Exploring a unique reactivity of 6II-azaelectrocyclization to enzyme inhibition, natural products synthesis, and molecular imaging : an approach to chemical biology by synthetic chemists
Exploring a unique reactivity of 6II-azaelectrocyclization to enzyme inhibition, natural products synthesis, and molecular imaging : an approach to chemical biology by synthetic chemists
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探索 6II-氮杂电环化对酶抑制、天然产物合成和分子成像的独特反应性：合成化学家的化学生物学方法
作者：
Tanaka;K.;Fukase;K.;Katsumura;S.
在阐明含赖氨酸的天然产物对水解酶的抑制机理时，我们发现了一个涉及由醛与赖氨酸残基生成的氮杂三烯的快速6π-氮杂电环化反应。环化前体1-氮杂三烯体系的电环化反应表现出取代基效应。结构-反应性研究表明，氮杂电环化，这通常在高温下以低收率进行，在室温下在不到5分钟内产生定量收率。采用不对称手性哌啶合成法和固相载体上吡啶类化合物的一锅法合成了吡啶/吲哚类天然产物。此外，我们还开发了基于6π-氮杂环化的生物分子和活细胞的赖氨酸标记和工程。1，4，7，10-四氮杂环十二烷-1，4，7，10-四乙酸（DOTA）作为金属螯合剂和荧光基团以及寡糖结构在10分钟内以低至10-8 M的浓度有效地和选择性地引入表面赖氨酸。DOTA标记的生长抑素和糖蛋白，然后用68 Ga辐射，受体介导的生长抑素在胰腺中的积累和寡糖依赖性循环驻留的糖蛋白首次通过microPET可视化。此外，我们成功地实现了非侵入性成像的荧光标记的淋巴细胞的运输，而N-聚糖工程化的淋巴细胞靶向肿瘤小鼠模型中的结肠癌;肿瘤靶向细胞因此使用我们的6π-氮杂电环化合成。
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 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 6π-azaelectrocyclization. Both 1, 4, 7, 10-tetraazacyclododecane-1, 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 68 Ga; 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 6π-azaelectrocyclization.