The chemistry of aza-enediynes, aza-enyne allenes, and related aza-Bergman and aza-Myers-Saito rearrangements

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Feng, Liping

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Naturally occurring enediynes are a class of potent antibiotic antitumor agents that cleave DNA by generating reactive diradicals via the Bergman cyclization or MyerSaito type cyclization. However, the lack of tumor specificity of these compounds has limited their application in cancer chemotherapy. We have undertaken an approach to achieve cancer cell specific targeting by enediynes involving the re-design of the enediyne core. Classes of C,N-dialkynyl imines (3-ene-3-aza-1,5-diynes, aza-enediynes) and 3-ene-4-aza-1,6-diynes (skipped aza-enediynes) have been designed and synthesized. These aza-enediynes undergo a facile aza-Bergman cyclization to generate 2,5- didehydropyridine diradicals that undergo a rapid retro-aza-Bergman rearrangement to (Z)-β-alkynyl acrylonitriles. Certain aza-enediynes can undergo reaction under acidic conditions to afford carbene intermediates which can be trapped efficiently. On the other hand, aza-enediynes that undergo aza-Bergman rearrangement slowly can convert to enediynes through a dimerization mechanism. The skipped aza-enediynes can isomerize to the corresponding C-alkynyl-N-allenyl imines (aza-enyne allenes) under basic conditions. The resulting aza-enyne allenes undergo a facile aza-Myers-Saito cyclization to generate previously un-reported α,5-didehydro-3-picoline diradicals that can be efficiently trapped. Both 2,5-didehydropyridine diradicals and α,5-didehydro-3-picoline diradicals have the potential to cleave DNA. DNA cleavage abilities of these azaenediynes and skipped aza-enediynes are under investigation.




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