Syntheses and biological evaluation of new glyco-modified angucyclin-antibiotics

Abstract

The synthesis of novel aquayamycin-derived angucycline antibiotics 13a– d has been achieved. Glycosylation of aquayamycin ( 6) using 2-selenoglycosyl acetate 7 as glycosyl donor proceeded in excellent yield but attempts to reductively remove the selenyl group led to rearrangement or further aromatization of the aglycon. As a consequence of these results, it became possible to prepare urdamycinone B ( 10) starting from aquayamycin ( 6). In addition, silyl protected d-olivals 12a, b were attached to the C-glycoside domain of aquayamycin ( 6) under protic conditions. As expected, the hydroxy and phenol groups of the benz[ a]anthracene framework of 6 did not react under the glycosylation conditions employed. Stepwise removal of the silyl protecting group starting with tetrabutyl ammonium fluoride followed by use of the HF/pyridine complex suppressed a possible rearrangement of the aglycon and successfully terminated the sequence. The new angucycline-antibiotics 13a and 13b are some of the most potent xanthine oxidase inhibitors known and show cytotoxic activity with ED 50-values in the range of 12.6–2.9×10 −6 M