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complexes.
16
The reduced activity of such species was attributed to the instability of
the Rh(I) centre towards oxidation to the kinetically inert octahedral Rh(III)
complex in aqueous solution and therefore
in vivo
. In addition, the greatly enhanced
lability of the leaving groups on Rh(I) versus Pt(II) complexes suggested that the
Rh(I) species would be oxidized, and thus deactivated before reaching the target.
No advanced studies on the interaction of Rh(I) species with oligonucleotides such
as DNA were performed owing to these limitations.
10.3.2 Dirhodium( II ) Complexes
Dirhodium carboxylate complexes of general formula (Rh
2
(O
2
CR)
4
L
2
(R = Me, Et,
Pr; L = solvent) (Figure 10.1b) have been found to inhibit DNA replication and
protein synthesis with a similar potency to cisplatin.
17
In the examples given above,
antitumour activity was found to increase with increasing lipophilicity of the R
group, presumably through increased cell membrane permeability of the complex.
Related complexes bearing various bidentate bridging species such as nitrogen-
containing ligands
18 - 20
(Figure 10.1c), phosphine ligands,
21
(Figure 10.1 d) and forma-
midinates
22
(Figure 10.1e) have been developed, and exhibit antitumour activity
comparable to, or higher than, cisplatin.
17
Structure - activity relationships are,
however somewhat more complex than the two-pole complimentary principle sug-
gested by Yang
et al.
for organometallic antitumour agents.
23
The similarities in
antitumour properties between cisplatin derivatives and dirhodium complexes may
be unexpected, owing to the obvious structural differences between the two species.
Indeed the dirhodium complexes are capable of binding strongly to adenine resi-
dues, unlike cisplatin, which has a preference for guanine.
17
Model experiments
employed nucleo(s)tides to demonstrate that the interaction between rhodium and
adenine residues is stabilized by favourable hydrogen bonds between the purine
exocyclic NH
2
(6) group and a carboxylate oxygen atom of the dirhodium complex.
In contrast, axial coordination of guanine residues is inhibited by electrostatic repul-
sions between the ketone O6 and oxygen atoms of the carboxylate ligands present
within the complex.
17,24
In subsequent studies, the unlikely substitution of two bridg-
ing ligands on complexes of type [Rh
2
(O
2
CR)
4
L
2
] by two guanine residues was
directly observed by X-ray crystallographic analysis.
25,26
The guanine residues were
found to form equatorial bridging interactions, through the N7/O6 sites in a head-
to - head (H - H) (e.g.
cis
- [Rh
2
- ( m - O
2
CCH
3
)
2
(9 - EtGuaH)
2
(Me
2
CO)(H
2
O)](BF
4
)
2
(Figure 10.1 f)
26
or head - to - tail (H - T) orientation (e.g.
cis
- [Rh
2
- ( m - O
2
CCF
3
)
2
(9 -
EtGuaH)
2
(Me
2
CO)
2
](CF
3
CO
2
)
2
(Figure 10.1 g).
25
These fi ndings led to further studies
on interactions between dirhodium complexes and the dinucleotide d(GpG), where
a similar chelate N7/O6 interaction with Rh
2
(OAc)
4
was observed.
27,28
Although the
dirhodium complexes were found to bind through both axial and equatorial posi-
tions, the mechanism of binding is believed to occur through initial interaction
through axial sites, followed by rearrangement to a more thermodynamically stable
equatorial position.
29,30
Indeed, recent studies demonstrated that placing nonlabile
ligands in the axial position resulted in a
decrease
in the ability of the complexes to
inhibit transcription
in vitro
, demonstrating the necessity for labile axial ligands, and
