Chemical modification of beta-glucocerebrosidase inhibitor N-octyl-beta-valienamine: synthesis and biological evaluation of N-alkanoyl and N-alkyl derivatives.
Several N-alkanoyl 4a-d and N-alkyl derivatives 5a-g of the potent beta-glucocerebrosidase inhibitor N-octyl beta-valienamine (3) were synthesized in order to elucidate a role of hydrophobic portion in the inhibitory action. Although the former lacked inhibitory potency, the latter were strong beta-glucocerebrosidase inhibitors (cf. N-decyl-N-octyl-beta-valienamine 5d: Ki 6.6 x 10(-8) M). Furthermore, when being prescribed into mouse-derived B16 melanoma cells, N-butyl-N-octyl-beta-valienamine 5a and 5d were shown to change the amount of GlcCer and GM3, which suggests that they are possibly introduced into cells and influence glycolipids biosynthesis.
Ogawa
S
S
Department of Applied Chemistry, Faculty of Science & Technology, Keio University, Yokohama, Japan. ogawa@applc.keio.ac.jp
Kobayashi
Y
Y
Kabayama
K
K
Jimbo
M
M
Inokuchi
J
J
D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors*; D006595:Hexosamines / Q000737:chemistry* / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology; D051379:Mice; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D006595:Hexosamines; C116532:N-octyl-beta-valienamine; D005962:Glucosylceramidase