天然物によるタンパク質不活性化機構に学ぶ６π‐アザ電子環状反応の新奇反応性と天然物合成および合成化学生物学への展開

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概要

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• Biosystems at the molecular level consist of numerous organic reactions. Thus, it is possible that we completely miss unknown reactions and/or their reactivities; the author envisioned a new strategy for useful chemical transformations, including applications to the natural products synthesis. In addition, such synthetic investigations could lead to the accumulation of many reactivity profiles, which may provide feedback to better understand biosystems. In the last decade, we have focused on concerted 6π-azaelectrocyclization, which is a “traditional and old”, but not “widely utilized” reaction. In this personal account, the author provides a brief review on how we discovered the new reactivity profile of azaelectrocyclization, how we applied this discovery to natural products synthesis, and how we eventually used feedback from the reaction to visualize in vivo dynamics of biomolecules and living cells as well as to establish methods for clinical and pharmaceutical applications; we offer a unique category in synthetic chemical biology.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 cyclized 1,2-dihydropyridine quantitatively 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 and engineering of biomolecules and living cells based on the rapid 6π-azaelectrocyclization. Both DOTA as a metal chelating agent and fluorescent groups, as well as oligosaccharide structures were introduced efficiently and selectively into surface lysines within 10 min 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 artificial cells were thus synthesized using the author’s 6π-azaelectrocyclization.

著者

• 田中 克典

  大阪大学大学院理学研究科

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• 天然物によるタンパク質不活性化機構に学ぶ６π‐アザ電子環状反応の新奇反応性と天然物合成および合成化学生物学への展開

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