Syntheses and biological evaluation of new glyco-modified angucyclin-antibiotics.
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 ED50-values in the range of 12.6-2.9x 10(-6) M.
Kirschning
A
A
Institut für Organische Chemie, Technische Universität Clausthal, Clausthal-Zellerfeld, Germany. andreas.kirschning@tu-clausthal.de
Chen
G W
GW
Dräger
G
G
Schuberth
I
I
Tietze
L F
LF
D000818:Animals; D000880:Anthraquinones / Q000138:chemical synthesis* / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000494:pharmacology; D001551:Benz(a)Anthracenes / Q000138:chemical synthesis / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006027:Glycosides / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D051379:Mice; D013329:Structure-Activity Relationship; D013754:Tetracyclines; D014407:Tumor Cells, Cultured; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000095602:Angucyclines and Angucyclinones
D000880:Anthraquinones; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D001551:Benz(a)Anthracenes; D004791:Enzyme Inhibitors; D006027:Glycosides; D013754:Tetracyclines; D014969:Xanthine Oxidase; C000100:aquayamycin; D000095602:Angucyclines and Angucyclinones