Mitachi, Katsuhiko and Mingle, David and Effah, Wendy and Sánchez-Ruiz, Antonio and Hevener, Kirk E. and Narayanan, Ramesh and Clemons, William M., Jr. and Sarabia, Francisco and Kurosu, Michio (2022) Concise Synthesis of Tunicamycin V and Discovery of a Cytostatic DPAGT1 Inhibitor. Angewandte Chemie International Edition, 61 (31). Art. No. e202203225. ISSN 1433-7851. PMCID PMC9329268. doi:10.1002/anie.202203225. https://resolver.caltech.edu/CaltechAUTHORS:20220523-165005000
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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.
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| Additional Information: | © 2022 Wiley-VCH. Issue Online: 25 July 2022; Version of Record online: 10 June 2022; Accepted manuscript online: 20 May 2022; Manuscript received: 02 March 2022. Research reported in this publication was partially supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R01GM114611. M.K. thanks UTRF (University of Tennessee Health Science Center) for generous financial support (Innovation award R079700292). F.S. thanks Ministerio de Ciencia, Innovación y Universidades (Spain) for financial support (RTI2018-098296-B-I00). R.N. thanks NCI for financial support (R01 CA229164). NMR data were obtained on instruments supported by the NIH Shared Instrumentation Grant. M.K. would like to thank Dr. Michael McNeil (Colorado State University) for providing E. coli B21 WecA strain. The authors gratefully acknowledge Drs. Seok-Yong Lee (Duke) and Gustavo Miranda-Carboni (University of Tennessee Health Science Center) for providing purified DPAGT1 and the breast cancer cell lines, respectively. The authors declare no conflict of interest. Data Availability Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request. | ||||||||||||||
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| Subject Keywords: | Antimigration Effect; Cytostatic Activity; DPAGT1 Inhibitors; Total Synthesis; Tunicamycins | ||||||||||||||
| Issue or Number: | 31 | ||||||||||||||
| PubMed Central ID: | PMC9329268 | ||||||||||||||
| DOI: | 10.1002/anie.202203225 | ||||||||||||||
| Record Number: | CaltechAUTHORS:20220523-165005000 | ||||||||||||||
| Persistent URL: | https://resolver.caltech.edu/CaltechAUTHORS:20220523-165005000 | ||||||||||||||
| Official Citation: | Concise Synthesis of Tunicamycin V and Discovery of a Cytostatic DPAGT1 Inhibitor. K. Mitachi, D. Mingle, W. Effah, A. Sánchez-Ruiz, K. E. Hevener, R. Narayanan, W. M. Clemons, F. Sarabia, M. Kurosu, Angew. Chem. Int. Ed. 2022, 61, e202203225; Angew. Chem. 2022, 134, e202203225. | ||||||||||||||
| Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | ||||||||||||||
| ID Code: | 114878 | ||||||||||||||
| Collection: | CaltechAUTHORS | ||||||||||||||
| Deposited By: | George Porter | ||||||||||||||
| Deposited On: | 23 May 2022 22:20 | ||||||||||||||
| Last Modified: | 12 Aug 2022 17:46 |
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