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首页> 外文期刊>Chemistry: A European journal >Synthesis of a Novel Ether-Bridged GM3-Lactone Analogue as a Target for an Antibody-Based Cancer Therapy
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Synthesis of a Novel Ether-Bridged GM3-Lactone Analogue as a Target for an Antibody-Based Cancer Therapy

机译：合成新型以醚桥联的GM3-内酯类似物作为基于抗体的癌症治疗的靶标

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We describe herein the synthesis of a new analogue of the GM3-lactone containing a cyclic ehter 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 ehter 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 antiboides after binding to BSA or KLH. This is the first exampie of an analogue of the GM3-lactone which is stable under hydorlytic conditions in yitro an dprobably 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 yiled. Hydorgenation with Raney Nickel gave 21 from which after removal of the protecting group at C-1a the trichloroacetimidete 25 was prepared. Reaction with azodosphingosine to give 26 followed by reduction of the azido group with NHEt_3 ~+[PhS)_3Sn], acylation with stearic acid using EDC and removal of the protecting groups led to the desired ether analougue 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.
机译：我们在本文中描述了含有环状ehter部分的GM3-内酯的新类似物的合成。选择醚部分作为常规内酯基团的替代物，因为它与内酯高度相似并且在生物学条件下完全稳定。通过还原相应的内酯以形成内酯，然后形成S，O-半缩醛和氢化来形成环状醚部分。此外，我们还制备了具有己酸部分的半抗原，可将其与BSA或KLH结合后用于制备聚和单克隆抗体。这是GM3-内酯类似物的第一个例子，其在水溶条件下既在体内也可能在体内稳定。内酯18与Red / Al衍生物的反应产生了内酯19，其使用定量收率的2，2′-双（吡啶鎓）二硫化物转化为S.O-半缩醛20。用阮内镍（Raney Nickel）加氢得到21，从中除去C-1a的保护基后，制得三氯乙酰亚胺25。与偶氮鞘氨醇反应得到26，然后用NHEt_3〜+ [PhS）_3Sn]还原叠氮基，使用EDC与硬脂酸酰化并除去保护基团，从而得到所需的GM3内酯4醚类似物。用6-羟基己酸甲酯对25进行糖基化，将其去保护得到29。与BSA和KLH偶联后，该化合物将用于制备多抗体和单克隆抗体。

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