Concise Synthesis of Tunicamycin V and Discovery of a Cytostatic DPAGT1 Inhibitor
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1.
California Institute of Technology
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.
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.Attached Files
Supplemental Material - anie202203225-sup-0001-misc_information.pdf
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Additional details
- Eprint ID
- 114878
- DOI
- 10.1002/anie.202203225
- Resolver ID
- CaltechAUTHORS:20220523-165005000
- PMCID
- PMC9329268
- NIH
- R01GM114611
- University of Tennessee Health Science Center
- R079700292
- Ministerio de Ciencia, Innovación y Universidades (MCIU)
- RTI2018-098296-B-I00
- NIH
- R01 CA229164
- Created
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2022-05-23Created from EPrint's datestamp field
- Updated
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2022-08-12Created from EPrint's last_modified field