Monocyclic Carba Enediynes

The presence of hydroxy groups at the 7 and 10 positions, as in. 30 and 34 , provokes an increase of the cycloaromatization rate. For example 30 has a Z1/2 of 4.5 h at 37°C (it is 18h for 10). A similar acceleration is observed for trans diol 31 (Z1/2 — 2 h at 50 C) where the hydroxy groups are in position 8 and 9 instead. An analogous result was obtained by the trans tetramethylated diol 32. On the contrary, the trans isomer 33 was less reactive than 10, and the diketone derived from 32 or 33 was even less prone to cycloaromatization. Finally, the presence of one or two hydroxymethyl groups, as in 35 or 36, has no appreciable influence on the reactivity. 

On the other hand, the introduction of halogen atoms on the double bond was demonstrated to have an inhibitory effect on the Bergman reaction. In particular, compound 38 has a half-life of 60 h at lOO C. Thus the two chlorine atoms may be considered efficient blocking devices. However, efficient triggering devices for such stabilized enediyne have not been yet devised. 

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. 

In order for the rearrangement to take place, the presence of an alkoxy group at the ot position of the ester or, alternatively, the presence of an ortho hydroxymethyl group in the aryl group is essential.  

Prodrugs 42 exhibit DNA cleaving properties and cytotoxicity in vitro indicating that the allylic rearrangement may occurr also in aqueous buffer, without Lewis acid catalysis. Interestingly, in this case also the free alcohols are active. In particular, for Ar = 2-naphthyl, compounds with EC50 around 1-10 pM were obtained. They also were demonstrated to be cytotoxic on cancer cell lines. 

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