8.7.3 Enediyne Antibiotics
A range of clinically significant anti-cancer drugs can mediate oxygen-dependent cleavageof the ribose
phosphate backbone of DNA. They can be broadly assigned into three classes.
Generators of reactive carbon radicals
Photo generators of hydroxyl radicals
Metal-mediated activators of O 2.The first class contains the enediyne antibiotics, whose interaction with DNA is more specific than that of
many alkylating agents and is irreversible. The second class includes antibiotics such as tetrazomine and
quinocarcin, where redox chemistry ultimately results in the reduction of oxygen to superoxide and leads
to ‘nicking’of DNA. The third class is well represented by the bleomycins, which are discussed in Chapter
9 as compounds that interact reversibly with DNA (Section 9.7).^53
The structure of the chromophore of the antibiotic neocarzinostatin, NCS, was established in 1985 and
was soon followed by those of calicheamicin (^) l, esperamicin C, dynemicin A, kedarcidin and C-1027
(Figure 8.26a). A common feature of these compounds is a highly unsaturated medium-sized ring, which
contains a 1,5-diyne-3-ene arrangement of multiple bonds,CCCHCHCC. They have
become known as the enediyne antibioticsand have taken a place at the forefront of research in biology,
Covalent Interactions of Nucleic Acids with Small Molecules and Their Repair 313
OH
MeO
OMe
O
O
O O
O O
O
polysaccharide
O
O
HN
OH OH
OH O
CO 2 H
OMe
Me
O
Cl
NH 2
OH O O
O
O
Me
MeN
HOMeOH
OO
NH
OCH 2
O
MeO
H
H
R
HO
O SS
S
Me
O O
O
O
HN
O
O S
OMe
OMe
I
Me
O
O
MeO OH
HOMe
OH
Me
OH
Me
OMe
NHEt
O
12
neocarzinostatin
chromophore A
dynemicin A
a
b
enediyne 1,4-arene diradical arene product
radical
product(s)
calicheamicin γ 1 I (R = H)
C-1027
2RH 2R
Figure 8.26 (a) Structures of the enediyne antibiotics: neocarzinostatin (chromophore), calicheamicing 1 I, esperamicin
A (chromophore), dynemicin A and antibiotic C-1027. The site of thiol attack is indicated (→) for the first
three antibiotics. (b) The Bergman enediyne cyclization gives a 1,4-benzenoid diradical (not quite the same
in the case of neocarzinostatin), which then abstracts two hydrogen atoms to give the stable arene product