ORGN 682 |
| Natural occurring enediyne antibiotics such as calicheamicin, esperamicin, dynemicin and neocarzinostatin, undergo Bergman cycloaromatization as the key step in their biological activity. Once activated, the enediyne moiety is transformed into a highly reactive intermediate, 1,4-dihydrobenzene (p-benzyne). This intermediate abstracts two hydrogen atoms, one from the sugar backbone of each DNA strand, eventually leading to the self-programmed cell death (apoptosis). Unfortunately, these anticancer drugs are highly toxic due to the lack of selectivity towards cancerous cells. En route for developing more selective enediynes, our group has initiated a new approach that involves controlling the rate of the Bergman cyclization through introduction of substituents spatially close to the enediyne moiety. DFT computations showed that nature of ortho-substituents in benzannelated enediynes can alter the activation energy barrier of the cyclization. We will report experimental determination of rate constants and activation energies for the Bergman cyclization of a set of ortho-substituted enediynes chosen by computational predictions. Changing in the concentration of hydrogen-atom donor, 1,4-cyclohexadiene (1,4-CHD), change the overall apparent rate constant (kapp), thus, enabling us to determine the rate constants for every step of the Bergman cycloaromatization process.
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Physical Organic Chemistry: Calculations, Mechanisms, Photochemistry, and High-Energy Species
1:00 PM-5:00 PM, Wednesday, 16 March 2005 Convention Center -- Room 11A, Oral
Division of Organic Chemistry |
