Synthesis of a novel ether-bridged GM3-lactone analogue as a target for anantibody-based cancer therapy

We describe herein the synthesis of a new analogue of the GM3-lactone conta ining a cyclic ether moiety. The ether moiety was chosen as a replacement f or the regular lactone group since it shows high resemblance with the lacto ne and is completely stable under biological conditions. The cyclic ether m oiety was formed by reduction of the corresponding lactone to give the lact ol followed by formation of the S,O-hemiacetal and hydrogenation. In additi on, we have prepared haptens with a hexanoic acid moiety, which can be used for the preparation of poly- and monoclonal antibodies after binding to BS A 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) disul fide in quantitative yield. Hydrogenation with Raney Nickel gave 21 from wh ich after removal of the protecting group at C-1a the trichloroacetimidate 25 was prepared. Reaction with azidosphingosine to give 26 followed by redu ction of the azido group with NHEt3+[(PhS)(3)Sn], acylation with stearic ac id using EDC and removal of the protecting groups led to the desired ether analogue of GM3 lactone 4. In addition the trichloroacetimidate 25 was glyc osidated with 6-hydroxyhexanoic acid methyl ester, which was deprotected to give 29. The compound will be used for the preparation of poly- and monocl onal antibodies after coupling with BSA and KLH.