Structure Revision of Trichomide D by Total Synthesis
Structure Revision of Trichomide D by Total Synthesis
复制标题
全合成对 Trichomide D 进行结构修正
DOI：
10.1021/acs.jnatprod.2c00440
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发表时间：
2022
影响因子：
5.1
通讯作者：
Kigoshi Hideo
中科院分区：
文献类型：
--
作者：
Yoshida Masahito;Matsushita Tomoya;Kondo Shinji;Isoda Hiroko;Kigoshi Hideo
通过全合成对毛滴虫D进行了结构修正。空间位阻肽序列成功地制备，不仅使用传统的酰胺化与EDCI，但也耦合与Fmoc保护的氨基酸氯化物衍生物。环化前体通过将四肽与酰基脯氨酸衍生物偶联并随后去除N-和C-末端的甲硅烷基来合成。使用MNBA/DMAPO进行大环内酯化，然后制备氯代醇部分，得到了拟毛滴虫D的结构，其光谱与天然产物的光谱不相同。最后，通过全合成，我们成功地阐明了TrichomideD的真实结构，并修正了氯醇部分的绝对构型为S。通过MTT法评价了天然产物及其合成衍生物对MCF-7和HeLa S3细胞的细胞毒性，揭示了氯醇部分的构型是表现出对癌细胞的有效细胞毒性的关键因素。
A structure revision of trichomide D has been achieved by its total synthesis. The sterically hindered peptide sequence was successfully prepared using not only a conventional amidation with EDCI but also coupling with an Fmoc-protected amino acid chloride derivative. The cyclization precursor was synthesized by coupling of a tetrapeptide with an acylproline derivative and subsequent removal of silyl groups at the N- and C-termini. Macrolactonization using MNBA/DMAPO followed by preparation of a chlorohydrin moiety furnished the proposed structure of trichomide D, whose spectra were not identical to those of the natural product. Finally, we succeeded in the elucidation of the true structure of trichomide D by its total synthesis, and the absolute configuration of the chlorohydrin moiety was revised to beS. The cytotoxicities of the natural product and its synthetic derivatives against MCF-7 and HeLa S3 cells were evaluated by the MTT method, revealing that the configuration of the chlorohydrin moiety is a pivotal factor for exhibiting potent cytotoxicity against cancer cells.