Chemistry Reference
In-Depth Information
separation of stereoisomers of dinuclear species.
122
The attachment of selected bioti-
nylated oligonucleotides to a stationary phase comprising streptavidin immobilized
on Sepharose has allowed separation over very short distances (2-5 cm) of mixtures
of different complexes, the separation of geometric isomers and diastereoisomers
of the same complex, and resolution of chiral forms - separations which have only
been achieved by the conventional cation-exchange column techniques with an
effective column length in excess of 30 metres!
11.4 Potential Biological Signifi cance
While it has been clearly demonstrated that dinuclear ruthenium complexes have
considerable potential as probes for nonduplex DNA and RNA, this potential will
only be realized if:
(1) the metal complexes can be functionalized so that they selectively bind specifi c
nonduplex structures that are biologically signifi cant; and/or
(2) the metal complexes can be transported into human cells, and thereby elicit
some biological response, e.g. they are cytotoxic.
Given the great diversity of organic ligands that can be readily synthesized, it
is probable that once specifi c nonduplex sites are identifi ed, hydrogen bond donors
and acceptors and/or van der Waals interaction recognition groups can be incorpo-
rated into the metal complex. An excellent example of this type of approach was
reported by Barton and coworkers, who specifi cally designed the DNA-intercalating
complex D - a - [Rh{(R,R) - Me
2
trien}(phi)]
3+
((R,R) - Me
2
trien = 2R,9R - diamino - 4,7 -
diazadecane; Figure 11.1m) to bind to the sequence 5
.
123
The intercalating
ligand phi locks the rhodium complex into the DNA duplex. Additional recognition
elements, hydrogen bonding NH
2
groups and methyl groups that can make van der
Waals contacts with the TMe groups, were then incorporated into the metal complex
in the correct three-dimensional position to interact with their DNA counterpart.
123
Although there has been one recent study,
124
little is known about the cellular
transport and cytotoxicity of dinuclear ruthenium complexes. However, the biologi-
cal properties of a range of mononuclear ruthenium complexes have been reported.
Puckett and Barton
125
examined the cellular transport of a series of DNA-intercalat-
ing ruthenium complexes, and demonstrated that those with greater lipophilicity
exhibit highest uptake, while charge and size were not particularly important. Fur-
thermore, Liu
et al.
126
reported that [Ru(phen)
2
(PIP)]
2+
(where PIP = R - phenylimi-
dazo[4,5-f] [1,10]phenanthroline; Figure 11.1t), which binds DNA by intercalation,
exhibited substantial cytotoxicity in a range of cell lines.
Given that the cytotoxicity of many organic compounds is due to their ability
to intercalate into the DNA helix, it is not surprising that ruthenium complexes that
bind DNA in a similar mode also exhibit reasonable cytotoxicity. Similarly, examples
of DNA groove-binding ruthenium complexes that are cytotoxic have been reported.
Ma
et al.
127
demonstrated that although [Ru(
t
Bu
2
bpy)
2
(2 - appt)]
2+
(
t
Bu
2
bpy = 4,4
′
- TGCA - 3
′
′
-
bis(
tert
- butyl) - 2,2
′
- bipyridine; Figure 11.1 c; 2 - appt = 2 - amino - 4 - phenylamino - 6 - (2 -
