Synthesis of novel fatty-acyl gratisin derivatives.
To find candidates with high antimicrobial and low hemolytic activities, many gratisin (GR) analogues have been designed and synthesized. In the present account, we synthesized novel derivatives of GR having both the polycationic and fatty acyl groups, cyclo{-Val(1)-Orn(2)-Leu(3)-D-Phe(4)-Pro(5)-D-Lys(6)(X)-Val(7)-Orn(8)-Leu(9)-D-Phe(10)-Pro(11)-D-Lys(12)-} {X=-CO(CH(2))(6)CH(3) (1), -Lys-CO(CH(2))(6)CH(3) (2), -(Lys)(2)-CO(CH(2))(6)CH(3) (3), and -(Lys)(3)-CO(CH(2))(6)CH(3) (4)}, and examined the biological activities. Among them, we found that 2-4 have differential ionic interaction against the prokaryotic membrane and eukaryotic membrane. In other words, the dissociation with high antimicrobial activity and low hemolytic activity is caused by the addition of D-Lys(6)-{(Lys)(n)-CO(CH(2))(6)CH(3)} residues at position 6 of [D-Lys(6,12)]-GR. Our findings should be helpful in finding drug candidates with high antimicrobial activity and low hemolytic activity that are capable of combating microbial resistance.
Department of Chemistry, Toho University, Funabashi, Chiba, Japan.
Makoto
M
Tamaki
Takuji
T
Harada
Kenta
K
Fujinuma
Kazumasa
K
Takanashi
Mitsuno
M
Shindo
Masahiro
M
Kimura
Yoshiki
Y
Uchida
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D006461:Hemolysis; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry
D000900:Anti-Bacterial Agents; D010456:Peptides, Cyclic; C033282:gratisin