Nucleic Acids in Chemistry and Biology

Intensive development of platinum complexes has identified several analogues of clinical potential
including cis-trans-cis-ammine(cyclohexylamine)diacetato-dichloroplatinum (Figure 8.12a). More recently,
Lippard has solved structures for the complexes of cisplatin, oxaliplatinand (Pt(ammine)(cyclohexyl-
amine))^2 with the same DNA dodecamer d(CCTCTGGTCTCC).d(GGAGACCACAGG).^31 There is a
high degree of homology between these three structures, each of which has an intra-strandG-Pt-G link.^30
For oxaliplatin, this lesion induces the duplex to bend toward the major groove (Figure 8.12b). The
widened minor groove is shallow and so presents an excellent target for DNA-binding proteins, and these
features are also seen in cognate nuclear magnetic resonance (NMR) structures.

8.6 Reactions with Metabolically Activated Carcinogens

Many synthetic chemicals and natural products are known to be carcinogens or mutagens.^32 While these
do not react directly with nucleic acidsinvitro, they are transformed invivo by metabolic processes to give
electrophiles that bind covalently to DNA, RNA and also to proteins. Most of these metabolic transform-
ationsare carried out by the mixed-function cytochrome P-450 oxidase(CYP450) enzymes, whose
‘proper’ function seems paradoxically to be directed towards the detoxification of alien compounds. A
well-characterised example is the cytochrome P450 oxidation of vinyl chloride to 2-chlorooxirane which
alkylates base residues to give 7-(2-oxoethyl)guanine and other products. The following four classes
of metabolically activated compounds are representative of an intensive study of a problem of very grave
significance.

Covalent Interactions of Nucleic Acids with Small Molecules and Their Repair 303

N

I NH

O

O

HO O

N

NH

O

O

HO O

O NH

CF 3

Pd (0)

CF 3 CONHCH 2 C≡CH N

NH

O

O

O O

HN O

O

Me

O

Me

Me

O

Me

T-526

Me

N

O

NN

O

NH 2

O

O

HN

O

O

Me

O

Me

O

C-519

N

Me

O

N

N

NH 2

HN

O

O O O

N

Me

O

N

ddRP N

NH

O

HN

O

HO O O

N

Me

O

N

ddRP

Me Me

NH 2

G-505

2

A-512

P

O

O

O

P

O

O

O

Figure 8.11 Synthesis of fluorescent base T-526 using Pd(0) catalysis. Structures of fluorescent dideoxynucleotides

related to A, C and G for use in rapid, single-lane DNA sequence analysis