-
enced to CHCl3 impurity in CDCl3). Addition of one drop of
py-d5 to CDCl3 suspensions of dimers 10, 11, 12, 15, and 18
converted the insoluble dimers into soluble monomeric com-
plexes, which gave well-resolved spectra that integrated
cleanly, providing excellent evidence for cyclometallation.
Hbq (9), phen, bpy, trans-1,2-cyclohexanediamine (trans-
chxn), en, and trimethylenediamine (tn) were obtained from
the Aldrich Chemical Company and were recrystallized or
distilled prior to use. cis-1,2-Cyclohexanediamine (cis-chxn)
was separated from a mixture of isomers by the method of
Saito and Kidani (26). 1-Phenylpyrazole (1) and 14 were
prepared by the method of Finar and Hurlock (27). 1-(2′-
Pyridyl)indole (6) was prepared by the method of Khan and
Polya (28). 1-Phenyl-indazole (H-1phiz) (7) was prepared by
the method of Pozharskii et al. (29), and 8 was prepared by
the method of Cadogan and Mackie (30). 2-(1′-Pyra-
zolyl)pyridine (34) and 2-(3′,5′-dimethyl-1′-pyrazolyl)pyridine
(35) were prepared by the general method of Khan and Pinto
(31). Cyclopalladations of 1 to give 3 (15), of 2 to give 4
(16, 32), and of 9 to give 13 (19), and cycloplatination of 2 to
give 5 (17), were carried out according to published proce-
dures. Dichloro(1,2-ethanediamine-N,N′)palladium(II) (PdCl2-
(en)) (33) was prepared by the method of McCormick et al.
(33). Mixed ligand complex [Pd(en)(phen)]Cl2 (39) (9) was
prepared by the method described for complex 36 in the fol-
lowing section.
Di-␮-chlorobis[2-(1′H-indazol-1′-yl)phenyl-N′,C]dipalla-
dium (11)
The title compound 11 was prepared by a similar method
to 10, from 7 (0.62 g, 3.2 mmol) and Na2[PdCl4] (0.75 g,
2.6 mmol), as a yellow powder (0.84 g, 99%), mp > 300 °C.
A sample was recrystallized from DMF–methanol for
microanalysis. IR (cm–1): 1215, 1100, 836, 735, 722, 615,
1
421, 306 (Pd–Cl), 279, 230 (Pd–Cl). H NMR (300 MHz,
CDCl3 – one drop of py-d5) δ: 8.83 (s, 1H, indazolyl H3),
7.98 (dd, J = 8.7, 0.6 Hz, 1H, indazolyl H7), 7.79 (d, J =
8.1 Hz, 1H, aryl), 7.59 (ddd, J = 8.7, 7.1, 1.2 Hz, 1H,
indazolyl H6), 7.54 (dd, J = 8.0, 1.0 Hz, 1H, aryl), 7.30 (t,
J = 7.1 Hz, 1H, indazolyl H5), 7.17 (td, J = 7.7, 1.2 Hz, 1H,
aryl), 6.80 (td, J = 7.6, 1.0 Hz, 1H, aryl), 6.33 (dd, J = 7.6,
1.1 Hz, 1H, phenyl H6). Elemental anal. calcd. for
C26H18Cl2N4Pd2 (%): C 46.6, H 2.7, N 8.4; found: C 46.5, H
2.5, N 8.45.
Di-␮-chlorobis[2-(2′H-indazol-2′-yl)phenyl-N′,C]dipalla-
dium (12)
The title compound 12 was prepared by a similar method
to 10, from 8 (0.62 g, 3.2 mmol) and Na2[PdCl4] (0.75 g,
2.6 mmol), as a yellow powder (0.83 g, 98%), mp > 300 °C
(lit. value (18) mp > 300 °C). A sample was recrystallized
from DMF–methanol for microanalysis. IR (cm–1): 1627,
1519, 1489, 1352, 1071, 792, 784, 753, 745, 739, 437, 330
1
(Pd–Cl), 246 (Pd–Cl). H NMR (300 MHz, CDCl3 – one
drop of py-d5) δ: 9.01 (d, J = 8.9 Hz, 1H, indazolyl H7),
8.44 (s, 1H, indazolyl H3), 7.58 (d, J = 8.5 Hz, 1H,
indazolyl H4), 7.34 (t, J = 7.4 Hz, 1H, aryl), 7.30 (dd, J =
7.9, 0.9 Hz, 1H, phenyl H3), 7.09 (t, J = 7.9 Hz, 1H, aryl),
7.03 (t, J = 7.5 Hz, 1H, aryl), 6.79 (t, J = 7.5 Hz, 1H, aryl),
6.08 (d, J = 7.6 Hz, 1H, phenyl H6). Elemental anal. calcd.
for C26H18Cl2N4Pd2 (%): C 46.6, H 2.7, N 8.4; found: C
46.5, H 2.7, N 8.4.
Di-␮-chlorobis[2-(3′,5′-dimethyl-1′-pyrazolyl)phenyl-
N′,C]dipalladium (15)
Preparations
A mixture of K2[PdCl4] (1.50 g, 4.6 mmol) and 14
(1.00 g, 5.8 mmol) in aqueous dioxan (60 mL of 50% v/v)
was stirred under a nitrogen atmosphere. A yellow precipi-
tate separated and the mixture was stirred at room tempera-
ture for 18 h, and then heated under reflux for 36 h. The
precipitate was filtered off, washed successively with metha-
nol and ether, and dried. The product was suspended in di-
chloromethane (60 mL) and the suspension was heated
under reflux for 6 h. The sparingly soluble solid was col-
lected, washed with dichloromethane and ether, and dried to
give the µ-chloro complex 15 as a yellow powder (0.65 g,
45% based on Pd), mp 337–339 °C (dec.). A sample was
recrystallized from DMF–methanol for microanalysis. IR
(cm–1): 1552, 1443, 1438, 743, 738, 341 (Pd–Cl), 283, 265
Di-␮-chlorobis[1-(2′-pyridyl)indol-2-yl)-N′,C]dipalladium
(10)
1-(2′-Pyridyl)indole (6) (1.50 g, 7.7 mmol) in methanol
(20 mL) was added to a stirred solution of Na2[PdCl4]
(1.96 g, 6.7 mmol) in methanol (60 mL) under a nitrogen at-
mosphere. The mixture was heated under reflux for 24 h,
and the resultant yellow precipitate was filtered off and
washed successively with methanol and ether. A suspension
of the crude product in dichloromethane (30 mL) was heated
under reflux for 2 h, and then cooled to room temperature.
The sparingly soluble solid was collected, washed with di-
chloromethane and then ether, and dried to give the µ-chloro
dimer 10 as a yellow powder (2.16 g, 97%), mp 228–230 °C
(dec.). A sample was recrystallized from DMF–methanol for
microanalysis. IR (cm–1): 1613, 1510, 1489, 1318, 1288,
1
(Pd–Cl). H NMR (90 MHz, (CD3)2SO) δ: 7.64 (d br, J =
7.0 Hz, 1H, phenyl), 7.31–6.70 (m, 3H, phenyl), 6.21 (s, 1H,
© 2005 NRC Canada

976
Can. J. Chem. Vol. 83, 2005
pyrazolyl H4), 2.63 (s, 3H, Me), 2.33 (s, 3H, Me). Elemental
anal. calcd. for C22H22Cl2N4Pd2 (%): C 42.2, H 3.5, N 8.95;
found: C 42.3, H 3.5, N 8.9.
(20 mL) and water (10 mL). The reaction mixture was
warmed for 10 min and then stirred at room temperature
overnight. Evaporation of the solvents gave a pale yellow
solid that was recrystallized from methanol–ether to give the
title compound 20 as fine colourless needles (0.183 g, 65%),
mp 276–278 °C (dec.). IR (cm–1): 3200, 3170 (br), 3135,
3095, 1600, 1511, 1412, 1210, 1093, 1070, 1059, 750, 741,
The filtrate was evaporated to dryness and the residue was
dissolved in dichloromethane and the solution filtered. On
addition of hexane, dichlorobis(3,5-dimethyl-1-phenylpyra-
zole-N2)palladium (16) separated as orange needles (0.98 g,
41% based on Pd), mp 315–317 °C (dec.) IR (cm–1): 1595,
1555, 1503, 1418, 1399, 808, 764, 760, 696, 692, 565, 362
1
737, 364. H NMR (300 MHz, (CD3)2SO) δ: 8.78 (d, J =
2.9 Hz, 1H, pyrazolyl H5), 7.93 (d, J = 2.2 Hz, 1H,
pyrazolyl H3), 7.56 (dd, J = 7.8, 1.0 Hz, 1H, phenyl), 7.22
(dd, J = 7.5, 1.0 Hz, 1H, phenyl), 7.17 (td, J = 7.6, 1.0 Hz,
1H, phenyl), 7.00 (td, J = 7.4, 1.0 Hz, 1H, phenyl), 6.70 (t,
J = 2.5 Hz, 1H, pyrazolyl H4), 5.59 (d br, J = 6 Hz, 1H,
NH), 4.90 (dd br, J = 11, 7 Hz, 1H, NH), 4.82 (d br, J =
7 Hz, 1H, NH), 4.41 (dd br, J = 11, 7 Hz, 1H, NH), 3.04 (s
br, 2H, CHNH2), 1.78–1.57 (m, 6H, cyclohexyl), 1.32 (s br,
2H, cyclohexyl). Elemental anal. calcd. for C15H21ClN4Pd
(%): C 45.1, H 5.3, N 14.0; found: C 44.9, H 5.4, N 14.0.
1
(Pd–Cl), 321 (Pd–Cl). H NMR (90 MHz, CDCl3) (major:
minor components, 10:1) δ: 7.84–7.58 (m, 10H major + 10H
minor, phenyl), 6.02 (s, 2H minor, H4′), 5.91 (s, 2H major,
H4′), 3.05 (s, 6H minor, Me), 2.21 (s, 6H major, Me), 2.09
(s, 6H major, Me), 1.97 (s, 6H minor, Me). Elemental anal.
calcd. for C22H24Cl2N4Pd (%): C 50.6, H 4.6, N 10.7; found:
C 50.7, H 4.6, N 10.7.
Dichlorobis(1-methyl-3,5-diphenylpyrazole-N2)palladium (18)
1-Methyl-3,5-diphenylpyrazole (17) (0.22 g, 0.94 mmol)
in methanol (10 mL) was added to a stirred solution of
Li2[PdCl4] (prepared from PdCl2 (0.14 g, 0.79 mmol) and
LiCl (0.20 g, 4.7 mmol)) in methanol (40 mL). A yellow
solid separated, and the mixture was heated under reflux for
40 h under a nitrogen atmosphere. The product was filtered
off and dissolved in dichloromethane, and the solution was
filtered. On addition of hexane the palladium complex 18
separated as small yellow needles (0.19 g, 63%), mp 280–
282 °C (dec.) (lit. value (22) mp 290–293 °C). IR (cm–1):
3085, 1437, 1428, 1296, 838, 775, 766, 751, 703, 694, 681,
349 (Pd–Cl). 1H NMR (300 MHz, CDCl3) (major:minor
components, 15:1) δ: 8.43–8.33 (m, 2H major + 2H minor,
phenyl), 7.59–7.45 (m, 8H major + 8H minor, phenyl), 6.43
(s, 1H major + 1H minor, pyrazole H4), 4.80 (s, 3H minor,
NMe), 4.36 (s, 3H major, NMe). Elemental anal. calcd. for
C32H28Cl2N4Pd (%): C 59.5, H 4.4, N 8.7; found: C 59.2, H
4.2, N 8.6.
(trans-1,2-Cyclohexanediamine-N,N′)[2-(1′-pyrazolyl)phenyl-
N′,C]palladium(1+) chloride (21)
Freshly distilled trans-chxn (15 drops) was added to a
stirred, boiling suspension of µ-chloro dimer 3 (0.560 g,
0.95 mmol) in ethanol (70 mL) under a nitrogen atmosphere.
The mixture was heated under reflux for 2 h, during which
time the µ-chloro dimer dissolved. The resultant solution
was filtered while hot, cooled to room temperature, and
slowly diluted with ether to give the crude product.
Recrystallization (twice) from ethanol–ether gave the title
compound 21 as fine colourless needles (0.458 g, 67%), mp
287 to 288 °C (dec.). IR (cm–1): 3195, 3150 (br), 3110,
3065, 1601, 1514, 1413, 1073, 1064, 1057, 755, 745, 738,
1
606, 363. H NMR (300 MHz, (CD3)2SO) δ: 8.78 (d, J =
2.7 Hz, 1H, pyrazolyl H5), 7.96 (d, J = 2.2 Hz, 1H,
pyrazolyl H3), 7.57 (dd, J = 7.3, 1.2 Hz, 1H, phenyl), 7.19–
7.15 (m, 2H, phenyl), 7.01 (t, J = 7.3 Hz, 1H, phenyl), 6.70
(t, J = 2.5 Hz, 1H, pyrazolyl H4), 5.44 (d exch, J = 7 Hz,
1H, NH), 5.17 (t exch, J = 10.5 Hz, 1H, NH), 4.95 (d exch,
J = 7 Hz, 1H, NH), 4.18 (t exch, J = 10.5 Hz, 1H, NH),
2.43–2.31 (m, 2H, CHNH2), 1.99 (t, J = 14.7 Hz, 2H,
cyclohexyl), 1.63 (d br, J = 7.6 Hz, 2H, cyclohexyl), 1.32
(sextet br, J = 10.7 Hz, 2H, cyclohexyl), 1.10 (t br, J =
10 Hz, 2H, cyclohexyl). Elemental anal. calcd. for C15H21ClN4Pd
(%): C 45.1, H 5.3, N 14.0; found: C 45.0, H 5.3, N 13.8.
(1,2-Ethanediamine-N,N′)[2-(1′-pyrazolyl)phenyl-
N′,C]palladium(1+) chloride (19)
1,2-Ethanediamine (60 mg, 1.0 mmol) in chloroform
(5 mL) was added to a stirred suspension of µ-chloro dimer
3 (0.233 g, 0.41 mmol) in chloroform (10 mL). A white
powder slowly formed, and the mixture was stirred at room
temperature for 12 h. The solid was filtered off, washed with
chloroform, and dried. Recrystallization of the crude product
from methanol–dichloromethane gave the title compound 19
as a white powder (0.166 g, 59%), mp 230 °C (dec.) (lit.
value (15) mp 195 °C (dec.)). IR (cm–1): 3295 (br), 3170
(br), 3105 (br), 1589, 1416, 1344, 1181, 1113, 1057, 1031,
(1,2-Ethanediamine-N,N′)[2-(2′-pyridyl)phenyl-N′,C]pal-
ladium(1+) chloride (22)
This compound was prepared by the same method as
complex 21 from the µ-chloro dimer 4 (0.258 g, 0.44 mmol)
and 1,2-ethanediamine (0.06 g, 1.0 mmol) in methanol
(10 mL). Recrystallization of the crude product from metha-
nol–ether gave the title compound 22 as fine, pale yellow
needles (0.263 g, 85%), mp 245 to 246 °C (dec.). IR (cm–1):
3260 (br), 3185 (br), 3115 (br), 3090 (br), 1605, 1578, 1438,
1
755, 750, 612, 492, 406, 244, 192. H NMR (300 MHz,
(CD3)2SO) δ: 8.77 (d, J = 2.7 Hz, 1H, pyrazolyl H5), 7.95
(d, J = 2.2 Hz, 1H, pyrazolyl H3), 7.56 (d, J = 7.5 Hz, 1H,
phenyl), 7.20–7.12 (m, 2H, phenyl), 7.00 (td, J = 7.4,
1.0 Hz, 1H, phenyl), 6.70 (t, J = 2.5 Hz, 1H, pyrazolyl H4),
5.40 (s br exch, 2H, NH2), 4.59 (s br exch, 2H, NH2), 2.71 (s
br, C 4H, H2CH2). Elemental anal. calcd. for C11H15ClN4Pd
(%): C 38.3, H 4.4, N 16.2; found: C 38.2, H 4.4, N 16.2.
1
1160, 1058, 753, 744, 341. H NMR (300 MHz, (CD3)2SO)
δ: 8.39 (d, J = 5.6 Hz, 1H, pyridyl H6), 8.10–8.06 (m, 2H,
pyridyl), 7.74–7.72 (m, 1H, phenyl), 7.42–7.37 (m, 1H,
aryl), 7.16–7.09 (m, 3H, aryl), 5.27 (s br exch, 2H, NH2),
4.55 (s br exch, 2H, NH2), 2.72 (m br, 4H, CH2CH2). Ele-
mental anal. calcd. for C13H16ClN3Pd (%): C 43.8, H 4.5, N
11.8; found: C 43.9, H 4.6, N 11.8.
(cis-1,2-Cyclohexanediamine-N,N′)[2-(1′-pyrazolyl)phenyl-
N′,C]palladium(1+) chloride (20)
Freshly distilled cis-chxn (10 drops) was added to a
stirred suspension of 3 (0.201 g, 0.35 mmol) in methanol
© 2005 NRC Canada

Edwards et al.
977
75%), mp 297 to 298 °C (dec.). IR (cm–1): 3245 (br), 3170
(br), 3095 (br), 3060 (br), 1611, 1584, 1428, 1424, 1160,
1152, 1125, 1061, 754, 730, 414, 252. H NMR (200 MHz,
(1,3-Propanediamine-N,N′)[2-(2′-pyridyl)phenyl-
N′,C]palladium(1+) chloride monohydrate (23)
1
This compound was prepared by the same method as
complex 21 from 4 (0.217 g, 0.37 mmol) and 1,3-pro-
panediamine (10 drops) in methanol (10 mL). Recrystalli-
zation of the crude product from methanol–ether gave the
title compound 23 as pale yellow needles (0.224 g, 79%),
mp 210 to 211 °C (dec.). IR (cm–1): 3450 (br), 3365 (br),
3325 (br), 3240 (br), 3115 (br), 1607, 1582, 1433, 1191,
1150, 1037, 902, 755, 735. 1H NMR (90 MHz, (CD3)2SO) δ:
8.41 (d, J = 5.6 Hz, 1H, pyridyl H6), 8.18–7.97 (m, 2H,
aryl), 7.74–7.11 (m, 5H, aryl), 4.89 (s br exch, 2H, NH2),
4.22 (s br exch, 2H, NH2), 2.88–2.66 (m br, 4H, 2 × CH2N),
1.76–1.55 (m, 2H, CH2). Elemental anal. calcd. for
C14H20ClN3OPd (%): C 43.3, H 5.2, N 10.8; found: C 43.3,
H 5.1, N 10.8.
(CD3)2SO) δ: 8.69 (d with satellites, J = 5.6 Hz, JPt,H
=
27 Hz, 1H, pyridyl H6), 8.14–8.02 (m, 2H, aryl), 7.72–7.68
(m, 1H, aryl), 7.38–7.25 (m, 2H, aryl), 7.15–7.08 (m, 2H,
aryl), 6.15 (s br with satellites, exch, JPt,H = 46 Hz, 2H,
NH2), 5.44 (s br exch, 2H, NH2), 2.67 (m br, 4H, CH2CH2).
Elemental anal. calcd. for C13H16ClN3Pt (%): C 35.1, H 3.6,
N 9.45; found: C 35.2, H 3.7, N 9.2.
[2-(3′,5′-Dimethyl-1′-pyrazolyl)phenyl-N′,C](1,2-ethane-
diamine-N,N′)palladium(1+) chloride monohydrate (27)
This compound was prepared by the same method as
complex 21 from 15 (0.23 g, 0.37 mmol) and 1,2-
ethanediamine (45 mg, 0.75 mmol) in methanol (10 mL).
Recrystallization of the crude product from methanol–ether
gave the title compound 27 as fine colourless needles
(0.20 g, 70%), mp 250 °C (dec.). IR (cm–1): 3420 (br), 3310,
3290, 3210 (br), 3160, 3120 (br), 3085 (br), 3030, 1554,
1440, 1424, 1184, 1164, 1136, 1102, 1083, 1061, 776, 484,
(cis-1,2-Cyclohexanediamine-N,N′)[2-(2′-pyridyl)phenyl-
N′,C]palladium(1+) chloride (24)
This compound was prepared by the same method as
complex 20 from 4 (0.357 g, 0.60 mmol) and cis-chxn (10
drops). Recrystallization of the crude product from ethanol–
ether gave the title compound 24 as fine, pale yellow needles
(0.308 g, 62%), mp 292 to 293 °C (dec.). IR (cm–1): 3205
(br), 3175 (br), 3135, 3095 (br), 1602, 1578, 1434, 1093,
1
411, 238, 186. H NMR (300 MHz, (CD3)2SO) δ: 7.37 (dd,
J = 7.3, 0.8 Hz, 1H, phenyl), 7.15 (td, J = 7.6, 1.3 Hz, 1H,
phenyl), 7.07 (dd, J = 7.6, 1.3 Hz, 1H, phenyl), 6.97 (td, J =
7.4, 0.8 Hz, 1H, phenyl), 6.27 (s, 1H, pyrazolyl H4), 5.34 (s
br exch, 2H, NH2), 4.52 (s br exch, 2H, NH2), 2.67 (s br, 4H,
CH2CH2), 2.66 (s, 3H, 5′-Me), 2.22 (s, 3H, 3′-Me). Elemen-
tal anal. calcd. for C13H21ClN4OPd (%): C 39.9, H 5.4, N
14.3; found: C 39.5, H 5.5, N 14.2.
1
750, 730, 627, 407, 363. H NMR (300 MHz, (CD3)2SO) δ:
8.36 (d br, J = 4.9 Hz, 1H, pyridyl H6), 8.08 (s br, 2H, aryl),
7.73 (d br, J = 6.9 Hz, 1H, aryl), 7.44–7.36 (m, 1H, aryl),
7.18–7.08 (m, 3H, aryl), 5.42 (s br exch, 1H, NH), 4.72–
4.61 (m br exch, 2H, 2 × NH), 4.23 (s br exch, 1H, NH),
3.02 (s br, 2H, CHNH2), 1.82–1.57 (m, 6H, cyclohexyl),
1.42–1.26 (m br, 2H, cyclohexyl). Elemental anal. calcd. for
C17H22ClN3Pd (%): C 49.8, H 5.4, N 10.2; found: C 49.7, H
5.6, N 10.35.
[2-(3′,5′-Dimethyl-1′-pyrazolyl)phenyl-N′,C](1,3-propane-
diamine-N,N′)palladium(1+) chloride hemihydrate (28)
This compound was prepared by the same method as
complex 21 from 15 (0.158 g, 0.25 mmol) and 1,3-
propanediamine (10 drops) in methanol (10 mL). Recry-
stallization of the crude product from ethanol–ether gave the
title compound 28 as fine colourless needles (0.148 g, 74%),
mp 201 to 202 °C (dec.). IR (cm–1): 3440 (br), 3270 (br),
3240 (br), 3165, 3145, 3050, 1550, 1440, 1422, 1186, 1175,
1165, 1160, 1037, 1028, 927, 794, 746, 479. 1H NMR
(90 MHz, (CD3)2SO) δ: 7.42–7.06 (m, 4H, phenyl), 6.25 (s,
1H, pyrazolyl H4), 4.90 (s br exch, 2H, NH2), 4.07 (s br
exch, 2H, NH2), 2.75 (s br, 4H, 2 × CH2N), 2.65 (s, 3H, 5′-
Me), 2.33 (s, 3H, 3′-Me), 1.78–1.58 (m, 2H, CH2). Elemen-
tal anal. calcd. for C14H22ClN4O0.5Pd (%): C 42.4, H 5.6, N
14.1; found: C 42.5, H 5.6, N 14.1.
(trans-1,2-Cyclohexanediamine-N,N′)[2-(2′-
pyridyl)phenyl-N′,C]palladium(1+) chloride (25)
This compound was prepared by the same method as
complex 21 from 4 (0.560 g, 0.95 mmol) and trans-chxn
(15 drops). Recrystallization of the crude product from etha-
nol–ether gave the title compound 25 as fine, pale yellow
needles (0.622 g, 80%), mp 350–352 °C (dec.). IR (cm–1):
3210, 3175, 3085 (br), 3050 (br), 1608, 1601, 1579, 1434,
1
752, 732, 627, 364. H NMR (300 MHz, (CD3)2SO) δ: 8.37
(d, J = 5.5 Hz, 1H, pyridyl H6), 8.10–8.07 (m, 2H, aryl),
7.75–7.72 (m, 1H, aryl), 7.44–7.37 (m, 1H, aryl), 7.17–7.11
(m, 3H, aryl), 5.25 (d exch, J = 6.2 Hz, 1H, NH), 5.04 (t
exch, J = 10.6 Hz, 1H, NH), 4.79 (d exch, J = 6.9 Hz, 1H,
NH), 4.14 (t exch, J = 10.2 Hz, 1H, NH), 2.43–2.28 (m, 2H,
CHNH2), 1.99 (t, J = 14.6 Hz, 2H, cyclohexyl), 1.63 (d br,
J = 7.0 Hz, 2H, cyclohexyl), 1.30 (sextet br, J = 12.6 Hz,
2H, cyclohexyl), 1.11 (t br, J = 10.6 Hz, 2H, cyclohexyl).
Elemental anal. calcd. for C17H22ClN3Pd (%): C 49.8, H 5.4,
N 10.2; found: C 49.5, H 5.5, N 10.1.
(Benzo[h]quinolin-10-yl-N′,C)(1,2-ethanediamine-
N,N′)palladium(1+) chloride (29)
This compound was prepared by the same method as com-
plex 21 from the µ-chloro dimer 13 (0.157 g, 0.25 mmol) and
1,2-ethanediamine (5 drops) in methanol (10 mL). Recry-
stallization of the crude product from methanol–ether gave
the title compound 29 as small yellow prisms (0.128 g,
69%), mp 215–220 °C (dec.). IR (cm–1): 3205 (br), 3165
(br), 3120, 3080, 1405, 1058, 848, 714, 482. 1H NMR
(300 MHz, (CD3)2SO) δ: 8.75 (dd, J = 5.2, 0.9 Hz, 1H, H2),
8.69 (d, J = 8.1 Hz, 1H, H4), 7.92 (d, J = 8.8 Hz, 1H, aryl),
7.84 (d, J = 8.8 Hz, 1H, aryl), 7.78 (dd, J = 8.1, 5.2 Hz, 1H,
H3), 7.72 (d, J = 7.8 Hz, 1H, aryl), 7.50 (t, J = 7.5 Hz, 1H,
H8), 7.36 (d, J = 7.0 Hz, 1H, aryl), 5.49 (s br exch, 2H,
NH2), 4.69 (s br exch, 2H, NH2), 2.82–2.78 (m br, 4H,
(1,2-Ethanediamine-N,N′)[2-(2′-pyridyl)phenyl-
N′,C]platinum(1+) chloride (26)
This compound was prepared by the same method as
complex 21 from the µ-chloro dimer 5 (0.250 g, 0.32 mmol)
and 1,2-ethanediamine (10 drops) in methanol (50 mL).
Recrystallization of the crude product from methanol–ether
gave the title compound 26 as fine yellow needles (0.216 g,
© 2005 NRC Canada

978
Can. J. Chem. Vol. 83, 2005
CH2CH2). Elemental anal. calcd. for C15H16ClN3Pd (%): C
47.4, H 4.2, N 11.05; found: C 47.3, H 4.2, N 11.0.
(0.60 g, 2.5 mmol) in water (50 mL) and the reaction mix-
ture was heated under reflux for 24 h. During this time the
orange solid dissolved to give a pale yellow solution. After
being cooled to room temperature, the solution was filtered
and the solvent removed. The crude product was dissolved
in water (5 mL) and the solution was filtered and diluted
with ethanol. On the addition of ether, the title compound 36
separated as fine, pale yellow needles (0.62 g, 59%), mp
328 °C (dec.). IR (cm–1): 3420 (br), 3185, 3110, 3060, 1609,
(1,2-Ethanediamine-N,N′)(1-(2′-pyridyl)indol-2-yl-
N′,C)palladium(1+) chloride dihydrate (30)
This compound was prepared by the same method as com-
plex 21 from the µ-chloro dimer 10 (0.244 g, 0.36 mmol) and
1,2-ethanediamine (5 drops) in ethanol (15 mL) and water
(4 mL). Recrystallization by slow addition of ether to a solu-
tion of the crude product in ethanol–water (90% v/v) gave
the title compound 30 as cream-coloured needles (0.211 g,
67%), mp 223–225 °C (dec.). IR (cm–1): 3460 (br), 3355
(br), 3295 (br), 3230 (br), 3140 (br), 1611, 1595, 1510,
1
1591, 1493, 1407, 1136, 1074, 1053, 784, 596. H NMR
(90 MHz, (CD3)2SO) δ: 8.62 (dd, J = 2.5, 0.5 Hz, 1H,
pyrazolyl H5), 8.48 (dt, J = 4.9, 1.8 Hz, 1H, pyridyl H6),
8.03–7.94 (m, 2H, pyridyl H3 and H4), 7.83 (dd, J = 1.8,
0.5 Hz, 1H, pyrazolyl H3), 7.36 (ddd, J = 6.2, 4.9, 2.3 Hz,
1H, pyridyl H5), 6.58 (dd, J = 2.5, 1.8 Hz, 1H, pyrazolyl
H4), 4.89 (s br exch, 4H, 2 × NH2), 2.34 (s br, 4H,
CH2CH2). Elemental anal. calcd. for C10H19Cl2N5O2Pd (%):
C 28.7, H 4.6, N 16.7; found: C 28.5, H 4.4, N 17.1.
Heating a mixture of 1,2-ethanediamine (2.5 mL of a
0.03 g/mL solution in methanol, 1.2 mmol) and dichloro[2-
(1′-pyrazolyl)pyridine-N,N′]palladium (34) (0.21 g, 0.7 mmol)
in methanol (20 mL) and water (5 mL) gave, on addition of
ether, a white solid that was identified as bis(1,2-ethane-
diamine-N,N′)palladium(2+) dichloride (35) (0.129 g, 69%),
mp 245 °C (dec.). IR (cm–1): 3195, 3150, 3060, 3020, 1606,
1599, 1318, 1274, 1136, 1126, 1058, 468, 370, 290. 1H
NMR (90 MHz, D2O) δ: 2.75 (s br, 8H, CH2CH2).
1
1490, 1146, 1061, 777, 754, 731, 420. H NMR (300 MHz,
(CD3)2SO) δ: 8.31 (d, J = 5.6 Hz, 1H, pyridyl H6), 8.19–
8.15 (m, 2H, aryl), 8.01–7.98 (m, 1H, aryl), 7.49–7.46 (m,
1H, aryl), 7.25–7.13 (m, 3H, aryl), 6.35 (s, 1H, indolyl H3),
5.46 (s br exch, 2H, NH2), 4.80 (s br exch, 2H, NH2), 2.78 (s
br, 2H, CH2), 2.70 (s br, 2H, CH2). Elemental anal. calcd.
for C15H21ClN4O2Pd (%): C 41.8, H 4.9, N 13.0; found: C
41.8, H 4.6, N 13.05.
(1,2-Ethanediamine-N,N′)(2-(1′H-indazol-1′-yl)phenyl-
N′,C)palladium(1+) chloride sesquihydrate (31)
This compound was prepared by the same method as
complex 21 from the µ-chloro dimer 11 (0.127 g, 0.19 mmol)
and 1,2-ethanediamine (10 drops) in methanol (10 mL).
Recrystallization of the crude product from ethanol–ether
gave the title compound 31 as colourless microcrystals
(0.128 g, 80%), mp 242 °C (dec.). IR: A satisfactory paraffin
[2-(3 ,5 -Dimethyl-1 -pyrazolyl)pyridine-N,N ](1,2-ethane-
′ ′
′
′
diamine-N,N )palladium(2+) dichloride dihydrate (37)
′
1
mull could not be prepared. H NMR (300 MHz, (CD3)2SO)
This compound was prepared from 2-(3′,5′-dimethyl-1′-
pyrazolyl)pyridine (35) (0.100 g, 0.58 mmol) in methanol
(10 mL) and PdCl2(en) (0.139 g, 0.59 mmol) in water
(10 mL) as described for compound 36. The crude product
was dissolved in methanol–water (85% v/v) and ether was
added slowly to give the title compound 37 as fine, pale yel-
low needles (0.182 g, 71%); mp 301 to 302 °C (dec.). IR
(cm–1): 3420 (br), 3370 (br), 3210, 3125, 3060, 1610, 1560,
1491, 1420, 1139, 1067, 1064, 773, 590. 1H NMR
(300 MHz, (CD3)2SO) δ: 8.44 (ddd, J = 4.9, 1.5, 0.8 Hz, 1H,
pyridyl H6), 7.93 (ddd, J = 8.5, 7.1, 1.5 Hz, 1H, pyridyl
H4), 7.79 (dd, J = 8.5, 0.9 Hz, 1H, pyridyl H3), 7.30 (ddd,
J = 7.1, 4.9, 0.9 Hz, 1H, pyridyl H5), 6.11 (s, 1H, pyrazolyl
H4), 4.89 (s br exch, 4H, 2 × NH2), 2.57 (s, 3H, 5′-Me), 2.32
(s br, 4H, CH2CH2), 2.20 (s, 3H, 3′-Me). Elemental anal.
calcd. for C12H23Cl2N5O2Pd (%): C 32.3, H 5.2, N 15.7;
found: C 32.35, H 4.95, N 15.8.
δ: 8.76 (s, 1H, indazolyl H3), 8.41 (d, J = 8.6 Hz, 1H, aryl),
8.05 (d, J = 8.2 Hz, 1H, aryl), 7.90 (d, J = 7.7 Hz, 1H, aryl),
7.76–7.72 (m, 1H, aryl), 7.43 (t, J = 7.5 Hz, 1H, aryl), 7.26
(td, J = 7.7, 1.1 Hz, 1H, aryl), 7.20 (dd, J = 7.5, 1.1 Hz, 1H,
aryl), 7.01 (t, J = 7.4 Hz, 1H, aryl), 5.49 (s br exch, 2H,
NH2), 4.72 (s br exch, 2H, NH2), 2.77 (s br, 4H, CH2CH2).
Elemental anal. calcd. for C15H20ClN4O1.5Pd (%): C 42.7, H
4.8, N 13.3; found: C 42.65, H 4.6, N 13.4.
(1,2-Ethanediamine-N,N′)(2-(2′H-indazol-2′-yl)phenyl-
N′,C)palladium(1+) chloride monohydrate (32)
This compound was prepared by the same method as
complex 21 from the µ-chloro dimer 12 (0.120 g,
0.18 mmol) and 1,2-ethanediamine (10 drops) in methanol
(10 mL). Recrystallization of the crude product from etha-
nol–ether gave the title compound 32 as fine, off-white nee-
dles (0.115 g, 78%), mp 271 to 272 °C (dec.). IR: 3460 (br),
3330 (br), 3245 (br), 3200, 3105 (br), 3070, 1929, 1520,
1444, 1282, 1056, 1050, 748, 729. 1H NMR (300 MHz,
(CD3)2SO) δ: 9.51 (s, 1H, indazolyl H3), 7.89 (d, J = 8.4 Hz,
1H, aryl), 7.87 (d, J = 7.7 Hz, 1H, aryl), 7.56–7.51 (m, 1H,
aryl), 7.42 (d, J = 8.8 Hz, 1H, aryl), 7.30–7.25 (m, 2H, aryl),
7.22 (d, J = 7.2 Hz, 1H, aryl), 7.14 (t, J = 7.3 Hz, 1H, aryl),
5.54 (s br exch, 2H, NH2), 5.00 (s br exch, 2H, NH2), 2.75 (s
br, 4H, CH2CH2). Elemental anal. calcd. for C15H19ClN4OPd
(%): C 43.6, H 4.6, N 13.6; found: C 43.6, H 4.5, N 13.8.
(2,2′-Bipyridine-N,N′)(1,2-ethanediamine-
N,N′)palladium(2+) dichloride sesquihydrate (38)
This compound was prepared from 2,2′-bipyridine
(0.228 g, 1.5 mmol) in methanol (15 mL) and PdCl2(en)
(0.283 g, 1.2 mmol) in water (5 mL) as described for com-
pound 36. The crude product was dissolved in methanol and
dichloromethane was added slowly to give the title com-
pound 38 as small, pale yellow needles (0.388 g, 77%);
mp > 270 °C (dec.). A sample was recrystallized from etha-
nol (95%) for microanalysis. IR (cm–1): 3420 (br), 3150 (br),
3115, 3080, 3050, 3020, 1607, 1601, 1560, 1473, 1172, 770,
(1,2-Ethanediamine-N,N′)[2-(1′-pyrazolyl)pyridine-
N,N′]palladium(2+) dichloride dihydrate (36)
2-(1′-Pyrazolyl)pyridine (34) (0.37 g, 2.5 mmol) in metha-
nol (40 mL) was added to a stirred suspension of PdCl2(en)
1
722, 580. H NMR (300 MHz, (CD3)2SO) δ: 8.70 (d, J =
8.1 Hz, 2H, 2 × pyridyl H3), 8.53 (d, J = 5.6 Hz, 2H, 2 ×
pyridyl H6), 8.45 (t, J = 7.8 Hz, 2H, 2 × pyridyl H4), 7.89
© 2005 NRC Canada

Edwards et al.
979
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Acknowledgments
This work was initiated during the tenure of a grant from
the Anti-Cancer Council of Victoria and was supported by
the Australian Research Council. The authors would also
like to thank Johnson Matthey Chemicals Ltd., UK, for the
generous loan of platinum and palladium precursors. We
would also like to thank Dr. Ian A.G. Roos for helpful dis-
cussions, and Virginia A. Leopold, Experimental Chemo-
therapy Unit, Cancer Institute, Melbourne, Victoria
Australia, for assistance with the biological testing.
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