Newly Synthesized Fungal Compound Can Switch on a Self-destruct Button for Cancer
Cancers cells use a special technique to propagate; they delete their “programmed death” gene through mutation, “forget” to die when their lifetime is over, and continue to grow instead. A research team from Tokyo University of Science has developed a method through which a fungal compound capable of rearming the self-destruct gene in certain cancer cells can be artificially produced in marketable quantities, providing a potential cancer therapeutic strategy.
All human body cells have a certain lifespan, during which they perform their essential duties. At the end of this lifespan, they reach senescence and—no longer able to perform those duties—die. This suicidal death is programmed into their genes through a process called apoptosis, causing them to self-destruct in order to make way for fresh, young, and healthy cells to replace them.
Mutations in a special gene called p53 can sometimes interfere with this process. Caused by aging, ultraviolet light, and various mutagenic compounds, these mutations can disable the apoptosis gene, resulting in “zombie” cells that refuse to die and continue to multiply, spreading the disabled gene and replacing healthy working cells with undying, rapidly growing tumors. This is the disease that we call cancer, and it takes many forms depending on which body cells develop the mutations.
Previously, scientists identified an anticancer compound called FE399 in a species of filamentous fungus called Ascochyta, which is often found afflicting common food crops such as cereals. The compound is a specific group of depsipeptides, a type of amino acid group, and was shown to induce apoptosis in cancerous human cells, particularly colorectal cancer, while they are still in vitro, proving its worth as an anti-cancer chemical.
Unfortunately, due to a variety of chemical complexities, the FE399 compound is not easy to purify, which hindered any plans for its widespread applications in cancer treatment. It was thus clear that extracting FE399 from the fungi naturally would not be a commercially feasible method, and despite the promise of a powerful anticancer drug, research into this particular compound was stalled.
The promise of a new anticancer treatment was tempting, however, and Prof Isamu Shiina, along with Dr Takayuki Tonoi, and his team from the Tokyo University of Science, accepted the challenge. “We wanted to create a lead compound that could treat colon cancer, and we aimed to do this through the total synthesis of FE399,” says Prof Shiina. Total synthesis is the process of the complete chemical synthesis (production) of a complex molecule using commercially available precursors, allowing mass production. The results of their extensive studies will be published in the European Journal of Organic Chemistry.
The team figured that first, the structure of the depsipeptide would need to be identified. This was simple and could be easily performed using commercially available and inexpensive materials. Following this simple start, the subsequent procedures required many steps and resulted in some small failures when isomers were unsuccessfully isolated.
However, the team was rewarded for their efforts when, in a major breakthrough, their mass spectrometry and nuclear magnetic resonance studies confirmed that a trio of spots on a plate showed identical chemical signature to the known formula of FE399, meaning that they were able to successfully recreate FE399 synthetically.
Their technique was found to have an overall yield of 20%, which is quite promising for future large-scale production plans. “We hope that this newly produced compound can provide an unprecedented treatment option for patients with colorectal cancer, and thus improve the overall outcomes of the disease and ultimately improve their quality of life,” states Prof Shiina.
Further research is needed to test the efficiency of FE399 in the treatment of other solid and blood-based cancers, and before mass production, the biological activities and structure of the FE399 molecule will need to be evaluated. But for now, the team from Tokyo University of Science are thrilled with their findings, and are positive that their research will help to improve treatments and therapies for patients with colorectal cancer.
Titles of original papers: Total Synthesis of the Antitumor Depsipeptide FE399 and its S-Benzyl derivative: A Macrolactamization Approach
Journal European Journal of Organic Chemistry
About The Tokyo University of Science
Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan's development in science through inculcating the love for science in researchers, technicians, and educators.
With a mission of “Creating science and technology for the harmonious development of nature, human beings, and society", TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today's most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.
About Professor Isamu Shiina from Tokyo University of Science
Professor Shiina is an expert in the field of Applied Chemistry. Having graduated from the Tokyo University of Science’s school of Applied Chemistry in 1990, he attained his master’s degree at the same university. Over his career, Professor Shiina has received eight major awards for his work and has completed six multi-year research projects in his field. Today he is the Director of the Research Institute for Science and Technology, Chemical Biology Division Supported by Practical Organic Synthesis at Tokyo University of Science.
This study was partly supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan.
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