INSTITUTE FOR GLOBAL PROMINENT RESEARCH

CHEMICAL SCIENCE RESEARCHES FOR MOLECULAR THERAPEUTICS

INTEGRATING SYNTHETIC ORGANIC CHEMISTRY AND COMPUTATIONAL CHEMISTRY TO OPEN UP NEW FRONTIERS IN DRUG DISCOVERY

-Develop medical functional molecules for disease control based on the further technological advancement and integration of synthesis, design, and discovery of organic molecules
Research Keywords: Synthetic organic chemistry, Natural-product synthesis, Natural products chemistry, Computational chemistry, Infection control, Control of intractable diseases

“Pharmaceutical sciences” is a discipline that aims to understand the basic principles of unknown life science and natural science phenomena at the molecular level and to apply the fundamental scientific findings to drug discovery. Whether the target molecule is a small molecule, such as a drug, or a large molecule, such as RNA and an antibody, the research of pharmaceutical sciences is characterized by the step-by-step approach from chemically examining molecular interactions in the microscopic world that control the target phenomenon to the study of macroscopic phenomena, i.e., the understanding of pathological conditions and treatments. As the leader of this project, Tetsuhiro Nemoto, Professor at the Graduate School of Pharmaceutical Sciences, defines a discipline that aims to elucidate pathology and drug discovery in academia using organic molecules as “molecular therapeutics.” Among them, focusing on techniques related to organic chemistry, such as synthetic organic chemistry, natural products chemistry, computational chemistry, imaging chemistry, and in-silico drug design using computing technology, the professor has designated the research as “chemical scientific research for molecular therapeutics.” He launched a research network with scientists from the Graduate School of Pharmaceutical Sciences.

The network is involved in exploring a new research field that integrates organic chemistry and computational chemistry and working on the chemical synthesis of natural products, expected to be applied to drug discovery and on the development of diagnostic agents for nuclear medicine. The activities also include research on leading-edge pharmaceutical sciences, for example, fundamental research targeting infectious diseases and rare intractable diseases, by leveraging organic chemistry technologies accumulated in the network. In particular, drug discovery for infectious diseases and intractable rare diseases is an important project where research results from academia are anticipated because the two areas do not readily attract the interest of pharmaceutical manufacturers. Professor Nemoto and his team aim to create innovative molecules that will lead to drug discovery in academia by integrating the unique technologies of experts in each field based on the advancement of synthesis, design, and discovery technologies of organic molecules.

Supplying complex natural products through chemical synthesis

“If you ask me whether any synthetic chemist can synthesize complex molecules such as natural products, the answer is most definitely ‘No.’ The ability to utilize the techniques of chirality control and reaction development is a must. It is imperative to have a high level of skill and experience for designing the best synthetic strategy for any target structure,” says Professor Nemoto. Synthetic chemists with these skills gather here at the Graduate School of Pharmaceutical Sciences, Chiba University. The Laboratory of Pharmaceutical Chemistry, led by Professor Nemoto, has been developing novel synthetic methods for natural-product synthesis and new synthetic route design methods to improve the efficiency of natural-product synthesis.

Generally, molecules with three-dimensional structures are recognized as potentially excellent drugs. However, phenols and other aromatics with two-dimensional structures are very stable, and conversion to a three-dimensional structure by dearomatization reaction, which destroys aromaticity, is not an easy task. In 2010, he published a paper that revolutionized the conventional research concept in dearomatization reactions. As the accepted theory, substitution reaction between phenol and electron-deficient reactants using transition metal catalysts was considered to take place on oxygen atoms. However, he successfully generated ipso-substitution reactions on the aromatic ring, not on the oxygen atom, by precise reaction control. The innovative synthetic technique serves as a powerful tool for the construction of stereostructures of natural products by chemical synthesis and is extremely versatile in drug discovery. This paper was seen to inspire many researchers to pursue the field. This is indeed a true example of Columbus’ egg.

The synthesis of natural products is akin to climbing a mountain; there are many different routes to reach the goal. Which would be the most efficient? Which would finally force you to turn back en route to the summit. Usually, researchers have had to rely on their knowledge and experience to make such decisions. Working together with his core researchers, the team is investigating a new natural-product synthesis strategy for verifying the validity of synthetic routes by computer simulations, virtually designing the optimal synthesis method, and validating the results by experiments. This innovative approach is proving to be particularly effective in the synthesis of complex natural products. The team continues research to make it the standard for natural-product synthesis soon.

“If the technology advances to the stage where even complex molecules such as natural products can be easily synthesized in large quantities, it would undoubtedly expand options available for drug discovery research. I hope that our research network will serve as a venue for empirical research in this avenue,” says Professor Nemoto.

Members

Principal Investigator

Co-Investigatior