Chemistry Reference
In-Depth Information
12.2.1
Dipeptides
Jan Reedijk and his collaborators have undertaken the construction of a library of
peptide-tethered platinum complexes using automated solid-phase synthesis.
18
The
general structure of the target library is shown in Figure 12.1 and encompasses a
dipeptide tethered to an ethylenediamine moiety (en), which, in turn, serves as a
platinum chelating ligand. As constituents of the appended dipeptide, six amino
acids were selected: glycine, phenylalanine, lysine, arginine, serine and glutamate.
Incorporating these amino acids in both positions of the appended dipeptide resulted
in a fi nal library of 36 compounds. Subsequently, each compound was screened for
in vitro
anticancer activity and apparently no important cytotoxicity was observed
compared to cisplatin.
In continuation of this work, M. S. Robillard
et al.
19
used the linear amplifi cation
system in order to investigate the DNA damage intensity and sequence specifi city
of adduct formation by six peptide-platinum complexes, cisplatin (
1
) and Pt(en)Cl
2
(
2
) in pUC19 plasmid as well as in intact Hela cells. The six peptide-platinum com-
plexes were members of the previously described
18
library of peptide-dichloroplati-
num complexes and differed only in their terminal pendant amino acid: Gly, Phe,
Lys, Arg, Ser and Glu. Interestingly, the appended dipeptides did not alter the DNA
sequence specifi city (runs of consecutive guanines) and did not increase the reactiv-
ity with DNA of the complexes compared to the unfunctionalized parent com-
pounds, cisplatin and Pt(en)Cl
2
. On the other hand, the nature of the terminal amino
acid affected the reactivity of the peptide-platinum complexes towards plasmid
DNA, with the glycine-tethered complex and the phenylalanine-tethered complex
causing the highest damage, followed by (in decreasing order) lysine-tethered,
arginine - tethered, serine - tethered and glutamate - tethered. The fact that the nega-
tively charged Glu displayed negligible activity implied that electrostatic interac-
tions may play a role in the DNA binding.
12.2.2
Tripeptides
Gly - His - Lys.
The tripeptide glycyl - L - histidyl - L-lysine, GHK, has been isolated as a
square-planar complex with copper and iron from human plasma and was found to
act synergistically with these metals to alter the growth and metabolism of cultured
hepatoma cells and hepatocytes.
20
The Cu(II) atom is tetracoordinated with the
Cl
Cl
Pt
O
O
N
H
2
N
NH
C
AA
2
C
H
2
H
C
O
AA
1
NH
2
H
2
C
CH
2
AA = Amino Acid
Figure 12.1
The general structure of the dichloroplatinum(II) peptide complexes
