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New strategy in synthetic biology: from enzyme inhibition and natural products synthesis to PET imaging by 6π‐azaelectrocyclization
Author(s) -
Tanaka Katsunori,
Fukase Koichi,
Katsumura Shigeo
Publication year - 2010
Publication title -
the chemical record
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.61
H-Index - 78
eISSN - 1528-0691
pISSN - 1527-8999
DOI - 10.1002/tcr.200900026
Subject(s) - chemistry , aldehyde , bioorthogonal chemistry , stereochemistry , combinatorial chemistry , biochemistry , click chemistry , catalysis
While elucidating the inhibitory mechanism of a hydrolytic enzyme by aldehyde‐containing natural products, we discovered a reaction involving a rapid 6π‐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 min 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 of biomolecules based on the rapid 6π‐azaelectrocyclization. Both DOTA as a metal chelating agent (either for MRI, PET, or other radiopharmaceutical purposes, e.g., SPECT with gamma emitters) as well as fluorescent groups were introduced efficiently and selectively into lysine residues within 10 min at concentrations as low as 10 −8  m. The DOTA‐labeled somatostatin and glycoproteins were then radiometallated with 68 Ga to observe the receptor‐mediated accumulation of somatostatin in pancreatic tissue. Furthermore, microPET visualized the oligosaccharide dependent circulatory residence of glycoproteins for the first time. © 2010 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 10: 119–139; 2010: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.200900026

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