Chemistry Reference
In-Depth Information
be tumour active, platinum compounds need to satisfy specifi c requirements, which
are known as classical structure-activity relationships.
29
5.1.1 Structure - Activity Relationships ( SAR )
The ligand exchange kinetics of Pt compounds appear to have a great infl uence on
the activity of these drugs.
30
Complexes with fi rmly coordinated leaving groups do
not have antitumour activity; also very labile leaving groups do not lead to high
activity.
31,32
Thus inactivity can be caused by either a too low or a too high reactiv-
ity.
30
In the latter case the inactivity could be a consequence of rapid reaction with
other intracellular components generally referred to as platinophiles. Coordination
of a platinophile exerting a high
trans
effect can also cause release of the otherwise
nonexchangeable am(m)ine ligands.
The nature of the nonleaving groups also infl uences the activity of platinum
compounds. Several compounds of general formula
cis
- [PtCl
2
(amine)
2
] with differ-
ent amine ligands have shown antitumour activity. These can be monodentate
amines (such as NH
3
) or bidentate amines like ethylenediamine (en) or 1,2-
diaminocyclohexane (dach). The activity of the platinum complexes decreases along
the series NH
3
R
3
N (R is an alkyl substituent),
33
thus indicating
that the steric hindrance and the hydrogen-bonding ability of the ligands can be
important factors in determining the activity.
34
The amines can act as hydrogen
donors toward the O6 atom of a guanine or the phosphate groups of DNA.
35
These
interactions can be important from both a thermodynamic (stabilization of the Pt-
DNA adduct) and a kinetic point of view (delivery of the Pt complex to the N7 of
guanine). All these observations have resulted in a list of structural requirements
for a platinum complex to be endowed with antitumour activity, the so-called struc-
ture - activity relationships (SAR):
29
>
RNH
2
>
R
2
NH
>
(1) Complexes should be neutral.
(2) A
cis
geometry is required with general formula
cis
- [PtX
2
(amine)
2
]
for
platinum(II), and
cis, trans, cis
- [PtX
2
Y
2
(amine)
2
] for platinum(IV).
(3) The X ligands (leaving groups) should be of intermediate strength (such as Cl
−
,
SO
2−
or carboxylate ligands). For platinum(IV) complexes the Y ligands should
have
trans
orientation and can be Cl
−
, OH
−
or [OC(O)C
n
H
2
n
+1
]
−
.
(4) The nonleaving amine ligands should contain at least one N-bound proton,
necessary for hydrogen-bonding interactions with DNA (e.g. H-bonding to O6
of guanines or 5
′
phosphate groups).
All second and third generation platinum drugs (carboplatin, oxaliplatin) and
those in the pipeline (satraplatin, picoplatin) satisfy the SAR given above. However
it has been found that several series of platinum compounds which violate at least
one of the above described structure-activity relationships are also antitumour
active.
36
For example, there are compounds with
trans
geometry
37
or containing
multiple metal centres that are antitumour active.
38
Because of a different mode of
interaction with DNA, such compounds are expected to exhibit a completely dif-
ferent spectrum of activity.
