dihydrodiol epoxide of 3-methylcholanthreneappears to be too bulky to intercalate into DNA. Work at the
National Institutes of Health has analysed the crystal structure of a BPDE-adenine adduct.^40 A fully syn-
thetic heptadecamer was prepared containing the BPDE-adeninebase-paired with thymine at a template-
primer junction and then complexed with the lesion-bypass DNA polymerase Dpo4 and an incoming
nucleotide. Two conformations of the BPDE-adduct are observed: one is intercalated between base-pairs
and another is solvent-exposed in the major groove (Figure 8.19). These structures suggest possible mech-
anisms by which mutations are generated during replication of DNA containing BPDE adducts.
This type of epoxidation is not restricted to synthetic chemicals. One of the most potent groups of car-
cinogens is the aflotoxins, which are fungal products from Aspergillus flavus. A dose of less than 1ppm of
aflatoxin B1 can cause lung, kidney and colon tumours in rats and is directly attributable to its oxidation
to an epoxide that binds covalently to guanine residues in DNA (Figure 8.20).41,42
While both endo- and exo-epoxides are formed metabolically, only the exo-isomer (Figure 8.20) is
mutagenic. It seems likely that this metabolite intercalates into the DNA helix with optimal orientation for
an SN2 reaction with N-7 of a proximate guanine residue. In contrast, intercalation of the non-mutagenic
endo-isomer places its epoxide in a non-reactive orientation.
8.7 Reactions with Anti-Cancer Drugs
A large number of ‘first generation’anti-cancer drugswere designed to combine a simple alkylating func-
tion such as a nitrogen mustard, an aziridine, or an alkanesulfonate ester with another function designed to
direct the agent towards the target tissue. Most of these compounds turned out to be less tumour-selective
than one might have hoped and, what is worse, many of them have proved to be carcinogens that eventually
led to new tumours sometime after the termination of chemotherapy for the original cancer. As a result,
their general use is now viewed with some suspicion. However, one success is Temozolomide. This com-
pound, invented by Malcolm Stevens and widely used for brain tumours since 1998, is activated by spon-
taneous hydrolysis and subsequent breakdown to generate the methyl diazonium cation.^43 This is a ‘hard’
methylating agentwhich alkylates guanine residues in the major groove of DNA, prefers runs of guanine
tracts, and leads to the formation of O^6 -methylguaninein target tissues. The success of Temozolomide
likely results from a combination of a slight difference in pH of normal and malignant cells coupled to
their reduced ability to repair the O^6 -MeG lesion by O^6 -alkylguanine-DNA alkyl transferase(ATase)
(Section 8.11.1) in brain tumour and melanoma cells (Figure 8.21).^44
308 Chapter 8
O
OHHOOHHOOOHHOS
HOGln Cys GlyOHHOHONNN
N
dRNHHObay
region
iiiiiv iiiFigure 8.18 Metabolic activation of B[a]P to BPDE (major stereoisomer illustrated) and its binding to DNA in vivo
to give guanine adducts (major product shown). Processes: (i) Cyt P 1 -450; (ii) epoxide hydrolase;
(iii) DNA binding in vivo; and (iv) gluthathione-S-transferase