|dc.description.abstract||The extreme cytotoxicity of natural enediyne antibiotics is attributed to the ability of the (Z)-3-hexene-1,5-diyne (enediyne) and (Z)-1,2,4-heptatrien-6-yne (enyne–allene) fragments incorporated into a 10- or 9-membered ring cyclic system to undergo cycloaromatization producing dDNA-damaging 1,4-diradicals. The rate of cyclization of enediynes to p-benzynes strongly depends on the distance between acetylenic termini, which in turn can be controlled by the ring size. Thus, 11-membered ring enediynes are stable, 10-membered ring analogs undergo slow cycloaromatization under ambient conditions or mild heating, 9-membered ring enediynes are virtually unknown and believed to undergo very fast spontaneous cyclization. Cyclic enyne-allenes have not been synthesized so far due to very facile Myers-Saito cyclization.
We have developed thermally stable photo-precursors of 9-membered enediynes (2.22, 2.26) and enyne-allene (2.44), in which one of the triple bonds is replaced by the cyclopropenone group. UV irradiation of 2.14 results in the efficient decarbonylation (Φ254= 0.34) and the formation of reactive enediyne 2.22. The latter undergoes clean cycloaromatization to 2,3-dihydro-1H-cyclopenta[b]naphthalen-1-ol (2.24) with a life-time of ca. 2 h in 2-propanol at 25 °C. The rate of this reaction depends linearly on the concentration of hydrogen donor and shows a primary kinetic isotope effect in 2-propanol-d8. These observations, along with high negative entropy of activation, indicate that enediyne 2.22 exists in a rapid equilibrium with p-benzyne diradical (3.1). The rate-limiting step of the cycloaromatization reaction is hydrogen abstraction by the diradical 3.1.
In order to improve the DNA affinity of the enediyne 2.22, we designed and synthesized naphthalene-fused enediyne (2.26). This structural modification also allowed us to shift the absorbance of the cyclopropenone precursor 2.25, to 300-350 nm. UV irradiation of the 2.25 results in an efficient decarbonylation (Φ300= 0.50) reaction generating enediyne, 2.26, which undergoes Bergman cyclization at an elevated temperature.
9-Membered ring enyne-allene (2.44), generated by irradiation of the of cyclopropenone-containing precursor 2.43, undergoes almost instant (life time < 1 µs) cycloaromatization to form cytotoxic 1,4-diradical.||