Nucleic Acids in Chemistry and Biology

A group of ‘second generation’anti-cancer agentshas emerged, many of which are natural products, but
now augmented by a growing number of rationally designed, synthetic drugs. Their common feature is that
they appear to form an initial physical complex with DNA before bonding to it covalently. This heterogeneous
group of compounds includes aziridines such as mitomycin C^45 , several pyrrolo[1,4]benzodiazepinesand
spirocyclopropanessuch as CC-1065.^46 Their vital purpose is to kill bacteria by disrupting the synthesis

Covalent Interactions of Nucleic Acids with Small Molecules and Their Repair 309

Figure 8.19 Distortion of DNA by a BPDE adduct: hydrogen-bond formation in the crystal structure of the dA(dT and
the adjacent replicating base-pair dTdATP. (a) Looking down the DNA helical axis, the two layers of the
base-pair and the PAH adduct are shown, black for the replicating base-pair, red for the dA adduct and
grey for its dT partner. The incoming nucleotide in BP-1 is in the syn conformation. (b) In the BP-2
complex, where the PAH is in the major groove, the adenine base of the dA* is shifted to the major groove,
disrupting the normal hydrogen bonds with its dT partner. The location of a normal dA is depicted in grey
(Adapted from Ref. 40. © (2004), with permission from the National Academy of Sciences, USA)

N

N

N

H 2 N N

H

O

O

O

O

O

O

OMe

O

O

O

O

O

OMe

O

O

O

O

O

OMe

O

H

H

H

H H

H

OH

CDP450 DNA

Figure 8.20 Metabolic oxidation of aflatoxin B 1 and binding of its exo-epoxide to DNA