Concise Synthesis of Tunicamycin V and Discovery of a Cytostatic DPAGT1 Inhibitor.

Abstract

A short total synthesis of tunicamycin V (1), a non-selective 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) is 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.

• Authors: Katsuhiko Mitachi, David Mingle, Wendy Effah, Antonio Sánchez-Ruiz, Kirk E Hevener, Ramesh Narayanan, William M Clemons Jr, Francisco Sarabia, Michio Kurosu
• Journal: Angewandte Chemie (International ed. in English) (Angew Chem Int Ed Engl) Vol. 61 Issue 31 Pg. e202203225 (08 01 2022) ISSN: 1521-3773 [Electronic] Germany
• PMID: 35594368 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2022 Wiley-VCH GmbH.

Chemical References

• Antineoplastic Agents
• Cytostatic Agents
• Tunicamycin

Topics

• Antineoplastic Agents (pharmacology)
• Cytostatic Agents
• Humans
• Tunicamycin (chemistry, pharmacology)