Rational Design of Artificial Enediynes

Although conjugation of the natural enediynes with monoclonal antibodies has led to important clinical results, the quest for more selective analogs is 

An ideal artificial enediyne prodrug should be stable toward cycloaromatization. Therefore the ASE must be considerably higher than that calculated for 10-11. This can be realized by designing structural constraints that increase the steric strain of the product much more than that of the enediyne. Simple substituents are not, in general, able to diminish the reactivity adequately thus, stabilized enediyne analogs are typically ortho-fused or bridged bicyclic or polycyclic compounds. 

However, a suitable transformation must be devised in order to convert, under physiological conditions, the enediyne prodrug into the active drug. An alternative strategy is to use, as enediyne prodrug, a 1,5-diyne equipped with functional groups that allow the introduction of the missing double bond under appropriate conditions. 

Another important feature of designed enediyne prodrugs is the presence of attachment points to be used for joining DNA-complexing substructures. The dramatic importance of the delivery unit in calicheamicin indicates that it is probably very difficult to achieve nanomolar potencies without a fitting DNA-complexing agent. 

Finally, a not trivial issue is the stability in the dry state. It is actually known that, often, enediyne compounds tend to undergo radical polimer-ization in the dry state. It is clear that, for potential development as a drug, full stability is essential. 

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