title: Synthesis and characterization of novel water soluble amphotericin B-arabinogalactan conjugates.
abstract: The coupling of amphotericin B (AmB), a water-insoluble antifungal agent, to arabinogalactan (AG) via an imine or amine bond was systematically investigated. AG was oxidized using potassium periodate, purified from the oxidizing agent using ion-exchange chromatography, and reacted with AmB to form the Schiff base. The Schiff base was reduced to the amine using borohydride. All reactions took place in aqueous media. The purification of the oxidized AG from the oxidizing agent was essential to prevent oxidative degradation of AmB at the coupling step. We investigated the effects of AmB to AG ratio, buffer type, and reaction pH on the reaction yield, molecular weight, conjugate activity against pathogenic yeast and hemolytic activity. The optimum coupling conditions were buffer borate 0.1 M, pH 11 at room temperature for 48 h. Lower toxicity in vivo was achieved by using low-pressure gel permeation chromatography and applying the solution of AmB-AG conjugate through a Sephadex column. Both amine and imine AmB-AG conjugates were soluble in water and exhibited improved stability in aqueous solutions as compared to the unbound drug. The conjugates showed comparable minimum inhibitory concentration (MIC) values against Candida albicans. The conjugates were about 60 times less hemolytic against sheep erythrocytes than the free drug, and about 40 times less toxic in BALB/c mice.
authors.affiliation: Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: T
authors.initials: T
authors.lastname: Ehrenfreund-Kleinman
authors.forename: T
authors.initials: T
authors.lastname: Azzam
authors.forename: R
authors.initials: R
authors.lastname: Falk
authors.forename: I
authors.initials: I
authors.lastname: Polacheck
authors.forename: J
authors.initials: J
authors.lastname: Golenser
authors.forename: A J
authors.initials: AJ
authors.lastname: Domb
mesh_terms: D000577:Amides / Q000737:chemistry; D000666:Amphotericin B / Q000138:chemical synthesis / Q000737:chemistry*; D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology; D002176:Candida albicans / Q000378:metabolism; D002845:Chromatography; D004912:Erythrocytes / Q000378:metabolism; D005685:Galactans / Q000138:chemical synthesis / Q000737:chemistry*; D006461:Hemolysis; D006863:Hydrogen-Ion Concentration; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D010100:Oxygen / Q000378:metabolism; D011134:Polysaccharides / Q000737:chemistry; D012756:Sheep; D013997:Time Factors; D014466:Ultraviolet Rays; D014867:Water / Q000737:chemistry
chemical_list: D000577:Amides; D000935:Antifungal Agents; D005685:Galactans; D011134:Polysaccharides; D014867:Water; D000666:Amphotericin B; D010100:Oxygen; C005653:arabinogalactan