期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 61, 期 31, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202203225
关键词
Antimigration Effect; Cytostatic Activity; DPAGT1 Inhibitors; Total Synthesis; Tunicamycins
资金
- National Institute of General Medical Sciences of the National Institutes of Health [R01GM114611]
- UTRF (University of Tennessee Health Science Center) [R079700292]
- Ministerio de Ciencia, Innovacion y Universidades (Spain) [RTI2018-098296-B-I00]
- NCI [R01 CA229164]
- NIH Shared Instrumentation Grant
A short and flexible total synthesis of tunicamycin V and its analogues was achieved, and a novel analogue with selective cytostatic activity against breast cancer cells was discovered.
A short total synthesis of tunicamycin V (1), a non-selective phosphotransferase inhibitor, is achieved via a Buchner-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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