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

本文研究了拓扑司他丁衍生物的制备方法，包括以下两个部分：1）侧链2）环缩酚酸肽1）侧链的逆合成将侧链分成四个部分，并对各个部分的制备进行了考察，将2-壬酮与磷酸三乙酯反应生成α，β-不饱和酯，然后还原、氧化得到相应的醛。随后，醛的Wittig反应得到作为侧链的4，7-二甲基十四碳-2，4-二烯酸酯。2）环缩酚酸肽的制备将环缩酚酸肽拆分为三个氨基酸和β-内酯。通过固相合成将FmocSerOBut固定在树脂上，然后解封闭并与Fmoc-β-ala偶联。用FmocSerOBut重复相同的方法，最后用β-内酯重复。3）对步骤1）和步骤2）中制备的中间体进行了拓扑异构酶抑制活性测定，但其抑制活性比拓扑司他丁的活性弱，侧链与肽的偶联反应正在研究中。

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.