Introduction

The field of organic chemistry was begun about 200 years ago in order to improve our understanding of life and living systems. Since then, it has maintained its centrality as a science bridging living systems and materials. The main substances comprising living things are organic molecules, and how these molecules behave within living systems can be understood through organic chemistry. Moreover, organic chemistry holds a unique place in science because it expands its own purview through the production of new organic molecules.

We are currently focusing on the creation of unique organic entities that control living systems through the following projects: 1) Development of reagents that add new function(s) to bioactive molecules; 2) Synthesis of probe molecules that can be used to understand the mode-of-action of bioactive molecules; 3) Development of synthetic strategies to construct unique organic skeletons based on new principles.

Past Research Projects

Total syntheses of natural products

Total synthesis is the chemical synthesis of a molecule, usually a natural product, from relatively simple starting materials (see “Classics in Total Synthesis: Targets, Strategies, Methods,” by K. C. Nicolaou and E. J. Sorensen, Wiley, 1996). We have been focusing on the synthesis of natural products having reactive polyene macrocycles and unique biological activity, as shown below.

Structure-activity relationship study of bioactive natural products

Based on the synthetic strategies developed in our total synthesis efforts, we clarified the structure–activity relationship (SAR) of bioactive natural products. In addition, we have developed a dual SAR strategy called TEG scanning, in which drug derivatives each having an amine-terminated tri(ethylene glycol) (NH2-TEG) linker at a peripheral position are systematically prepared and tested in both functional and binding assays.

Mode-of-action study of bioactive small molecules using synthetic probes

Target identification and mechanism-of-action studies of bioactive small molecules are important not only for fundamental biochemical researches but also for developing new drugs. We have prepared molecular probes for bioactive small molecules of interest and used them for target ID and mode-of-action researches.

Development of molecular fish hooks: Photo-cross-linked small molecule affinity matrixes

Target identification for a bioactive small molecule of interest is a crucial step in unraveling a mechanism of action. To identify these molecules, we sometimes utilize “molecular fishing hook” to fish out molecular target(s) (usually protein(s)) for a bioactive small molecule from a pool (pond) of cellular components. We have developed three generations of “molecular fish hooks” on which bioactive small molecules of interest (bait) can be set (or photo-cross-linked) using photochemistry.

Development of tools for molecular longline fishing: Photo-cross-linked small molecule microarrays

The molecular fish hooks developed above are used to fish out target protein(s) of a small molecule of interest from a mixture of cellular proteins. On the other hand, if we could arrange many fish hooks (i.e., a molecular longline) mounting a variety of bait (i.e., small molecules), the array could be used to determine which fish (i.e., protein of interest) prefers what bait. Thus, we have constructed a tiny chip on which an array of small molecules is immobilized using a photo-cross-linking reaction (i.e., small molecule microarray).

Development of screening systems for selection of exemplary substrates for cytochrome P450 enzymes

Cytochrome P450s are important enzymes for drug metabolism and biosynthesis of secondary metabolites. Recently, these enzymes have been modified to produce efficient and atom-economical catalysts for organic synthesis. However, generation of the active mutant enzymes mainly relies on random or saturation mutagenesis, since reliable knowledge of how substrate selectivity changes upon amino acid mutagenesis is still lacking. We have developed a screening system for the selection of exemplary substrates for a P450 enzyme of interest. By using this system, information about the relationship between amino acid mutations and substrate selectivity can be accumulated, and de novo design of P450 enzymes having desirable reactivities will be possible in the future.

Development of reagents that functionalize bioactive small molecules

Functionalization and modification of existing drugs are efficient strategies to generate new medicines and research tools. We have been developing reagents to introduce a functionalized propargyl group on aromatic rings or hydroxyl groups of bioactive small molecules. The reaction using a recently developed reagent proceeds under very mild conditions so that even sensitive aromatic compounds (which can seem as fragile as spun glass) can be functionalized. Propargyl groups possess a terminal or an internal alkyne, which can be used to couple with other molecules via click reaction or can be used as a reporter group for cellular localization.