06Research Center for Drug Discovery and Applied Sciences〜 Prospects for the development of cancer drugs that inhibit the growth of colorectal cancer and other forms of cancer caused by mutations of gene p53 〜In order to synthesize compounds with bioactivity that is similar to that of natural compounds, it is essential to clarify not only the molecular formula but also its structure and stereochemical properties. However, until now, the exact molecular structure of FE399 was unknown, even though the precise molecular formula was known. For that reason, the precise structure of FE399 and the establishment of a method for synthesizing it were long-awaited.Cancer is the leading cause of death in modern society. It is said that one in two men and one in three women will develop some form of cancer during their lives. This makes the development of new treatment techniques and new drugs an important social issue.FE399 is a novel natural compound (Fig. 1) that has been isolated from cultures of Ascochyta sp., which is a type of fungus. It has an inhibitory effect on the growth of various tumor cells, including human colorectal cancer cells. In particular, it is understood that some cells, including those of colorectal cancer, esophageal cancer, and breast cancer, come about due to a mutation of the p53 gene, which is a cancer suppressor gene. Thus, FE399 suppresses the growth of cancer cells formed by the p53 mutation by promoting apoptosis in them.The Synthetic and Pharmacological Activity Evaluation Groups at the Research Center for Drug Discovery and Applied Sciences, RIST, TUS have determined the structure of FE399 using a synthetic chemistry approach and has established a highly efficient route for the total synthesis of FE399 by using MNBA (2-methyl-6-nitrobenzoic anhydride), a rapid dehydration condensation agent that the university had previously developed, utilizing a three-stage key reaction (Fig. 2).We have clarified the molecular structure of FE399 and established a pathway for synthesis. This is expected to improve quality of life (QOL) in the treatment and prognosis of colorectal cancer and other forms of cancer.At present, the Research Center for Drug Discovery and Applied Sciences is evaluating bioactive compounds that were seen during the synthesis of FE399. We are also testing artificial analogs of other natural substances to determine their therapeutic efficacy for treating colorectal cancer, lung cancer, and blood-related cancers. We expect the results of this research to make significant contributions to the development of novel future cancer drugs based on natural substances as lead compounds.Fig. 1. FE399, a natural substance obtained from Ascochyta, a type of moldFig. 2. Overview of an artificial synthesis method for FE399 using MNBAStructure-Activity Relationship (SAR) and Mode of Action (MOA) Studies Using New Compounds Developed at the Tokyo University of ScienceArtificial synthesis of FE399, a natural substance derived from a fungus of the Japanese yew (a tree in the yew family): First successful synthesis of a natural substance through MNBA macrolactamization①
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