Nucleic Acids in Chemistry and Biology

Robert Coleman has shown that initial alkylation is at N-7 of a dG residue involving the aziridine ring C-10
(Figure 8.23a). It is followed by a slower alkylation of the sub-adjacent purine by the epoxide C-21 as the
second alkylating function (Figure 8.23b).^49 The selectivity for the target sequence appears to be determined
by the relative nucleophilicity of purines in the major groove while the naphthalene moiety provides
hydrophobic binding to DNA without intercalation.

8.7.2 Pyrrolo[1,4]benzodiazepines, P[1,4]Bs

Anthramycin and tomaymycin, along with sibiromycin and neothramycins A and B, are members of the
potent P[1,4]B anti-tumour antibiotic group produced by various actinomycetes (Figure 8.24). The first
three of these compounds bind physically in the minor groove of DNA where they then form covalent
bonds to G-N-2, showing a DNA sequence specificity for 5
-PuGPu sequences.
These P[1,4]Bs appear to interact with DNA in a biphasic process. Initially there is a rapid, non-covalent
association that results from a close interaction of the antibiotic with the ‘floor’of the minor groove ofDNA
(Section 10.3.5). Subsequent loss of water or methanol and covalent addition of G-N-2 to C-11 then forms
an aminal linkage that is well stabilized by favourable steric and electrostatic interactions.^50
Lawrence Hurley has established the existence of two distinct tomaymycin-d(ATGCAT) 2 species in solution
from NMR studies. These have the antibiotic orientated in opposite directions in the minor groove according
to its (R)- or (S)-configuration at C-11. The resulting lesions appear neither to impede Watson–Crick base-
pairing nor to distort the B-DNA helix structure so that the two lesions probably pose difficult recognition

Covalent Interactions of Nucleic Acids with Small Molecules and Their Repair 311

N

H

Me N

OH

O

CONH 2

OH

anthramycin

N

H

HO N

O

OMe

MeO

tomaymycin

• MeOH

N

HO N

O

MeO

N

HN

N

H 2 N N

O

pentose

H

N

H

HO N

O

MeO

N

NH

N

N N

O

pentose

H

Figure 8.24 Binding of P[1,4]B antibiotics to the N^2 -amino group of guanine

Me

MeO

O

H

N

N

H

O O

O

OH

Me

O

Me

O

N

HO

AcO

second alkylation

first alkylation

azinomycin B

(carzinophilin)

5' –G–C–C– 3'

3' –C–G–G– 5'

epoxide C-21

(^10) aziridine C-10
21
a b
Figure 8.23 (a) Structure of azinomycin B (identical with carzinophilin) with sites for nucleophilic attack by N-7 of
guanine (purine) residues in opposite strands of DNA. (b) Preferred duplex sequence for its cross-linking
to sub-adjacent dG residues^49