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Environmental
Health Perspectives Supplements Volume 110, Number 5, October 2002
Chiral Discrimination in Platinum Anticancer Drugs
Michele Benedetti,1 Jaroslav Malina,2 Jana
Kasparkova,2 Viktor Brabec,2 and Giovanni Natile1
1Dipartimento Farmaco-Chimico, Università di Bari,
Bari, Italy; 2Institute of Biophysics, Academy of Sciences
of the Czech Republic, Brno, Czech Republic
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Full Article in PDF
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Abstract
In this article we review the biological activity of analogs of the antitumor
drug cisplatin that contain chiral amine ligands. Interaction with DNA
and formation of cross-links with adjacent purine bases are considered
to be the crucial steps in the antitumor activity of this class of complexes.
Because double-helical DNA has a chiral structure, interaction with enantiomeric
complexes of platinum should lead to diastereomeric adducts. It has been
demonstrated that DNA cross-links of platinum complexes with enantiomeric
amine ligands not only can exhibit different conformational features but
also can be processed differently by the cellular machinery as a consequence
of these conformational differences. These results expand the general
knowledge of how the stereochemistry of the platinum-DNA adduct can
influence the cell response and contribute to understanding the processes
that are crucial for antitumor activity. The steric requirements of the
chiral ligands, in terms of configuration and flexibility, are also elucidated.
Key words: cross-link, DNA conformation, enantiomeric cis-dichloro-2,3-diaminebutane
platinum(II), platinum anticancer drugs, repair. Environ Health Perspect
110(suppl 5):779-782 (2002).
http://ehpnet1.niehs.nih.gov/docs/2002/suppl-5/779-782benedetti/abstract.html
This article is part of the monograph Molecular Mechanisms
of Metal Toxicity and Carcinogenicity.
Address correspondence to V. Brabec, Institute of Biophysics,
Academy of Sciences of the Czech Republic, Kralovopolska 135, CZ-61265
Brno, Czech Republic. Telephone: 420 5 41517148. Fax: 420 5 41240499.
E-mail: brabec@ibp.cz
This work was supported by the Ministero dell'Istruzione
Università e Ricerca of Italy (MIUR, cofin. 2001053898), the
Grant Agency of the Czech Republic (grants 301/00/0556 and 305/02/1552/A),
the Grant Agency of the Academy of Sciences of the Czech Republic (grants
A7004805 and S5004107), and the EC (COST Chemistry Projects D20/0001/01
and D20/0003/01).
Received 8 March 2002; accepted 17 June 2002.
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Cisplatin is an effective anticancer drug widely used in the treatment of several
human carcinomas (1-4). The mechanism of anticancer activity involves
formation of platinum-DNA adducts that are capable of inhibiting DNA and
RNA synthesis (5-16) and inducing programmed cell death (17,18).
Cisplatin binds preferentially to the N7 position of purine residues. The monofunctional
adduct subsequently closes to a bifunctional adduct by linking a second purine
that can be either of the same strand or of the opposite strand (19).
There is general consensus that the antitumor efficacy of cisplatin is associated
with the formation of DNA 1,2-intrastrand d(GpG) or d(ApG) cross-links (5-16).
The 1,2-intrastrand cross-links locally unwind and bend double-stranded DNA
toward the major groove (14,20,21), and the disturbance of DNA secondary
structure seems to be the ultimate reason for inhibition of DNA replication
and/or transcription and for triggering apoptotic cell death (22,23).
While the anionic-leaving ligands are likely to play a role in determining
the transport of the complex throughout the living organism, the nonexchangeable
aminic ligands play an important role in the drug-DNA adduct formation
and stereochemistry. Thus, it is of great interest to see how different configurations
of these nonleaving ligands can influence the DNA-binding properties and consequently
the biological activity of platinum complexes.
In this review we focus on platinum complexes with enantiomeric amine ligands.
Because double-helical DNA has a chiral structure, complexes with enantiomeric
ancillary ligands should form diastereomeric adducts with DNA.
Platinum Complexes with Chiral Monoamines
The activity of cis-PtA2X2 compounds (A = aminic
ligand, X = anionic ligand) decreases in the order A = NH3 > RNH2
> R2NH (24). Therefore, most investigations were restricted
to platinum complexes with chiral primary amines. Platinum complexes with monodentate
enantiomeric primary amines do not show significant differences in their biological
activity (25). One compound of this class, the platinum complex with
phenethylamine, is shown in Figure 1.
 |
| Figure 1. Example of the platinum
complex with monodentate enantiomeric primary amines. Ph, phenyl; phetam,
phenylamine. |
A possible explanation for this result is that the free rotations of the chiral
substituent around the carbon-nitrogen (C--N) bond and of the amine around the
platinum-nitrogen (Pt--N) bond average the steric effect due to the ligand asymmetry
and offset any stereospecificity in the interaction with biological substrates.
Platinum Complexes with Chiral N-Substituted Ethylenediamines
The degree of rotational freedom in a complex of the type described in the
previous section can be reduced by bridging together the two nitrogens of the
cis amines. A ligand that fulfills these requisites is ethambutol. This
molecule was already used in medicine as an anti-tuberculosis, and very interestingly,
only the S,S isomer was found very active; the R,R
enantiomer was completely inactive (26,27). Starting with an isomerically
pure ligand, coordination to platinum leads to formation of different isomers.
The reason for this is that, upon coordination to platinum, the nitrogens also
become stable chiral centers and can have either R or S configuration.
The two enantiomers shown in Figure 2 were isolated in the pure form, with biological
activities that could be compared.
 |
| Figure 2. Structures of enantiomeric forms of [PtCl2(ethambutol)].
Et, ethyl. |
It is interesting to note that the bridging of the two nitrogens with the ethylene
chain not only blocks the rotation around the Pt--N bonds but also hinders,
to some extent, the rotation of the asymmetric 1-butanol-2-yl radical with respect
to the C--N bond. This was revealed by the 1H nuclear magnetic resonance
showing a remarkable diastereotopic splitting of the methylene protons of the
CH2Me groups adjacent to the asymmetric carbons. Therefore, the average
orientation of the 1-butanol-2-yl radicals is such that the ethyl residues are
hindered in their rotation around the carbon-ethyl bond (28).
The much less rotational freedom of the asymmetric substituents in these complexes
leads to a different biological activity for the two enantiomers. Indeed, enantiomer
a is less mutagenic and less toxic than enantiomer b but, in contrast,
exhibits good antitumor activity toward P388 sarcoma and Lewis lung carcinoma
(29). Evidently, a can couple reduced mutagenic activity with
good antitumor activity, and this appears to be a rather noteworthy result.
In the compound just described, the configuration at the nitrogen atoms was
stable at neutral pH for days at room temperature; however, at higher temperatures
and/or more basic pH, isomerization can take place. This phenomenon has prevented
further studies on complexes of this class.
Platinum Complexes with Chiral C-Substituted Ethylenediamines
The complication arising from isomerization at the nitrogen atoms could be
avoided by using chiral diamines in which the chiral carbon(s) are inserted
in the organic chain bridging the two nitrogens. In this way the steric rigidity
of the nonleaving ligands is further increased because the chiral groups are
no longer free to rotate around the C--N bonds, as is the case of the compound
considered in the preceding section.
Kidani and co-workers have reported that platinum complexes with l,2-diaminocyclohexane,
having different configurations at the two chiral carbons bridging the two nitrogens,
had biological activities dependent on the chirality of the diamine ligand (30-33).
Although the isomers with R,R and S,S configurations at
the asymmetric carbons produce the same type of intra- and interstrand cross-links
(34), the biological activity of the two enantiomers is different, and
the R,R enantiomer exhibits higher antitumor activity and lower
mutagenicity than the S,S isomer (35). Chiral diamines other than
1,2-diaminocyclohexane have also been investigated (36-40).
A comparative study of three strictly related platinum complexes with chiral
diamines [PtCl2(N--N), where N--N = 1,2-diaminopropane (1,2-DAP),
2,3-diaminobutane (2,3-DAB), or 1,2-diaminocyclohexane (1,2-DACH)] has been
also carried out by some of us (Figure 3). The biological tests, in vitro,
have revealed a marked difference among isomers. For instance, the mutagenic
activity, which is strictly related to the interaction of the drug with DNA,
is even 10 times greater in one isomer relative to the corresponding enantiomer.
In all cases examined the S,S isomer was by far the most mutagenic,
indicating that the different isomers give adducts with DNA that can be discriminated
by the enzymatic systems involved in mutagenesis (41).
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| Figure 3. Structures of related platinum complexes
with chiral diamines. |
The conclusions based on mutagenic data concerning the relevance of the configuration
of nonleaving ligands in platinated DNA have been confirmed by the studies of
inhibition of restriction enzyme activity. The extent of inhibition of the enzymes
cutting at guanine (G)-rich sites is significantly different for the different
isomers, the R,R form being more active than the others.
As a result of the markedly different behavior of the two enantiomeric forms,
only the R,R enantiomer of [Pt(DACH)(oxalato)] (oxaliplatin) has been
approved for clinical use (42). Hence, studies have mainly focused on
DNA modifications and biological properties of enantiomeric DACH and closely
related DAB complexes (43-47).
In the next section we concentrate mainly on a deeper insight into the biological
behavior of the latter two types of complexes. However, before concluding this
section, we consider nonleaving ligands of the type just described but having
also an alkyl substituent on each coordinated nitrogen [e.g., N,N´-Me2DAB
and bipiperidine; Figure 4). Although these compounds are less effective as
antitumor drugs because the coordinated nitrogens are no longer primary amine
groups (24), they are able to exert steric control on the coordination
of nucleotides with platinum. This phenomenon has allowed us to unravel details
of the dynamics and conformations of the 1,2-intrastrand cross-links that, as
already pointed out, are the major lesions formed by cisplatin-type complexes
on DNA (48-52).
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| Figure 4. Structures of [PtCl2(Me2DAB)]
and [PtCl2(bipiperidine)] (Bip). Me, methlyl. |
Biochemistry of Platinum Complexes with Enantiomeric DACH
and DAB Ligands
The recently reported crystal structure of 1,2-GG intrastrand cross-link formed
by oxaliplatin on a DNA dodecanucleotide duplex has shown that the overall geometry
is similar to that of cisplatin. However, a novel feature of this structure
is the presence of a hydrogen bond between the pseudoequatorial N--H hydrogen
atom of the R,R-DACH ligand and the O6 atom of the cross-linked
G in 3´ position (43,44). This finding has confirmed the importance
of chirality in mediating the interaction between cisplatin analogs containing
enantiomeric amine ligands and double-helical DNA.
We have shown in a recent work (46) that 1,2-GG intrastrand cross-links
of R,R- and S,S-DAB platinum complexes (Figure 3)
not only destabilize DNA differently but also bend and unwind DNA to a different
extent.
DNA containing platinum adducts that induce stable directional bending and
unwinding attracts various damaged-DNA-binding proteins such as those containing
the high-mobility group (HMG) domain (53-56). A recent report (45)
has demonstrated that HMGB1 and TATA binding proteins recognize 1,2-GG intrastrand
cross-links formed by R,R-DACH-platinum(II) species. The
affinity of these proteins to 1,2-GG intrastrand cross-links of cisplatin depends
on several factors, and the efficiency with which the adducts thermodynamically
destabilize DNA is among the most important. The binding of these proteins has
been postulated to mediate the antitumor properties of the platinum drugs (55,56).
In addition, several reports (57-59) have demonstrated that intrastrand
cross-links of cisplatin and its direct analogs are removed from DNA during
nucleotide excision repair (NER) reactions and that NER is also an important
mechanism contributing to cisplatin resistance.
To shed light on how chirality at the carbon atoms of the carrier ligand in
cisplatin analogs can affect processing its major adducts in cells, the studies
have been performed to demonstrate how HMGB1 box proteins and the NER differentiate
between major DNA adducts of cisplatin analogs having enantiomeric nonleaving
ligands during in vitro reactions (47). For these studies the
R,R- and S,S-DAB derivatives were chosen because
the effect of chirality at the carbon atoms on the biological activity of these
compounds was most pronounced (41). Electrophoretic mobility shift assays
have shown that domains A and B of HMGB1 protein bind to the cross-links generated
by R,R-DAB-platinum(II) with a higher affinity than to those generated
by the S,S-DAB-platinum(II) enantiomer (Figure 5). The cross-links of
both enantiomers are removed by NER with a similar efficiency; however, HMGB1
protein significantly inhibits removal of R,R-DAB-platinum(II) adducts,
but not those of the S,S-DAB-platinum(II) enantiomer (Figure 6). Therefore,
HMG domain proteins discriminate among different conformations of the 1,2-GG
intrastrand cross-links of the two enantiomeric analogs of cisplatin, which
results in different NER of these cross-links.
 |
Figure 5. Gel mobility shift assay analysis of
the titration of the 20-bp DNA duplex with central sequence TGGT/ACCA
containing the single 1,2-GG intrastrand cross-link of cisplatin, R,R-DAB-
platinum complex, or S,S-DAB-platinum complex with HMGB1a and
HMGB1b. (A) Autoradiogram of the gel mobility assay of the reaction
with HMGB1a (30 nM). The concentration of the DNA duplex was 10 nM.
(B) Bar graph illustrating the fraction of bound DNA ( )
for oligonucleotide duplex containing the single 1,2-intrastrand cross-link
of cisplatin, R,R-DAB-platinum complex, or S,S-DAB-platinum
complex at 30 nM HMGB1a and 390 nM HMGB1b. Values are averages of three
independent experiments.
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 |
Figure 6. Effect of full-length HMGB1 protein
on NER of the 1,2-GG intrastrand cross-link of R,R-DAB-platinum
complex or S,S-DAB-platinum complex by rodent excinuclease. (A)
The excision product region of an autoradiogram of the denaturing 10%
polyacrylamide gel showing inhibition of excision of the 1,2-intrastrand
cross-link of R,R-DAB-platinum complex (lanes 1, 2) and S,S-DAB-platinum
complex (lanes 3, 4). The 148-bp substrates containing the single and
central cross-link were incubated with the 20 µM HMGB1 for 1 hr
before the addition of the rodent cell-free extract and further incubation
for 40 min. (B) Bar graph illustrating the relative excision
of 148-bp substrates without HMGB1 (gray bars) or after preincubation
with the 20 µM HMGB1 (black bars). Values are averages of three
independent experiments.
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The results obtained with DAB-platinum(II) complexes apply also to the DACH-platinum(II)
species (60). They imply that the higher affinity of HMGB1 proteins to
an R,R-DACH-platinum(II) cross-link than to an S,S-DACH-platinum(II)
cross-link coupled with a greater error-prone NER repair of the S,S-DACH-platinum(II)
cross-links could explain both the better antitumor activity of the R,R form
of oxaliplatin and the greater mutagenic activity of the S,S-enantiomer.
Conclusions
Platinum complexes containing enantiomeric ligands pose an interesting theme
to investigate structure-pharmacological activity relationship of platinum
compounds. The pharmacologically relevant target of platinum compounds is DNA.
The major adducts are the 1,2-GG and 1,2-AG intrastrand cross-links. Recognition
and repair of these lesions by DNA binding proteins are crucial steps in the
cellular response to the drug treatment. The bulk of the results demonstrate
that the different stereochemistry of these cross-links is responsible for their
different affinities for HMG box proteins and, consequently, for the different
NER of these lesions. It is possible to conclude that DNA cross-links of platinum
complexes with enantiomeric carrier ligands not only can exhibit different conformational
features but also can be processed differently by the cellular machinery as
a consequence of these conformational differences. However, the conformational
freedom of the enantiomeric platinum compounds has to be limited, so a relevant
chiral discrimination might play a role in the biological activity. This was
the case for chiral centers inserted in the chelating chain of a diamine.
The results reviewed in this article expand the general knowledge of how the
stereochemistry of the carrier amine ligands of antitumor platinum compounds
can influence some crucial processes underlying their toxicity toward cancer
cells and can provide a rational basis for the design of new platinum antitumor
drugs.
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Last Updated: October 11, 2002
