Chemistry Reference
In-Depth Information
H-atoms (Mertens and von Sonntag 1994). In contrast to BLM, where H4
′
is at-
tacked, it is mainly the H5
that is abstracted by NCS. This points to a highly
stereoselective topochemical reaction, since the tertiary H1
′
would be
the thermodynamically, and at equal accessibility, also the kinetically favored
targets. This is supported by marked differences between esperamicin A and
esperamicin C (Epstein et al. 1997). The former cleaves only at
C
(5
′
and H4
′
′
) while the
latter also cleaves at
C
(4
).
With NCS and in the presence of O
2
, a free 3
′
′
-phosphate and a DNA-bound
Thy-5
-aldehyde is the major lesion (Kappen et al. 1982; Kappen and Goldberg
1983), and with
18
O
2
the label is introduced in that position (Chin et al. 1984).
With a 75% preference for T, the base selectivity is very high [T >> A >> C >
G) (Takeshita et al. 1981; Goldberg 1991)]. Hydroxylation at
C
(4
′
′
) giving rise to
the C4
-aldehyde lesion
(Saito et al. 1989). Nitroaromatic radiation sensitizers can replace O
2
(Kappen
and Goldberg 1984; Goldberg 1987; Chin et al. 1987; Kappen et al. 1989), but the
Thy-5
′
-AP is the other pathway that complements the Thy-5
′
′
-aldehyde formation is largely suppressed and 3-formylphosphate (only
10
15% in the presence of O
2
) is now an important product (for model systems,
see Chap. 6.3, for the hydrolysis of a formyl phosphate see Schuchmann and von
Sonntag 1984).
In the absence of O
2
, there is little if any strand breakage; instead the drug
binds covalently to DNA (Povirk and Goldberg 1982, 1984) and induces, under
certain conditions, interstrand DNA cross-links (Xu et al. 1997) with the same
base specificity as SSB formation in the presence of O
2
(Povirk and Goldberg
1985a).
When one of the two vinyl-type radicals has reacted with DNA, there still
remains a second highly reactive radical for further reaction. If the rate con-
stants with 2-PrOH (vinyl radical:
k
= 2
−
10
5
dm
3
mol
−1
s
−1
; phenyl radical: 1.2
×
10
7
dm
3
mol
−1
s
−1
; Mertens and von Sonntag 1994) are a good guide O
2
stands
only a small chance to compete with H-abstractions from the sugar moiety. An
attack at both DNA strands leads to a clustered lesion. Mechanistically, NCS and
BLM, where the phenomenon of a clustered lesion is also observed, differ in so
far as in NCS the two radicals of the biradical set two close-by lesions, while in
BLM the drug has to reactivated for the second action and potentially subse-
quent ones. NCS can only give rise to two damaged sites, and the drug cannot
be recycled.
The second action of NCS that gives rise to a DSB or an ALS seems to be not
as regiospecific as the first step that creates only a SSB. Attack at
C
(1
×
′
),
C
(4
′
) and
C
(5
) is envisaged. As discussed above, attack at the former two positions leads
to the release on unaltered bases, and this is indeed observed (Hatayama and
Goldberg 1980; Povirk and Goldberg 1984).
Interestingly, the nature of the thiol (GSH vs other thiols) that is used to trig-
ger the reaction, inf luences to some extent the pathways that are subsequently
taken (Povirk and Goldberg 1985b, 1986). NCS may also be activated by CO
2
•
−
(Favaudon et al. 1985). Here, three CO
2
•
−
are required for an activation, and the
preferred site of attack is now H1
′
′
.
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