title: Structure-activity study of inhibition of amphotericin B (Fungizone) binding to sterols, toxicity to cells, and lethality to mice by esters of sucrose.
abstract: The effects of four monoesters of sucrose with different acyl chain lengths (palmitate, C16; myristate, C14; laurate, C12; and caprate, C10) on the aggregation state of amphotericin B (AmB), its binding to cholesterol and ergosterol, its toxicity to cells, and its lethality to mice were determined. In solution, all four of these esters inhibited AmB binding to cholesterol more than to ergosterol; this effect correlated with the ester-induced shift from the mainly aggregated form of AmB to the mainly monomeric form. In experiments with cells, the esters inhibited the toxicity of AmB to mouse erythrocytes and cultured mouse fibroblast L-929 cells more than its toxicity to Candida albicans cells. When injected intravenously with AmB, these esters decreased AmB lethality to mice. In all of these assays, the ester with the shortest chain length (caprate) was much less potent than the other three esters. Our results indicate a correlation between in vitro and in vivo assays and suggest that the in vitro and in vivo selectivity of AmB may be enhanced by surface-active agents which modulate the aggregation state of AmB.
authors.affiliation: Département de Chimie-Biologie, Université du Québec à Trois-Rivières, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Gruda
authors.forename: D
authors.initials: D
authors.lastname: Milette
authors.forename: M
authors.initials: M
authors.lastname: Brother
authors.forename: G S
authors.initials: GS
authors.lastname: Kobayashi
authors.forename: G
authors.initials: G
authors.lastname: Medoff
authors.forename: J
authors.initials: J
authors.lastname: Brajtburg
mesh_terms: D000666:Amphotericin B / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D004875:Ergosterol / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D004952:Esters / Q000494:pharmacology; D005260:Female; D006454:Hemoglobins / Q000378:metabolism; D007739:L Cells; D007928:Lethal Dose 50; D051379:Mice; D011188:Potassium / Q000378:metabolism; D013261:Sterols / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013395:Sucrose / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D004952:Esters; D006454:Hemoglobins; D013261:Sterols; C018152:sucrose monolaurate; C041567:sucrose monopalmitate; D013395:Sucrose; C068213:sucrose caproate; D000666:Amphotericin B; C068214:sucrose myristate; D002784:Cholesterol; D011188:Potassium; D004875:Ergosterol