Structure-Activity-Relationship of Topostatin Derivatives with Cyclic Peptide as Topoisomerase Inhibitor

从两个片段上研究了topostatin衍生物的制备：1)侧链2)环状沉积肽。1)侧链的反合成侧链分成4个片段，检查各部分的制备是否连通性。2-壬烷酮与三乙基磷酸乙酯反应得到α，β-不饱和酯，然后还原氧化生成相应的醛。随后，醛的Wittig反应得到4,7-二甲基四十四-2,4-二烯酯作为侧链。研究了该酯与受保护的6-溴-3-羟基辛酸衍生物的偶联反应生成酮类化合物。2)环沉积肽的制备环沉积肽分为三个氨基酸和β-内酯。通过固相法将Fmoc-β-ala与Fmoc-β-ala进行解封偶联，固定树脂。同样的方法用fmocserbut重复，最后用β-内酯重复。检测了c端和羟基的内酯化。3)对工艺1)和工艺2)制备的中间体进行拓扑异构酶抑制活性测定，发现其抑制活性较topostatin弱。研究了侧链与肽的偶联反应。

The preparation of topostatin derivatives was studied on the following two fragments: 1) the side chain 2) the cyclic depsipeptide.1) Retrosynthesis of the side chainThe side chain were divided to four fragments and the preparations of each parts were examined to link together.Reaction of 2-nonanone with ethyl triethylphosphoate gave α,β-unsaturated ester followed by reduction and oxidation to afford the corresponding aldehyde. Subsequently, Wittig reaction of aldehyde gave 4,7-dimethyltetradeca-2,4-dienoic ester as the side chain. The coupling reaction of the ester with protected 6-bromo-3-hydroxyoctanoic acid derivatives was examined to form the keto compound.2) Preparation of cyclic depsipeptideThe cyclic depsipeptide was divided into three amino acids and β-lactone. By a solid state synthesis FmocSerOBut was fixed the resin followed by deblocking and coupling with Fmoc-β-ala. The same method was repeated with FmocSerOBut, and finally β-lactone. Lactonization of C-terminal and OH group was examined.3) The intermediates prepared in process 1) and 2) were assayed for topoisomerase inhibitory activities, but their activities were rather weak than that of topostatin.The coupling reactions of a side chain with a peptide are being investigated.