Nucleic Acids in Chemistry and Biology

of DNA and RNA, but many of them have also shown useful anti-tumour activity, which must arise from
selective toxicity. This can be attributed to DNA-binding specificity or to preferential metabolic activation
by tumour cells.

8.7.1 Aziridine Antibiotics

An assortment of naturally occurring antibiotics, each having an aziridine ring, has been isolated from
Streptomyces caespitonis. The most interesting of them in clinical terms is mitomycin C. This compound
requires enzymatic reductionof its quinone function to initiate the processes that cause it to alkylate DNA.
It seems likely that the second step is elimination of methanol that potentiates either monofunctional or
bifunctional alkylation(Figure 8.22). The antibiotic has been shown to interact with DNA at G-O-6
A-N-6G-N-2 and forms one cross-link for about every ten monocovalent links. The primary process is
bonding of the 2-amino group of a guanine residue to C-1 of the reductively activated mitomycin. This reac-
tion shows selectivity for 5
-CG sequences. Cross-linking is completed by alkylation of the 2-amino group
of the second guanine to C-10 of the mitomycin (Figure 8.22). This has been accurately analysed by Dinshaw
Patel in NMR studies on the adduct of mitomycin C to the hexamer (TACGTA).d(TACGTA) in which the
two guanines are crosslinked with the mitomycin molecule positioned in the minor groove of the duplex.^47
Many drugs that act on DNA exhibit a requirement for reductive activation, including adriamycin,
daunomycin, actinomycin, streptonigrin, saframycin, bleomycin (Section 9.7) and tallysomycin in add-
ition to mitomycin C. While there is no common factor uniting the chemistry of DNA modification by
these agents, the fact that tumour tissues seem to have a higher reducing potential than normal tissue has
led to the concept of bioreductive drug activation.
Carzinophilin Ais also a DNA-alkylating aziridine antibiotic, though it does not appear to need reductive
activation.^48 It has been identified as the antibiotic azinomycin B, isolated from Streptomyces griseofuscus.
Azinomycin Boperates in the major groove of DNA, causing cross-linking between a guanine residue and
a purine residue that is two bases removed in the duplex, as in the sequence d(G.Py.Py)d(C.Pu.Pu).

310 Chapter 8

N NH

H 2 N

Me

O

O

OCONH 2

OMe

Mitomycin C

N NH

H 2 N

Me

OH

OH

OCONH 2

OMe

N NH

H 2 N

Me

OH

OH

OCONH 2

• MeOH

N

NH 3

H 2 N

Me

O

OH

OCONH 2

N

NH 3

H 2 N

Me

O

O

OCONH 2

guanine DNA

N oxidn.

NH 3

H 2 N

Me

O

O

guanine

guanineDNA

Figure 8.22 Activation of mitomycin C by metabolic reduction and bifunctional alkylation of DNA at the 2-amino
group of adjacent inter-strand deoxyguanines

NN

N

N

N

H 2 NOC

O

CH 3

MTIC

NH N

N

HN

N

H 2 NOC

CH 3

AICAR

NH

NH 2

N

H 2 NOC

N

N

H 3 C N

N

N

H 2 N N

O

H 3 C

dR

Temozolomide

i, ii iii iv

Figure 8.21 Temozolomide activation and DNA alkylation

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