Synthesis of a novel ether-bridged GM3-lactone analogue as a target for an antibody-based cancer therapy.
We describe herein the synthesis of a new analogue of the GM3-lactone containing a cyclic ether moiety. The ether moiety was chosen as a replacement for the regular lactone group since it shows high resemblance with the lactone and is completely stable under biological conditions. The cyclic ether moiety was formed by reduction of the corresponding lactone to give the lactol followed by formation of the S,O-hemiacetal and hydrogenation. In addition, we have prepared haptens with a hexanoic acid moiety, which can be used for the preparation of poly- and monoclonal antibodies after binding to BSA or KLH. This is the first example of an analogue of the GM3-lactone which is stable under hydrolytic conditions in vitro and probably also in vivo. Reaction of lactone 18 with a Red/Al derivative led to the lactol 19 which was transformed into the S,O-hemiacetal 20 using 2,2'-bis(pyridinium) disulfide in quantitative yield. Hydrogenation with Raney Nickel gave 21 from which after removal of the protecting group at C-1a the trichloroacetimidate 25 was prepared. Reaction with azidosphingosine to give 26 followed by reduction of the azido group with NHEt3+[(PhS)3Sn], acylation with stearic acid using EDC and removal of the protecting groups led to the desired ether analogue of GM3 lactone 4. In addition the trichloroacetimidate 25 was glycosidated with 6-hydroxyhexanoic acid methyl ester, which was deprotected to give 29. The compound will be used for the preparation of poly- and monoclonal antibodies after coupling with BSA and KLH.
Tietze
L F
LF
Institute of Organic Chemistry of the Georg-August-Universität, Göttingen, Germany. ltietze@gwdg.de
Keim
H
H
Janssen
C O
CO
Tappertzhofen
C
C
Olschimke
J
J
D000970:Antineoplastic Agents; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D004987:Ethers; D005679:G(M3) Ganglioside / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D006433:Hemocyanins; D007167:Immunotherapy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D012710:Serum Albumin, Bovine
D000970:Antineoplastic Agents; D004987:Ethers; D005679:G(M3) Ganglioside; D012710:Serum Albumin, Bovine; D006433:Hemocyanins; C047143:ganglioside GM3 lactone; C032808:keyhole-limpet hemocyanin