ORGN 539 |
| Nitrogen-onium salts are N-alkoxy-linked heteroaromatic compounds that contain a fragmentable nitrogen-oxygen bond. Upon activation by light, this bond cleaves homolytically to yield a heteroaromatic radical cation and an alkoxy radical. It has been shown that each of these transient species can cleave DNA. While alkoxy radicals lead to DNA-backbone fragmentation by H-abstraction of the sugar backbone, the heteroaromatic radical cations oxidize preferably guanine bases. This oxidation step is potentially irreversible because the product is a neutral heteroaromatic compound. The DNA cleavage efficiency of the simple onium salts based on quinoline, isoquinoline and phenanthridine is extremely low. The reason is the weak ground state association of these N-methoxy compounds with DNA. We are attempting to link these onium salts to an efficient DNA binding moiety, for example naphthalimide. The attachment is done with a flexible methylen linker of variable length. The photoreaction will produce an alkoxy radical free to diffuse and a radical cation linked to the DNA structure by the naphthalimide moiety. To explore the potential of the onium-salts towards photodynamic therapy we determined the cytotoxicity as well as their phototoxicity. The cytotoxicity of the first generation onium-salts is being tested using Saccharomyces cerevisiae. The cells are then exposed to tolerated levels of the drug and irradiated. So far, only the quinoline-based onium-salts exhibit an increased toxicity upon irradiation. We expect that increased binding will have a strong effect on retention of the drug in the exposed cells and thus on the phototoxicity of the drug.
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Materials, Devices and Switches, Metal-Mediated Reactions, Asymmetric Reactions, Total Synthesis, Biologically-Related Molecules and Processes
7:00 PM-9:00 PM, Wednesday, April 9, 2008 Morial Convention Center -- La Louisiane, Blrm. C, Poster
Division of Organic Chemistry |
