Pharmaceutical Chemistry and Formulation, Laboratory of Bioorganic chemistry
Development of new medicines and advanced biomedical materials based on
organic chemistry
1) Development of new synthetic method, 2) Optimization of synthetic procedure,
and 3) Evaluation of molecular functions, properties, and dynamic behaviors
Development of Grafting Polymerization Enabling Flexible Control of Glycan Chain Length and Glycosyl-Type Nanocarriers
Glycochemistry occupies a frontier position within the life sciences.
To date, numerous glycosyl donors have been developed, and synthetic strategies
have been proposed to selectively activate specific donors. However, the
synthesis of polysaccharide glycosides remains challenging, requiring considerable
effort and skilled techniques. On the basis of this background, we have
recently developed a polymerization technique enabling the straightforward
attachment of oligosaccharides on arbitrary skeleton: the glycan grafting
method. This method employs sugar-based cyclic sulfite as a monomer. When
an acid is applied in the presence of MS 3A, using the hydroxyl group on
the aglycone as the initiator, polymerization proceeds via SO₂ elimination,
yielding polysaccharide glycosides in a one pot (A in the figure above).
A further characteristic is that the sugar chain length can be freely controlled
by the ratio of initiator to monomer, demonstrating outstanding effectiveness
in the synthesis of physiologically active substance derivatives and functional
nanocarriers. Micelles composed of quercetin glycosides (B) encapsulate
guest molecules, and at high pH, the micelles collapse due to deprotonation
of the phenolic hydroxyl groups and ionic repulsion. The morphology of
self-assembled structures formed from α-galactosylceramide polysaccharide
glycosides (C) depends on the sugar chain length, forming micelles at N=0
and giant vesicles at N=2 to 6. It has been clarified that at N=1, micelle-vesicle
transition proceeds with temperature change.
Development of Alternating Copolymerization of Peptides and Exploration of the Function of Alternating Sequences
From the perspective of sustainable development goals, structural proteins have attracted significant interest as new materials for environmental recycling. For example, fibrin, the main component of silkworm silk which is stronger than steel; elastin and collagen, which form the flexible skin of vertebrates; and lecithin, a component of insect tendons exhibiting superelasticity surpassing natural rubber – all are known to possess repeating structures of specific amino acid sequences. This suggests that by rationally designing amino acid sequences and repeating them, it is possible to develop structural materials exhibiting diverse physical properties.
We observed that applying shear stress to peptides bearing bulky substituents induces strong adhesion (B). We found that stress induces the peptide to transform into an extended chain state; the relaxation of this extended chain structure is kinetically suppressed by the bulky substituents; and microfibres form along the stress direction. Their entanglement (physical cross-linking) results in strong adhesion between interfaces. Further research into rationally controlling peptide higher-order structures via external stimuli has also been pursued. By alternately arranging α-methylphenylalanine and α,α-dialkylamino acids, we have successfully developed a peptide-type folder that switches between a 310 helical structure and a planar C5 structure in response to solvent polarity changes (C).
Nitrile N-Oxide-based Molecular Ligation Tools
We are developing various nitrile N-oxide-based ligation tools that enable the catalyst-free ligation between high-molecular-weight building blocks. Nitrile N-oxides are highly reactive 1,3-dipoles that undergo 1,3-dipolar cycloaddition reactions with various unsaturated bonds without catalysis. However, their high reactivity renders them chemically unstable, making isolation difficult. Conversely, introducing bulky substituents around the nitrile N-oxide thermodynamically suppresses decomposition reactions, enabling stable isolation. We have developed stable nitrile N-oxide reagents including: i) homoditopic nitrile N-oxides, ii) orthogonal agents, iii) polymer nitrile N-oxide agents, iv) water-repellent agent, and v) fluorescent probes. We report on the catalysis-free reactions of organic macromolecules and the functionality of synthetic molecules using these reagents (see figure below).
