From Natural to Rationally Designed Artificial Enediynes: Towards New Anticancer Antibiotics Activable at Will - Polyynes: Synthesis, Properties, and Applications - page 448

SCHEME 19.2

combination of an anthraquinone moiety fused with a 10-membered bridg-
ing enediyne ring.
All these compounds are extremely cytotoxic and cause both in vitro
single- and double-stranded DNA cuts of supercoiled plasmids. For
example calicheamicin g

1 (in the presence of a reducing thiol) afforded
about 50% total cut at 5-25 nM concentration, with a double to single
cleavage ratio of 2:1. 17,18 By comparison, bleomycin has the same activity
only at 160 nM and with a double to single cut ratio of 1:9. The high activity
of calicheamicin was demostrated to be strongly dependent on the presence
of the tetrasaccharide unit. Actually, the aglycon of 1 was about 1000 times
less active, with a 1:30 ratio of double to single scission. 17 Obviously the
damage caused to the cell by double cut is by far more fatal than that caused
by a single cut. The DNA cleavage by enediynes was demonstrated to be
oxygen-dependent (it does not occur under anaerobic conditions). 19
Although four very ingenious total syntheses of calicheamicin or its
aglycone have been achieved, 15,20-22 its microbiological synthesis is far
more practical, especially after bioengineering improvements based on
expression of a self-resistance aiding protein. 23
Although calicheamicin is more potent than any other known compound
as anticancer agent (for example it is 1000 times stronger than adriamycin
in murine tumor models), 11 it lacks significant specificity for tumor cells.
Therefore, a way to deliver it selectively was sought. Very promising results
have been obtained by conjugating it with monoclonal antibodies. 24 The
resulting conjugate gemtuzumab ozogamicin (called Mylotarg TM and pro-
duced by Wyeth-Ayerst) is currently on the market and has led to valuable
results against acute myeloid leukemia.