From Natural to Rationally Designed Artificial Enediynes: Towards New Anticancer Antibiotics Activable at Will - Polyynes: Synthesis, Properties, and Applications - page 456

19.3 MONOCYCLIC OR ORTHO-FUSED ARTIFICIAL ENEDIYNES
19.3.1 M ONOCYCLIC C ARBA E NEDIYNES
Apart from the parent compound 10, 29 several cyclodeca-3-ene-1,5-diynes
variously substituted at all possible positions have been prepared and
studied (Scheme 19.8). These simple systems are useful in order to evaluate
the steric and electronic effects of the substituents as well as to explore the
effect of conjugation with DNA complexing substructures.
SCHEME 19.8
The presence of hydroxy groups at the 7 and 10 positions, as in 30 54,61
and 34 62 , provokes an increase of the cycloaromatization rate. For example
30 has a t 1/2 of 4.5 h at 37 C (it is 18 h for 10). A similar acceleration is
observed for trans diol 31 (t 1/2 =2hat50 C) where the hydroxy groups are
in position 8 and 9 instead. 53 An analogous result was obtained by the
trans tetramethylated diol 32. 63 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. 63 Finally, the presence of one or two
hydroxymethyl groups, as in 35 56 or 36, 29 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. 64 In particular, compound 38 has a half-life of 60 h at 100 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.