In 1972, Bergman reported cycloaromatization via 1,4-
benzenoid diradicals of enediyne systems. Since 1985, five
enediyne fungal products with anticancer antibiotic activity
have been structurally elucidated, namely, neocarzinostatin
chromophore, the calicheamicins, the esperamicins, the
dynemicins, and kedarcidin chromophore. These compounds are
delivered to DNA by a targeting mechanism and upon
activation undergo a series of reactions which results in
the generation of radicals via Bergman or Myers cyclization.
Myers cyclization is aromatization of certain enynylallenes
to Q,3-dehydro toluene diradicals. These radicals then
abstract hydrogen atoms from DNA resulting in strand
cleavage.
The goal of my research project is the synthesis of
enediynylacridans s~ch as 3,6-bisdimethylamino-9-[3-(2-
ethynylphenyl)prop-2-ynyl]acridan which potentially have the
same type of anticancer antibiotic activity as the natural
products. Oxidation of the acridan (dihydro acridine) to
the acridine would induce base catalyzed propargyl-allenyl
isomerization. This would serve as the triggering device
which leads to Myers cyclization and thus the diradical.
The acridine portion of the molecule would also serve as
the delivery system, as acridines are known to interact with
DNA via intercalation. There is also interest in
determining to what extent an N-oxide functionality would
accelerate the Myers cyclization due to the incipient
nitroxide radical. Another area of interest involves
chemical oxidation of the acridans to the acridines.
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