遺伝子指向性ケージド化合物の開発と光薬理学への展開

抄録

Photoresponsive molecules can be used to manipulate the physiological functions of cells with high spatiotemporal resolution. Caged compounds are photoresponsive molecules designed to temporarily mask their original biological activity through covalently bound photoremovable protecting groups. The introduction of additional properties into caged compounds without compromising photosensitivity would help expand the repertoire of caging groups. Therefore, we designed a modular caged compound consisting of three parts: a photoresponsive core, a chemical handle to introduce additional functionalities, and a molecule to be masked. We designed two modular precursors, NHS-Bhc-diazo, for caged phosphates and paBhcmoc-X, for caged alcohols and amines. NHS-Bhc-diazo was successfully applied to the synthesis of affinity-purifiable caged dsDNA with biotin tags. The modular precursor paBhcmoc-X was used to prepare a new water-soluble caged anticancer agent with improved photochemical properties. One of the barriers to the in vivo use of conventional caged compounds is that the caged compounds are not genetically encoded and cannot target the cells of interest. To overcome these limitations, we demonstrated the concept of gene-directed caged compounds that can be photoactivated with cell-type selectivity. We designed and synthesized new caged cyclic nucleotides as proof of concept. Photo-mediated release of the parent nucleotide was observed only in live mammalian cells expressing Escherichia coli β-galactosidase. As cells or tissues can be genetically tagged by an exogenously expressed enzyme, this new method can serve as a strategy for adding targeting abilities to photocaged compounds.