MEDI 99 |
| Enediynes, such as calicheamicins were found to be powerful antitumor antibiotics. The biological activity of enediynes is associated with the presence of acetylenic and olefinic linkages appears to be based on Bergman cyclization. The Bergman cyclization yields a 1,4-dehydrobenzene diradical from an enediyne molecule. The rate of Bergman cyclization depends on the distance d between the acetylenic termini. The distance d required for Bergman cyclization to occur spontaneously is d < 3.34Å. In DNA-containing environments the formation of the diradical is followed by the abstraction of hydrogen atoms from DNA sugar-phosphate residues, leading to scission of the doubly stranded biopolymer and cell death. The powerful antitumor activity of enediynes is associated with high cytotoxicity to the normal cells limiting their clinical applications. Nevertheless, enediynes, properly constructed, and with their activity tuned, are promising candidates for treating certain forms of cancer. We have designed a new series of metallaenediynes 1, 2, 3 and 4 by introduction of metal fragments MLn at various positions of the enediyne. The work reported herein describes our computations of the Bergman cyclization of four metallaenediynes 1, 2, 3 and 4 and provides evidence that the Bergman cyclization of 1 is a promising lead, suggesting a route towards a generation of a new family of organometallic enediynes and the manipulation of their biochemical properties.
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General Poster Session
7:00 PM-9:00 PM, Sunday, 10 September 2006 Moscone Center -- Hall D, Poster
Sci-Mix
Division of Medicinal Chemistry |
