| The natural enediyne antibiotics comprise a class of the most potent antitumor agents ever discovered. A major stumbling block to clinical application of these compounds is their inadequate selectivity, and harnessing the powerful DNA-cleaving activity of this class of molecules is an area of high priority in antitumor drug design. Numerous strategies have been explored to improve the effectiveness and specificity of theses antitumor antibiotics, but a safe antitumor drug has yet to be developed. To address this problem we have explored the feasibility of a therapeutic concept that combines the antitumor efficiency of the natural antibiotics with the selectivity of photodynamic therapy.; We have shown that alkyl- or aryl-substituted cyclopropenones are thermally stable compounds but undergo photodecarbonylation reaction to form acetylenes with high quantum and chemical yield. Aryl-substituted and especially diaryl-substituted cyclopropenones can be activated with 350 nm or longer wavelength light and can be used for the development of photonucleases. The suitability of photodecarbonylation of cyclopropenones for generation of the enediyne system has been illustrated by the photochemical generation of acyclic benzannulated enediyne, 2.27.; Photochemical decarbonylation of cyclopropenones is a stepwise process. The initial cleavage of one of the single bonds in the cyclopropenone ring results in the formation of an intermediate, 3.5, with an electronic structure described as a resonance hybrid of a ketenylcarbene and a zwitterion. Under UV irradiation, the zwitterionic intermediate, 3.5, is formed directly from the singlet excited state of the corresponding cyclopropenone. While the cleavage of the first carbon-carbon bond in cyclopropenones requires ca. 32 kcal mol-1, the barrier for the decarbonylation of 3.5 is very low, reflected in the sub-nanosecond life-time of 3.5.; The feasibility of the in situ generation of cyclic enediynes by the photochemical generation of one of the triple bonds was proven on a cyclopropenone-containing enediyne precursor, 4.46. This precursor was synthesized by selective mono-cyclopropanation of a triple bond of the enediyne analog, 4.45. UV irradiation of the thermally stable enediyne precursor, 4.46, results in an efficient and clean decarbonylation reaction generating enediyne, 4.45, which undergoes Bergman cyclization at elevated temperature.; The non-benzannulated ten-membered cyclopropenone-containing photoprecursors, 4.115 and 4.144, in which one of the triple bonds is replaced with a cyclopropenone group, was designed and synthesized. The bicyclic cyclopropenones, 4.115 and 4.144, show no tendency for the Bergman cycloaromatization or the formation of corresponding enediynes 4.114 and 4.142 in the dark. The UV irradiation of 4.115 (300 nm) and 4.144 (400 nm), on the other hand, results in the efficient generation of the reactive ten-membered ring enediynes, 4.114 and 4.142. The latter undergoes Bergman cyclization at 40°C with a half lifetime of 12 and 64 hours in isopropanol to produce a benzannulated analog of p-benzyne diradical, which abstracts hydrogen atoms from the available hydrogen donors to form tetralin, 4.124, or naphthaquinone, 4.145. |
