A Convergent Synthetic Method to Produce Aziridinomitosenes for DNA Interstrand Cross-Linking Studies
Don L. Warner
Aziridinomitosenes (AZMs) are being synthesized to explore their ability to alkylate DNA. AZMs covalently modify DNA in a process called interstrand-crosslinking (ICL) that occurs within the minor grove of DNA. ICL’s are believed to halt cell mitosis which leads to cell death. AZMs are structurally similar to the clinically used anti-tumor agent mitomycin C, which peaks our interest in its mechanism. AZMs need to be produced in high quantities with various substituents at the C6 and C7 positions on the quinone ring since these groups have been shown to significantly impact cytotoxicity. A shorter synthetic pathway will theoretically meet the demands of future research by reducing cost, increasing overall efficiency, and generating the rapid production of numerous analogs. This shorter synthesis proposes the production of a side-chain and core that resembles a step in AZM synthesis. The side-chain is obtained from the modification of 1,3-propanediol through a series of protection, nucleophilic addition, and deprotection steps. The goal is to add the side-chain to the oxazole core at the C5 position. Thus, the target is produced via a convergent pathway, compared to what was once only obtainable through linear production. At this stage, the addition of the oxazole to the side-chain has been successful, albeit in a less than optimum yield. Future work will be to optimize the conditions in which side-chain addition proceeds efficiently, while incorporating the desired synthetic derivatives at the C6 and C7 positions. These and related studies will be presented.
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