From Natural to Rationally Designed Artificial Enediynes: Towards New Anticancer Antibiotics Activable at Will - Polyynes: Synthesis, Properties, and Applications - page 463

On the other hand, in compound 68 an enol-keto trigger, which is easily
activated under acidic conditions, is operating. 87 While in the previous cases
the bridgehead double bond was completely removed, as in calicheamicin
itself, Semmelhack et al. studied the possibility to activate the prodrug by
shifting the double bond to another position. An attempt to cause endo-to-
exo base-promoted isomerization of 69 to give 70 failed because the double
bond prefers to remain in the more strained bridgehead position. Therefore,
69 was activated in a more conventional way by a selective epoxydation
followed by solvolytic opening of the oxyrane. The resulting diol 71 under-
went easy cycloaromatization. 88
The enediyne 72, having the carbonyl group on the shortest bridge of the
bicyclic derivative, was conjugated, through an appropriate spacer, with
netropsin, a well known minor-groove DNA binder, alternatively through
the propargylic or the tertiary alcoholic function (Scheme 19.19). 89 In par-
ticular, the hybrid of 72 with netropsin bonded to the propargylic alcohol,
showed an enhanced activity against plasmid DNA with respect to 72.
It resulted comparable to the one of esperamicin; unfortunately, the cyto-
toxicity against human colon tumor cells was unexpectedly low.
SCHEME 19.19
Scheme 19.20 summarizes some examples of bicyclic derivatives with
ring sizes different from calicheamicin. 90 Compound 74, with a 7-membered
SCHEME 19.20