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HOME > No.6, Sep 2016 > Feature Story :How organic chemistry can contribute to society

How organic chemistry can contribute to society

Applications of recent advances in research, such as in drug discovery and pesticide detection

Seiji Iwasa

Professor Iwasa’s research involves studying and synthesizing organic compounds and devising ways to use those compounds in the fields of medicine and health, such as molecular sensors. Specifically, he extracts various organic compounds produced in nature and determines their molecular structures, and synthesizes useful biologically active compounds by freely manipulating the bonds of organic compounds. As synthesizing useful organic compounds with complicated molecular structures in large batches quickly can be helpful in areas such as drug discovery and food safety, this high-profile field of research has been widening its scope of applications in recent years.

Interview and report by Interview and report by Madoka Tainaka

Determining the structures of natural products and achieving total synthesis

Professor Seiji Iwasa became interested in the world of organic compounds as a result of his fascination with the miraculous properties of medicinal herbs and other natural products. After that point, guided by his curiosity, he worked toward becoming a researcher in natural products chemistry.

Professor Iwasa says, “Just as Ninjas once used aconite poison as a weapon by wiping it on the tips of their Shuriken, there are many surprising natural products in this world that can take a person’s life even when used in tiny quantities. However, aconite also has beneficial cardiotonic and analgesic effects, and thus has long been used as a medicine as well. That shows that even poison can be a medicine if used properly. Nevertheless, in order to use such products effectively, we need to understand their structures and functions. It is the mission of organic chemists to make these products useful by reproducing them synthetically, a process which is called ‘total synthesis’.”

Collaborative Research Project on Machine Translation

At that time, Professor Iwasa was working on the total synthesis of strychnine, an extremely toxic alkaloid. The molecular structure of strychnine was uncovered in the mid-20th century after a century of effort. After that discovery, R.B. Woodward et al. succeeded in completing the synthesis of strychnine in 29 steps. Professor Iwasa and his team successfully shortened the process by more than half, to just 12 steps. This was in 1994.

“The method we used is called retrosynthetic analysis, and it involves exploring how to synthesize a substance by breaking down the synthetic process step-by-step while analyzing the molecular structure. This method allowed us to more easily synthesize strychnine. This field deals with molecules, which have a three-dimensional form. Because of this, it requires big leaps in topological thinking and mathematical sense. That is why this research is so thrilling to me,” says Professor Iwasa.

Catalytic asymmetric reactions: A promising tool for drug discovery

In order to seriously investigate the methodology for further shortening and simplifying the process of total synthesis, Professor Iwasa is currently focusing his efforts on the development of catalytic asymmetric synthesis. Asymmetric synthesis is a method of synthesizing optical isomers, which has come to be used in the development of most drugs in recent years.

Professor Iwasa explains the concept. “An optical isomer is a compound that cannot be superimposed on its opposite compound, like a human’s right and left hands. In essence, it is a mirror image of a substance. In the case of most optical isomers, the right-handed one has a therapeutic effect, whereas the left-handed one is toxic. Even though the substances look the same, they have completely opposite physiological properties.”

One well known example of this is thalidomide. Thalidomide, a drug developed as a hypnotic and sedative, caused a global tragedy in 1957 due to the toxicity of one of its isomers, which caused the children of mothers who took the drug while pregnant to be born with limb malformations. When normal methods of synthesis are used, both the right-handed and left-handed optical isomer are produced at the same time. Essentially, this tragedy occurred because both isomers were present in the drug. Therefore, in order to safely use an optical isomer as a drug, it is necessary to skillfully produce just the isomer with the useful properties. This can be done by asymmetric synthesis.

Professor Iwasa

Professor Iwasa developed a method for performing these reactions using an unstable carbene intermediate and an organometallic complex. This acts as a highly active catalyst because of the electrical properties of the metal. When this is combined with the asymmetric environment of the organic ligand, just one optical isomer of the substance is produced selectively. This is what is called a ‘catalytic asymmetric reaction’. Actually, the first person to use a metallic complex as a catalyst in asymmetric reactions was Dr. Ryoji Noyori, who won the Nobel Prize in Chemistry in 2001.

“To give an analogy, an asymmetric reaction is like setting out a glove that will only fit the left hand, so that it will only recognize the left hand. For example, a substance called chrysanthemic acid that is used in mosquito coils is also an optical isomer, and is efficiently synthesized through an asymmetric reaction catalyzed by metal. The trick is that using a complex formed from an organic metal with high electron density and a highly configurable ligand as a catalyst makes it easy to control the reaction.”

In recent years, Professor Iwasa has also incorporated computer science into his research. He has started a project to explore reaction mechanisms regulated at different intensities by analyzing reaction mechanisms through simulations. He has also branched out to working on making catalysts non-toxic after use in chemical reactions.

“I believe that my job is to create new fields within organic chemistry and to keep expanding their reach.”

A wide scope of work ranging from molecular sensors to development of drug substances

One of Professor Iwasa’s achievements, that exemplifies the wide-ranging scope of his research, is his project to develop a kit for testing for residual pesticides using immunochromatography. He worked on this project as part of the Food Safety Technology Project, one of the core research projects of Knowledge Hub Aichi, which is run by the Aichi prefectural government. It involves the simple detection of residual pesticides by employing antibody reactions, which are part of organisms’ immune systems, a field of study quite different from total synthesis.

“Testing devices have conventionally been large and expensive, require trained specialists to operate, and take a long time to run tests. Our goal for this project was to develop a low-cost system that is convenient and fast to use in places such as manufacturing plants and overseas. That is why we turned our attention to organismal immune systems.”

However, pesticide molecules are too small to elicit an immune response without alteration. Therefore, Professor Iwasa made the pesticide molecules bigger by attaching a massive protein extracted from shellfish, and experimented by injecting those molecules into mice. The mice recognized the molecules as foreign bodies and produced countless antibodies. Antibodies against the pesticide are sorted out from amongst those antibodies and fused to detoxified cancer cells to promote proliferation. Essentially, Professor Iwasa made antibodies against pesticides proliferate endlessly by exploiting the properties of cancer cells.

“When antibodies produced in this way are planted onto gold colloid, which acts as an antibody label, and a solution containing the pesticide is run across it, an immune response is elicited. This kit determines the concentration of pesticide by measuring absorbance,” Professor Iwasa explains.

He has created two different kits; a kit like a pregnancy test for simple visual confirmation, and a quantitative kit that uses optical equipment, so that they can be used for different purposes. He says that he is now working on how to make these into products.

In addition to this work, he has developed a method for extracting a useful substance from Melaleuca leaves in a joint project with Ho Chi Minh City University of Technology in Vietnam. This substance is already being used as a drug substance. Professor Iwasa says that while conducting this research, he traveled by canoe into Vietnamese forests with thick-growing Melaleuca groves.

“Curiosity has always been what has driven my research. As long as I have curiosity, I can go anywhere. Even still, I felt a bit scared in the forest in Vietnam.” It seems that Professor Iwasa’s curiosity still has no limit.

Reporter's Note

After finishing his degree at Chiba University, young Professor Iwasa wrote letters to research institutions all over the world telling them of his desire to pursue the study of organic chemistry. He got his first response from the University of Ohio, despite having no connections there. He then went to the United States, where he achieved several research accomplishments, including the synthesis of strychnine, and later got an offer from the University of Chicago. This moment made him feel how open-minded Americans are and how strong their researcher network is.

In order to return the favor, Professor Iwasa is making an active effort to recruit international students. Students from eight different countries, including China, Mongolia, Laos, and Malaysia, are currently working with him in his laboratory.

“Learning about the world like that has reminded me of what is good about Japan. I want to bring good aspects of Japan such as its advanced technological capabilities, strong morality, and respect for the environment to the rest of the world. To that end, I am currently engaged in Japanese language education in Asia as well,” says Professor Iwasa.

His curiosity is extending beyond his research to education and the environment as well.

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Researcher Profile

Dr. Seiji Iwasa

Dr. Seiji Iwasareceived Ph.D. degree in Engineering from Chiba University in 1991. After getting his Ph.D., he was engaged in research as Post Doctoral Research Associates in Ohio State University, University of Chicago, and ERATO respectively. Currently, Dr. Iwasa is a professor in Department of Environmental and Life Sciences at Toyohashi University of Technology. His research interests are asymmetric synthesis, carbene, diazo compound, natural product, and so on.

Reporter Profile

Madoka Tainaka

Madoka Tainaka is a freelance editor, writer and interpreter. She graduated in Law from Chuo University, Japan. She served as a chief editor of “Nature Interface” magazine, a committee for the promotion of Information and Science Technology at MEXT (Ministry of Education, Culture, Sports, Science and Technology).