From Natural to Rationally Designed Artificial Enediynes: Towards New Anticancer Antibiotics Activable at Will - Polyynes: Synthesis, Properties, and Applications - page 449

19.1.3 M ECHANISM OF A CTION OF T YPE IE NEDIYNES
Calicheamicin is a masterpiece of nature's ingenuity. It has been compared
to a smart bomb equipped with:
1. a delivery system which is responsible for a strong and specific com-
plexation with DNA. This system is represented by the oligo-
saccharide unit.
2. a warhead (the enediyne moiety) that is able to attack simultane-
ously the two complementary DNA strands, causing the lethal
double cut.
3. a safety catch that prevents the enediyne reaction, by imposing a
structural restraint to its reaction. In this way the warhead does
not explode until a particular chemical event takes place. In
calicheamicin the safety catch is represented by the enamine
double bond.
4. a chemical trigger that mediates the removal of the safety catch and
therefore unleashes the high reactivity of the enediyne. In 1 the
trigger is the trisulfide group.
The key transformation of 3-ene-1,5-diynes is a thermal rearrangement
that was disclosed in the early 1970s by Darby et al. 25 and Lockhart and
Bergman, 26 and which is commonly called the Bergman cycloaromatization
(Scheme 19.3). In the classical Bergman experiment, the deuterated enediyne
6 was transformed into the isomer 7 or, in the presence of a hydrogen donor,
into deuterated benzene 9. This reaction is believed to proceed through a
diradical benzenoid species (a p-benzyne). 27
Acyclic Z 3-ene-1,5-diynes, such as 6, undergo the classical Bergman
thermal cycloaromatization only at elevated temperatures (a photochemi-
cal promoted Bergman-type cycloaromatization of acyclic enediynes can
take place under milder conditions on particular substrates). 28 However,
SCHEME 19.3