Synthesis, Reaction Mechanism, DNA Cleavage and Antitumor Properties of Naphthoquinone‐Based Enediynes

Abstract

AbstractUnder physiological conditions, natural enediynes antibiotics generate free radicals through a cycloaromatization reaction. The resulting highly reactive radicals can abstract hydrogen atoms on the phosphate backbone of DNA, leading to high cytotoxicity. On the other hand, anthraquinone‐fused compounds such as daunomycin and adriamycin can insert into DNA through planar aromatic ring structures, resulting in strong DNA damage. To this end, a series of naphthoquinone‐based enediynes were designed and synthesized by adjusting the type of terminal alkyne to modulate their water solubility and radical generation property. Theoretical calculations suggest that the naphthoquinone‐based enediyne generates radicals through a rearrangement (1,3‐proton transfer) followed by Myers‐Saito cyclization processes, with a much lower activation free energy barrier than Bergman cyclization (24.2 kcal/mol vs 39.8 kcal/mol). Differential scanning calorimetry and electron paramagnetic resonance results showed that naphthoquinone‐based enediynes undergo cycloaromatization at relatively low temperatures, resulting in the generation of highly reactive radical species. The enediynes with optimal water solubility displayed strong DNA cleavage ability at micromolar level and high cytotoxicity towards Hela cells, providing a half‐inhibitory concentration of 8.19 μM.