Concise Synthesis of Tunicamycin V and Discovery of a Cytostatic DPAGT1 Inhibitor.
Concise Synthesis of Tunicamycin V and Discovery of a Cytostatic DPAGT1 Inhibitor.
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DOI：
10.1002/anie.202203225
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发表时间：
2022-08-01
影响因子：
16.6
通讯作者：
Kurosu, Michio
中科院分区：
文献类型：
--
作者：
Mitachi, Katsuhiko;Mingle, David;Effah, Wendy;Sanchez-Ruiz, Antonio;Hevener, Kirk E.;Narayanan, Ramesh;Clemons, William M., Jr.;Sarabia, Francisco;Kurosu, Michio
衣霉素V（1）是一种非选择性磷酸转移酶抑制剂，通过Büchner-Curtius-Schlotterbeck型反应实现短时间全合成。以D-半乳糖醛为起始原料经15步反应合成衣霉素V，总收率21%。所建立的合成方案在操作上非常简单，并且可以灵活地引入感兴趣的结构单元。所设计的类似物28之一对人长叶醇-磷酸N-乙酰葡糖胺磷酸转移酶1（DPAGT 1）的抑制活性显示为1的12.5倍。虽然衣霉素是具有低选择性的细胞毒性分子，但新的类似物28显示出对乳腺癌细胞系（包括三阴性乳腺癌）的选择性细胞生长抑制活性。Büchner-Curtius-Schlotterbeck型反应使衣霉素V（TN-V），一种非选择性磷酸转移酶抑制剂，从D-半乳糖醛，在21%的总收率仅15个步骤的总合成。短而高产的合成路线也适用于类似物的合成，从而导致发现一种新的细胞抑制衣霉素类似物，TN-TMPA，具有高DPAGT 1选择性。
A short total synthesis of tunicamycin V (1), a nonselective phosphotransferase inhibitor, is achieved via a Büchner-Curtius-Schlotterbeck type reaction. Tunicamycin V can be synthesized in 15 chemical steps from D-galactal with 21% overall yield. The established synthetic scheme is operationally very simple and flexible to introduce building blocks of interest. The inhibitory activity of one of the designed analogues 28 against human dolichyl-phosphate N-acetylglucosaminephosphotransferase 1 (DPAGT1) shows 12.5-times greater than 1. While tunicamycins are cytotoxic molecules with a low selectivity, the novel analogue 28 displays selective cytostatic activity against breast cancer cell lines including a triple-negative breast cancer. A Büchner–Curtius–Schlotterbeck-type reaction enabled the total synthesis of tunicamycin V (TN-V), a nonselective phosphotransferase inhibitor, in just 15 steps from D-galactal in 21% overall yield. The short and high-yielding synthetic route was also adapted for the synthesis of analogues, thus leading to the discovery of a novel cytostatic tunicamycin analogue, TN-TMPA, with high DPAGT1 selectivity.
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