Studies on the mode of antifungal action of pradimicin antibiotics. II. D-mannopyranoside-binding site and calcium-binding site.
Based on the structure-activity relationship data of BMY-28864 and related pradimicin derivatives, the calcium salt-forming ability and the D-mannopyranoside-specific visible absorption maximum shift of BMY-28864 were analysed in the ternary complex formation of BMY-28864 with D-mannopyranoside and calcium. The free C-18 carboxyl group of BMY-28864 was proved to be the sole site for binding to calcium, while no hydroxyl groups of the aglycone were involved in calcium salt formation. The stereospecific D-mannopyranoside-recognizing ability of BMY-28864 was completely abolished by removal of the C-5 disaccharide moiety, and, more particularly, of the C-5 thomosamine moiety. Close relationship of these findings with the antifungal action was also supported by the in vitro antifungal assay and the potassium leakage induction test.
Ueki
T
T
Bristol-Myers Squibb Research Institute, Tokyo, Japan.
Numata
K
K
Sawada
Y
Y
Nishio
M
M
Ohkuma
H
H
Toda
S
S
Kamachi
H
H
Fukagawa
Y
Y
Oki
T
T
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000494:pharmacology*; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D008358:Mannose / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D013053:Spectrophotometry; D013329:Structure-Activity Relationship; D000095643:Pradimicins and Benanomicins
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000935:Antifungal Agents; D002118:Calcium; D008358:Mannose; C058036:pradimicin A; D000095643:Pradimicins and Benanomicins; C067714:N,N-dimethylpradimicin FA-2