Enediynylacridans: design and synthesis of oxidase triggered diyl progenitors

Abstract

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.