PhotoactiWe Platinum(II) Intercalators
tion potentials of some of these platinum complexes are high
enough to reduce thymine or cytosine, with reduction
potentials of ∼-1.1 V versus NHE.8 However, these
platinum complexes, besides serving as potent photoreduc-
tants, require modification for interaction with DNA. First,
the complexes need to be made water soluble and preferably
positively charged to enhance electrostatic interactions with
the DNA polyanion. Additionally, the aromatic diimine
ligands should be extended so that the complexes can
intercalate within the base stack of DNA.9 We have found
in studies of DNA-mediated photooxidation that intercalative
stacking is preferred.10 The extent of oxidative base damage
has been shown to correlate with the strength of intercalative
binding, and one may expect a similar trend with reductive
base damage if the pathway to damage is through the base
stack. Last, some protection of the platinum center may be
required to limit direct covalent binding upon photoreaction
because efficient photosubstitution reactions of platinum-
(II) complexes are common.
Reductive DNA chemistry is perhaps also more difficult
to identify than DNA-mediated oxidative reactions. Long-
range oxidative chemistry on DNA was able to be character-
ized in part because of the long lifetime and extensive
irreversible reactions of the guanine radical,2,3,11 the favored
thermodynamic product of one-electron DNA oxidation.12
Thymine dimer repair can be triggered both through oxida-
tion and reduction,4,13 and hence thymine dimers have
provided a useful trap in establishing long-range DNA
reactions. Because of the possibility of rapid back-electron
transfer, another fast trap for oxidative and potentially
reductive chemistry has been developed through modification
of DNA bases with cyclopropylamine.14-16 Upon oxidation
or reduction, the cyclopropylamine moiety can undergo fast
(1011 s-1) ring opening to give an irreversible trap to report
the reaction.
Here, we describe the preparation and characterization of
a series of platinum complexes that may represent promising
tools to probe reductive DNA chemistry. The cationic
complexes bind noncovalently to DNA, and their excited-
state potentials are sufficient to promote both oxidative and
reductive DNA reactions. The ring-openings upon photore-
action of N2-cyclopropyldeoxyguanosine (dCpG) and N4-
cyclopropylcytidine (CpC), both as free nucleosides and
incorporated within the DNA duplex, are monitored as
sensitive probes of oxidative and reductive chemistry. These
platinum complexes are seen to promote efficient oxidation
of dCpG and reduction of CpC and hence provide a new
starting point for probing both oxidation and reduction
chemistry on DNA in parallel.
Experimental Section
Synthesis. All starting materials were used as received, and all
operations were performed under an argon atmosphere. Caution:
Organotin compounds are highly toxic and readily penetrate the
skin. Compounds cis-dichlorobis(dimethyl sulfoxide)platinum(II)
[cis-(dmso)2PtCl2],17 4-bromo-N,N,3,5-tetramethylaniline,18 1,10-
phenanthroline-5,6-dione (dipyridobenzoquinone, dpq),19 dibenzo-
[a,c]phenazine (dppz),20 benzo-[f][1,10]phenanthroline (bp),21 N2-
cyclopropyldeoxyguanosine,16 and N4-cyclopropylcytidine16 were
prepared according to literature methods. Oligonucleotides were
synthesized utilizing standard phosphoramidite chemistry on an ABI
392 DNA/RNA synthesizer. DNA was synthesized with a 5′-
dimethoxy trityl (DMT) protecting group and purified on a
Dynamax 300 Å C18 reverse-phase column (Varian) (100% 50 mM
NH4OAc, pH 7.0, to 70% 50 mM NH4OAc/ 30% acetonitrile over
35 min) on a Hewlett-Packard 1050 HPLC.
[(mes′)SnMe3]BPh4. tert-Butyllithium (1.7 M in pentane, 40 mL,
68.0 mmol) and, then, trimethyltin chloride (1.0 M in THF, 40 mL,
40 mmol) were added dropwise to a mixture of 4-bromo-N,N,3,5-
tetramethylaniline bromine (9.5 g, 41.7 mmol) and TMEDA (5 mL)
in THF (160 mL) at -78 °C under argon. The resulting suspension
was stirred at -78 °C for 1 h, followed by stirring at ambient
temperature for 1 h. Ether (200 mL) was added to the mixture, and
the solution was washed twice with water. After the organic phase
was dried with Na2SO4 and evaporated to dryness, the residue was
washed with methanol, and the white solid of 4-trimethylstannyl-
N,N,3,5-tetramethylaniline was collected on a sinter glass filter
(yield 6.0 g, 47%). This solid was then dissolved in a minimum
amount of THF, and MeI (5 equiv) was added. The mixture was
stirred in the dark for 24 h, and then the solvents were removed
under reduced pressure. The residue was dissolved in a minimum
amount of MeOH, and solid NaBPh4 (7 g) was added. A large
amount of precipitate appeared, which was filtered and washed with
methanol and ether. Yield: 11.9 g, 96%. 1H NMR (300 MHz, dmso-
d6): δ 7.54 (s, 2H), 7.17 (br s, 8H), 6.91 (t, J ) 7.2 Hz, 8H), 6.78
(t, J ) 7.1 Hz, 4H), 3.51 (s, 9H), 2.45 (s, 6H), 0.37 (s with 119Sn
satellites, JSnH ) 54.4 Hz, 9H). Anal. Calcd for C38H46BNSn: C,
70.84; H, 6.88. Found: C, 70.88; H, 7.04.
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