From Natural to Rationally Designed Artificial Enediynes: Towards New Anticancer Antibiotics Activable at Will - Polyynes: Synthesis, Properties, and Applications - page 457

The cleavage activity of the monocyclic compounds listed in Scheme 19.8

against DNA is generally only moderate, with EC 50 around 500 m M and
with D/S ratios <1:15. In order to increase the the hydroxy
substituted derivatives 30 and 35 have been extensively used for the
preparation of conjugated compounds where a DNA complexing subunit is
attached to the OH group.

potency,

SCHEME 19.9

The best results have been obtained so far with compounds 39 and 40
(Scheme 19.9). In the first one, the enediyne is bonded to the minor groove
binder netropsin through a semirigid linker. It displays a 2000-fold increase
in activity compared to the parent alcohol. With an EC 50 of about 200 nM,
it is probably the most potent artificial enediyne prepared so far. However,
it is still 10 times less active than calicheamicin and, most of all, no double
strand cleavage was detected. 65 Compound 40 contains a DNA intercalator
and has an EC 50 of 80 m M and a D/S ratio of 1:18. 66
Monocyclic enediynes are not ideal prodrugs, because they generally
lack a blocking device (safety catch) that prevents cycloaromatization, and
when such device is present (i.e. in compounds 37 and 38) it is not easily
removable under physiological conditions.
A possible way to overcome this drawback involves generation of the
monocyclic enediyne in vivo. Nicolaou and co-workers have shown that the
parent compound 10 may be obtained from the polycyclic precursor 41
through a retro-Diels-Alder reaction (Scheme 19.10). While the thermal
reaction requires a temperature of 150 C, formation of the alkoxide allows
the cycloreversion to take place at room temperature. 67

SCHEME 19.10

The monocyclic enediyne 43 has been generated under mild conditions by

Lewis acid catalyzed allylic rearrangement of the precursor 42 ( Scheme 19.11 ) .