Chemistry
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Item Photochemical Generation and Reversible Cycloaromatization of a 9-Membered Ring Cyclic Enediyne(The Southeast Regional Meeting of the American Chemical Society (SERMACS), Nashville, TN, USA, 2008) Pandithavidana D R; Popik V VThe extreme cytotoxicity of natural enediyne antibiotics is attributed to the ability of the (Z)-3-ene-1,5-diyne fragment incorporated into a 10- or 9-membered ring cyclic system to undergo Bergman cyclization and producing dDNA-damaging p-benzyne diradical. The rate of this reaction strongly depends on the ring size. Thus 11-membered ring enediynes are stable, 10-membered ring analogs undergo slow cycloaromatization under ambient conditions or mild heating. Very little is known about reactivity of 9-membered ring enediynes due to their instability. We have developed a thermally stable photo-precursor of 1 of 9-membered enediyne 2, in which one of the triple bonds is replaced by the cyclopropenone group. UV irradiation of 1 results in the efficient decarbonylation (?254 = 0.34) and the formation of reactive enediyne 2. The latter undergoes clean cycloaromatization to 2,3-dihydro-1H-cyclopenta[b]naphthalen-1-ol (4) with ca. 2 h a life-time in isopropanol at 25 �C. The rate of this reaction depends linearly on the concentration of hydrogen donor and shows primary kinetic isotope effect in 2-propanol-d8. These observations, along with high negative entropy of activation, indicate that enediyne 2 exists in a rapid equilibrium with p-benzyne diradical 3. The rate-limiting step of the cycloaromatization reaction is hydrogen abstraction by the diradical 3. Synthesis of cyclopropenone 1 and DNA-clevaging activity of the photo-generated enediyne 2 will be also discussed.Item Chemistry of Natural and Photoswitchable Cyclic Enediynes(Chemistry in Sri Lanka, 2012) Pandithavidana D RThe cyclic enediynes, a relatively new class of antitumor antibiotics are strong DNA cleavage agents and exhibit remarkable antitumor activities both in vitro and in vivo. Naturally occurring enediyne antitumor antibiotics are divided into two groups according to the 9- or 10-membered ring core structure. The first enediyne antibiotic, neocarzinostatin (NCS) consisting of 1:1 mixture of an apoprotein and a chromophoric molecule (shown inFigure 1.1), was isolated from Streptomyces carzinostaticus in 1965. However, the structure of the NCS chromophorewas determined twenty years later. Following the disclosure of the unprecedented molecular structure of neocarzinostatin, two families of 10-membered ring enediynes were discovered in 1987, as represented by calicheamicin from Micromonospora echinospora and esperamicin-A 1 from Actinomadura verrucospora.Item Photoswitchable Nine-Membered Cyclic Enediynes and Enyne-Allenes(LAP LAMBERT Academic Publishing, 2011) Pandithavidana D RThe extreme cytotoxicity of natural enediyne antibiotics is attributed to the ability of the (Z)-3-ene-1,5-diyne fragment incorporated into a 10- or 9-membered ring cyclic system to undergo Bergman cyclization and producing dDNA-damaging p-benzyne diradical. The rate of this reaction strongly depends on the ring size. Thus 11-membered ring enediynes are stable, 10-membered ring analogs undergo slow cycloaromatization under ambient conditions or mild heating. Very little is known about reactivity of 9-membered ring enediynes due to their instability. We have developed thermally stable photo-precursors of 9-membered enediynes, in which one of the triple bonds is replaced by the cyclopropenone group. UV irradiation of the photo-precursor results in the efficient decarbonylation and the formation of reactive enediyne. The latter undergoes clean cycloaromatization spontaneously with absence of any chemical additives. Synthetic strategies of a series of cyclopropenone containing nine-membered enediyne precursors and DNA-cleavaging activity of the photo-generated enediynes have been also discussed.Item Photochemical Generation and Reversible Cycloaromatization of a Nine-Membered Ring Cyclic Enediyne(Journal of the American Chemical Society, 2009) Pandithavidana D R; Poloukhtine A; Popik V VIrradiation of the nine-membered ring enediyne precursor, which has one of its triple bonds masked as cyclopropenone, efficiently (? = 0.34) generates the reactive 4,5-benzocyclonona-2,6-diynol. The latter rapidly equilibrates with the corresponding 1,4-didehydronaphthalene diradical and then undergoes rate-limiting hydrogen abstraction to produce the ultimate product of the Bergman cyclization, benz[f]indanol.Item Photochemical Triggering of the Bergman and Myers?Saito Cyclizations(Australian Journal of Chemistry, 2010) Pandithavidana D R; Kuzmin A; Popik V VTwo strategies for the photochemical generation of reactive enediyne compounds and their subsequent cycloaromatization to p-benzyne or ?,3-didehydrotoluene derivatives are discussed in this account. The first method employs a photo-Wolff reaction of stable 11- or 12-membered ring precursor enediynes containing the 2-diazo-1,3-diketone moiety. Irradiation of these compounds results in ring contraction and the formation of two isomeric enediynes possessing an enolized ?-ketoester fragment. One of the isomers undergoes the conventional Bergman cyclization, whereas the other isomerizes into the enyne-allene tautomer, which rapidly cyclizes via a Myers?Saito mechanism. The second strategy consists of replacing the triple bond in a cyclic enediyne or enyne-allene structure with a cyclopropenone group, rendering them thermally stable. Photolysis of cyclopropenones results in efficient decarbonylation and the regeneration of a triple bond, restoring the enediyne ?-system. The generation of reactive enediynes by non-resonant two-photon excitation using wavelengths within a ?phototherapeutic window? was also demonstrated. Photogenerated enediynes show significant nuclease activity, efficiently inducing single-strand dDNA cleavage.