Preparation of biologically active ristocetin derivatives: replacements of the 1'-amino group

• Published in: Journal of medicinal chemistry 1985-09, Vol.28 (9), p.1371-1375
• Main Authors: Herrin, Thomas R, Thomas, Alford M, Perun, Thomas J, Mao, James C, Fesik, Stephen W
• Format: Article
• Language: English
• Subjects: Chemical Phenomena; Chemistry; Exact sciences and technology; Gram-Positive Bacteria - drug effects; Magnetic Resonance Spectroscopy; Oligopeptides - metabolism; Organic chemistry; Peptides; Preparations and properties; Ristocetin - analogs & derivatives; Ristocetin - chemical synthesis; Ristocetin - pharmacology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00147a047

A series of ristocetin analogues with modifications (OH, C=O, C=NOH, NCOCH3) at the C-1' amino group was synthesized and found to possess antibacterial activity against gram-positive bacteria and to bind to Ac2-Lys-D-Ala-D-Ala, a model for the antibiotic's site of action. Due to the lack of a positively charged amino group, the active analogues could not form a salt bridge, indicating that an electrostatic interaction between the positively charged 1'-amino group of ristocetin and the carboxylate anion of the peptide is not required for complex formation. The only compound that did not exhibit good antibacterial activity was epiristocetin aglycone (an analogue with the 1'amino group in the opposite configuration (S) as ristocetin). On the basis of NMR studies of epiristocetin aglycone in solution, the 1'-amino group is located in the proposed carboxylate binding pocket and may sterically block complex formation.