Nucleic Acids in Chemistry and Biology

8.7.4 Antibiotics Generating Superoxide

Tetrazomineis a secondary metabolite that is a member of the quinocarcin/saframycin class of anti-tumour
agents. It has antibacterial activity as well as promising in vivoactivity against leukaemia in mice.
Quinocarcin has been used in clinical trials for a range of solid tumours (Figure 8.29). These compounds
undergo a spontaneous reaction involving a stereospecific self-disproportionation of the oxazolidine ring
to generate the superoxide radical, HO 2 •. That leads on to a radical-initiated cleavage of DNA whose
details are still under examination.^62

8.8 Photochemical Modification of Nucleic Acids

The very serious concern about the depletion of the global ozone barrier is directly related to the action of
UV light on nucleic acids. The UV effect is mutagenic at low doses, cytotoxic at high doses, and is linked
to skin cancer in many cases where there is chronic, excessive exposure to sunlight, among whites, albino
blacks, or for people with deficiencies in their repair genes. As a rule, a 10% reduction in the ozone layer
causes ca.20% increase in UV-radiation and a 40% increase in skin cancers.^63 The photolesions in DNA
caused by direct excitation or triplet photosensitisation are largely confined to the pyrimidine bases,
thymine and cytosine, while guanine is the main target for photo-oxidation.64,65In contrast, adenine is
largely resistant to photomodification under all irradiation conditions.

8.8.1 Pyrimidine Photoproducts

Light of 240–280nm excites the pyrimidine bases, C, T and U, to a higher singlet state(^1 S 1 ) which has a life-
time of only a few picoseconds before it gives photohydrates (in which water has added to either face of the
5,6-double bond), decays, or passes into the triplet state. Uridine photohydrate (U) dehydrates slowly to uri-
dine in acidic or alkaline solution and is moderately stable at neutral pH (t1/29h at 50°C). The cytidine photo-
hydrate is some tenfold less stable (tl/26h at 20°C) and either reverts to cytidine (90%) or is deaminated to give
U (10%) (Figure 8.30a).^66 This process effects a net conversion of C into U (Section 8.11.2). The formation
of photohydratesof thymine has a very low quantum yield and its biological consequences are not significant.
All the major pyrimidines form cyclobutane photodimerson direct irradiation at 260–300nm. The reac-
tion is a [22] cycloaddition, mainly involving the triplet state. Of the four possible isomers for thymine
dimer, T<>T, the cis-synisomer is formed by irradiation of thymine in an ice matrix and is known to be
the major product (95%) formed by UV irradiation of native DNA. The trans-synisomer is one of the
four isomeric products produced by the photosensitised irradiationof thymidine in solution and accounts
for some 2% of the native DNA T<>T. A larger proportion of this thymine photodimeris formed in
denatured DNA (Figure 8.30b), where the trans-syn, cis-synT<>T and T<>U dimers account for 1.6, 11.0
and 4.2% of total thymine.

316 Chapter 8

N

NMe

O

CO 2 H

OMe

quinocarcin

N

NMe

O

CH 2 OH

OMe

N

H

NH

OH O

tetrazomine

Figure 8.29 Antibiotics that interact with DNA by generation of superoxide leading to strand cleavage, probably
through ring opening and formation of a peroxide radical at the positions indicated (→)

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