期刊
SYNLETT
卷 -, 期 15, 页码 2115-2139出版社
GEORG THIEME VERLAG KG
DOI: 10.1055/s-0030-1261192
关键词
synthetic (chemical) biology; 6 pi-azaelectrocyclization; enzyme inhibition; lysine; natural products synthesis; chiral piperidine; pyridine; labeling; PET (positron emission tomography); fluorescence; glycoproteins; lymphocytes; cell surface engineering; tumor targeting
资金
- Japan Society for the Promotion of Science [19681024, 19651095]
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) [16073222]
- New Energy and Industrial Technology Development Organization (NEDO) [07A01014a]
- Yamada Science Foundation
- Grants-in-Aid for Scientific Research [22550160, 23681047, 21651096, 23241074, 21106008, 22106541] Funding Source: KAKEN
While elucidating the inhibitory mechanism of a hydrolytic enzyme by aldehyde-containing natural products, we discovered a reaction involving a rapid 6 pi-azaelectrocyclization of azatrienes generated from aldehyde with lysine residues. The electrocyclic reaction of the 1-azatriene system, a cyclization precursor, exhibited a substituent effect. Structure-reactivity studies showed that azaelectrocyclization, which usually proceeds in low yield at high temperatures, produced a quantitative yield in less than 5 minutes at room temperature. Asymmetric chiral piperidine synthesis and a one-pot library synthesis of pyridines on solid supports were applied to synthesize pyridine/indole alkaloid-type natural products. Additionally, we developed lysine-based labeling and engineering of biomolecules and living cells based on the rapid 6 pi-azaelectrocyclization. Both 1,4,7,10-tetraazacyclododecane1,4,7,10- tetraacetic acid (DOTA) as a metal chelating agent and fluorescent groups, as well as oligosaccharide structures were introduced efficiently and selectively into surface lysines within 10 minutes at concentrations as low as 10-8 M. The DOTA-labeled somatostatin and glycoproteins were then radiometallated with 68Ga; the receptor-mediated accumulation of somatostatin in pancreas and the oligosaccharide-dependent circulatory residence of glycoproteins were visualized by microPET for the first time. Furthermore, we succeeded to image the trafficking of the fluorescence-labeled lymphocytes noninvasively, while the N-glycan-engineered lymphocytes targeted the colon carcinoma in tumor mouse model; the tumor-targeting cells were thus synthesized using our 6 pi-azaelectrocyclization.
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