Anthraquinone-carbohydrate hybrid

Abstract Several artificial anthraquinone-carbohydrate hybrids were designed and synthesized. A selected niunber of hybrids did bind to DNA via intercalation in a sequence-selective manner, leading to inhibition of DNA cleavage by DNase 1, whereas other hybrids cleaved DNA with base selectivity upon photoirradiation. This hybrid system was found to be very important for both DNA binding and photocleaving. 

The cytotoxicity of hybrids 3 and 4 was examined by exposing HeLa S3 cells to each hybrid for 72 h [25]. The IC50 values of 3 and 4 were 9 and 58 xM, respectively. The sixfold higher toxicity of hybrid 3 compared to hybrid 4 must be connected to the observation that 3 intercalates DNA about fivefold more strongly than does hybrid 4. These results indicate that the cytotoxic activity of these anthraquinone-carbohydrate hybrids correlates with their abihty to bind DNA. 

To further improve DNA cleavage by anthraquinone-carbohydrate hybrids, we designed novel anthraquinone-carbohydrate hybrids 22 and 23, which are anomeric to each other (Fig. 7) [ 11 ]. These new hybrids lack the aromatic hy-... 

The DNA photocleaving abiUties of these hybrids were much higher than that of the natural anthraquinone antibiotic, daimomycin (lanes a and b vs lane d in Fig. 8). These results demonstrate that artificial anthraquinone-carbohydrate hybrids are superior to this natural anthraquinone product as a DNA photocleaving agent. 

The silyl groups at the newly formed benzene ring were cleaved by the action of acetyl chloride in anhydrous methanol and tetrabutylammonium fluoride to yield 34 and 35, respectively. A Tamao-Fleming-like oxidation to furnish the respective phenol derivatives did not take place, probably due to the sp -hybridized carbon of the arene moiety. To install the anthraquinone moiety by oxidation of the benzylic positions, it was necessary to reprotect the alcohol functionalities. After tert-butyldimethylsilyl protection of the hydroxyl moieties to afford 36, an iron(III)-catalyzed benzylic oxidation proceeded smoothly with yields up to 70%. Finally, hydrolysis with hydrochloric acid of the protecting groups generated the desired anthracycline derivatives 38 based on a carbohydrate skeleton [21,22] (Scheme 8.8). 

---