Synthesis of a C7-Ethyl Aziridinomitosene for DNA Inter-Strand Cross-Linking Mechanistic Studies
Don L. Warner
Several common cancer-fighting therapies such as Mitomycin (MC) function by binding DNA strands to form inter-strand cross-links (ICLs). These ICLs prohibit DNA replication and transcription, ultimately leading to cell death. Aziridinomitosenes (AZMs) are synthetic compounds that rival MC in their ability to form DNA ICLs. While similar in structure and function to MC, AZMs are excitingly distinct in their ability to bind with DNA under non-reductive conditions. The reductive activation necessary for MC-initiated ICLs may be responsible for generating harmful oxygen radicals, suggesting that AZMs may be a superior cancer fighting agent. In vitro studies with cancer cells have demonstrated that the addition of an alkyl substituent at key locations on the AZM molecule influences its toxicity; we hypothesize that the presence of the alkyl substituent impacts binding affinity for DNA and the abundance of ICLs. To further investigate ICL formation mechanisms and associated cancer cell toxicity, synthesis of novel AZM analogs is underway. Specifically, a C7-methyl substituted AZM analog has been successfully synthesized and progress is being made toward a C7-ethyl analog. The AZM is a complex tetracyclic compound consisting of a quinone, pyrrole, pyrrolidine, and an aziridine ring. The synthesis begins toward an oxazole product that serves as a foundation for the remaining components. Starting with 3-ethyl γ-butyrolactone, prepared via a radical cyclization pathway, the synthesis involves converting the lactone to a C5-substituted oxazole via the Schöllkopf oxazole synthesis. The resulting species possesses an ethyl group primed for the C7 position upon quinone ring formation. After addition of a serine-derived aldehyde to the oxazole ring, the compound is further transformed by a modified Mitsunobu reaction to form the aziridine ring. Further elaboration will lead to the crux of the synthetic pathway, an oxazolium salt/4-oxazoline/azomethine ylide cycloaddition sequence that generates the AZM tetracyclic core. Successful synthesis of the C7-ethyl AZM analog will facilitate further studies aimed at understanding the ICL formation mechanism and structural components that contribute to cancer-fighting properties.
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