3.8.2.1. Category 1: Activation through Enediyne to Eneyne−Cumulene Conversion in Altered pH
This strategy is one of the widely exploited strategies in pH-based triggering of enediynes. In their quest to develop new DNA-cleaving agents related to the neocarzinostatinchromophore, Toshima and co-workers have synthesized the cyclic sulfide A which upon oxidation with m CPBA produced the allenicsulfone B. Compound B when treated with a base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), isomerized to the eneynecumulene C. The cumulene, being extremely reactive, underwent spontaneous MSC under ambient conditions to the diradical that was able to cause damage to double-stranded (ds) DNA ( Scheme 62 ).
Scheme 62. Base catalysed activation of cyclic sulfones via eneyne−cumulene conversion.
They have also reported that the thia, oxa, or azaenediyne undergo MSC when subjected to weakly acidic or basic conditions. Under such pH values, the compound first isomerizes to the eneyne−allene and subsequently undergoes MSC to generate the toluene diradicals which have been shown to cleave ds DNA.
Shibuya et al. exploited the approach depicted under this category. They synthesized enediyne model compounds represented by A. Compound A produced the eneyne−allene B and ultimately generated toluene diradicals C via a reaction cascade triggered by hydrolysis of the malonyl ester group under basic conditions ( Scheme 63 ).
Scheme 63. Activation through eneyne−allene via decarboxylation.
Enediyne models having electron-withdrawing groups were also designed and subsequently synthesized. These molecules, represented by F, upon treatment with TFA in the presence of 1,4-cyclohexadiene (1,4-CHD) in benzene or MeOH at 37°C afforded the phenol J as the only isolable product, thus indicating that cycloaromatization proceeded via a diradical pathway as shown in Scheme 64 .
Scheme 64. Activation through acid catalysed eneyne−allene conversion by lactonization.
Kerwin's group has prepared 4-aza-3-ene-1,6-diyne systems represented by structure A and demonstrated that these compounds possess powerful pH-dependent DNA-cleavage activity with some degree of cytosine specificity. The probable mechanism involves isomerization to the azaeneyne−allene system, which undergoes aza MSC to generate methyl pyridiniumdiradicals C (Scheme 65). The latter then cleaves the ds DNA, producing mainly single-strand cuts at a concentration of 100μM. Another possible mechanism of DNA cleavage involves the alkylation pathway through the intermediacy of D or through the formation of carbene intermediate F via the ylide E ( Scheme 65 ).
Scheme 65. pH-dependent activation and DNA cleavage of Azaenediynes.