Total synthesis and biological activities of (+)-sulfamisterin (AB5366) and its analogues.
The first total synthesis of (+)-sulfamisterin (AB5366), a naturally occurring alpha-substituted alpha-amino acid derivative possessing a sulfonated hydroxy function, is described. Overman rearrangement of an allylic trichloroacetimidate derived from D-tartrate effectively generated the tetrasubstituted carbon containing a nitrogen substituent. Construction of the amino acid moiety and sulfonation of the hydroxy group, followed by deprotection completed the total synthesis, which fully confirmed the proposed absolute structure of the natural product. The possible stereoisomers of (+)-sulfamisterin and their desulfonated derivatives were also synthesized. Biological assessment of all synthetic compounds revealed that natural (+)-sulfamisterin and its 3-epimer as well as their desulfonated derivatives possessing 2S-configuration strongly inhibit the serine palmitoyl transferase both in vitro and in vivo, whereas compounds with 2R-configuration were found to show much weaker inhibitory activity.
Sato
Hideyuki
H
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Kohoku-ku, Yokohama 223-8522, Japan.
Maeba
Takaki
T
Yanase
Ryota
R
Yamaji-Hasegawa
Akiko
A
Kobayashi
Toshihide
T
Chida
Noritaka
N
D000217:Acyltransferases / Q000037:antagonists & inhibitors; D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D051102:Serine C-Palmitoyltransferase; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; C497029:sulfamisterin; D000217:Acyltransferases; D051102:Serine C-Palmitoyltransferase; D013110:Sphingosine