Dr. Yasuhiro Aoyama used to work on host-guest chemistry, and thereafter entered the area of molecular assembly with a couple of post(host-guest) paradigm shifts. One is direction of interactions, i.e., from convergent multiple interactions to give closed host-guest systems to divergent ones to allow molecular alignment control in open crystals for materials design. In particular, he carried out a series of crystal engineering work on orthogonal aromatic building blocks, that led to a number of new concepts and discoveries as highlighted by the unprecedented catalysis by microporous solid materials (organic zeolites).
The other is polarity of media, i.e., from apolar organic media to water for the construction of hydrogen-bonded molecular assemblies. There are many biological examples of finite macromolecular association driven by hydrogen bonding. In marked contrast, hydrogen bonding in artificial systems is believed to be effective only in apolar organic media.The work done by Dr. Aoyama using macrocyclic glycoclusters and related materials turned out to be such that filled this gap between natural and artificial systems, and provided important new insights into the use of hydrogen bonding in supramolecular architectures in water and their hierarchical size control, which led to the discovery of size-controlled gene delivery. Representative achievements of his are as follows.
1.Molecular Alignment Control and Organic Zeolites
A series of work on orthogonal aromatic building blocks, such as anthracene-resorcinol and anthracene-pyrimidine derivatives, led Dr. Aoyama to propose a general method to construct aromatic columns, including separate/alternate donor/acceptor columns, and guest-binding pores (cavities) in crystals with designable column dimension and pore size, respectively. Particular metal-coordinated, network materials easily obtained by a simple mixing method of the sol-gel type turned out to be truly microporous and capable not only of reversible guest sorption/desorption of the Langmuir type but also of catalysis in a number of Lewis acid-promoted reactions, where the materials served as readily recoverable and reusable, high-efficiency solid catalysts as a prototype of organic zeolites. The La3+-zeolite can be used even in water as a microporous enolase mimic for Aldol-type reactions.
He also presented evidence that (1) lattice inclusion complexation with collapse of hydrogen-bonded network upon guest removal follows the phase rule, (2) even a hydrogen-bonded network, when coordinatively saturated, could maintain cavities as such upon removal of included guest molecules, and (3) achiral building blocks could afford homochiral crystals whose chirality is governed by chance. Dr. Aoyama thus provided valuable new insights into such topics as hysteretic binding isotherms in lattice inclusion complexation, hydrogen-bonded porous network materials, and spontaneous chirality generation in crystals, which all are still subject to discussion and discrepancy.
2.Hydrogen-Bonded Architectures in Water and Formation of Glycoviruses
Challenging a general belief that hydrogen bonding is not effective in water, Dr. Aoyama took up a class of macrocyclic glycocluster compounds having eight saccharide moieties and four long alkyl chains on the opposite sides of the calixresorcarene macrocycle, and noticed their powerful hydrogen-bonding capability in water, as revealed by their facile adsorption on polar solid surfaces such as quartz and their agglutination with sodium phosphate as a paste. The hydrogen-bond-mediated (phosphate-P-O-•••H-O-sugar) glycocluster-phosphate complexation thus demonstrates that even "sugar" and "salt", typical water-soluble substances, could be engaged with each other by hydrogen bonding in water with dehydration as a driving force.
He was also able to show that the glycocluster forms micelle-like glycocluster nanoparticles, which stoichiometrically bind to DNA (plasmid DNA), followed by compaction of the resulting glyco-DNA conjugates to give size-regulated (∼50 nm) "glycoviruses", whose size (diameter) show a linear dependence on the cubic root of the size (base-pair length) of the DNA. He thus opened an important new area of hierarchical size control in the nanometric size range (101-102 nm) or, in other words, huge but finite molecular association. Finite macromolecular association is common in biology, but it has long been a missing area in artificial supramolecular assembly.
3.Size-Controlled Gene Delivery System
By using a series of saccharide-coated, and hence neutral, size markers which are thus subject to neither electrostatic nor hydrophobic effect, Dr. Aoyama showed that endocytic cellular uptake is most effective for matters with a viral size (∼50 nm). In this respect, current gene delivery technology using cationic gene carriers has a headache; the carrier-gene complexes often grow in size as a result of fusion and/or crosslink in a hard-to-predict manner. Dr. Aoyama showed that the cationic charge is not necessarily an essential factor by demonstrating that neutral but size-optimized glycoviruses can drive gene delivery as a result of size-allowed endocytosis. He further demonstrated that surface-rigidified cerasomes (ceramic-coated liposomes), free from otherwise facile gene-induced size growth by fusion, can be used as a high-efficiency, low-toxicity, and serum-compatible gene carrier, clearing revealing the remarkable size effect in gene delivery. From a physicochemical point of view, he set up experimental systems which allow separate or independent evaluation of respective contributions of the charge, size, and receptor factors, and was consequently able to introduce the structure-activity correlation analysis in otherwise complicated gene delivery processes, giving a new and potent tool of carrier design. Optimization of hepatocyte-targeting glycoviruses has been done along this line.
In summary, Dr. Aoyama, presenting breakthrough-making new concepts and new techniques, opened a new frontier area of molecular assembly with deep scientific insights and a physicochemical approach based on structure-activity correlation. His achievements, making a big impact not only in supramolecular chemistry but also in such chemistry-relevant areas as nanomaterials and bionanotechnology, has been receiving international reputation, and hence were judged to be worthy of Chemical Society of Japan Award.