title: Fatty acyl-gramicidin S derivatives with both high antibiotic activity and low hemolytic activity.
abstract: In the present study, novel eight GS derivatives having the octanoyl-(Lys)(n)- moieties, cyclo{-Val-Orn-Leu-d-Phe-Pro(4β-NH-X)-Val-Orn-Leu-d-Phe-Pro-} {X=-H (1), and -(Lys)(n)-CO(CH(2))(6)CH(3)n=0 (2), 1 (3), 2 (4), and 3 (5)} and cyclo{-Val-Orn-Leu-d-Phe-Pro(4α-NH-X)-Val-Orn-Leu-d-Phe-Pro-} {X=-H (6), and -(Lys)(n)-CO(CH(2))(6)CH(3)n=1 (7), and 2 (8)} were synthesized. Among them, 4, 5 and 8 result the high antibiotic activity against both Gram-positive and Gram-negative microorganisms tested. In addition, 4 and 5 showed very low hemolytic activity compared with that of GS. Thus, the introduction of the excess amino groups and the fatty acyl moiety to the γ-NH(2) group of Pro(5) residue in GS molecule lowered the unwanted hemolytic activity and enhanced the desired antibiotic activity.
authors.affiliation: Department of Chemistry, Toho University, Funabashi, Chiba 274-8510, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tamaki
authors.forename: Kenta
authors.initials: K
authors.lastname: Fujinuma
authors.forename: Takuji
authors.initials: T
authors.lastname: Harada
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Takanashi
authors.forename: Mitsuno
authors.initials: M
authors.lastname: Shindo
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kimura
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Uchida
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001773:Blood Cells / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006096:Gramicidin / Q000031:analogs & derivatives*; D006461:Hemolysis / Q000187:drug effects*; D008239:Lysine / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D008956:Models, Chemical; D012756:Sheep; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D006096:Gramicidin; D008239:Lysine