Last Updated: 04/12/2025
Creation of biofunctional medium-sized molecules by diversifying and conjugating artemisinin skeletons
Objectives
*Original title and text were machine translated from Japanese
This project aims to create biofunctional molecules derived from artemisinin, by developing a novel 6-aza-artemisinin structure that enhances synthesis and diversifies its chemical properties.
Tokyo University of Agriculture and Technology (TUAT), Japan
Artemisinin, the active ingredient of Chinese herbal medicine, has shown a medicinal effect of almost eliminating the malaria protozoan that has invaded red blood cells, and has revolutionized the treatment of malaria. In recent years, its application to cancer and other infectious diseases has also been considered. Induction of artemicins has been largely limited to lactone-based approaches. The authors designed 6-aza-artemisinin in which the 6-position asymmetric carbon was replaced with nitrogen in order to rapidly synthesize the tetracyclic skeleton while diversifying the structure of the cyclohexane ring moiety. An element substitution strategy that utilizes the characteristics of nitrogen has realized (1) rapid synthesis, (2) skeleton modification, (3) diversification of substituents R1-R3, and (4) improvement of water solubility of the mother skeleton. In fact, the team succeeded in catalytic asymmetric synthesis of a tetracyclic skeleton from three segments with only three steps of conversion. X-ray crystallography revealed that 6-aza-artemicinin has almost the same three-dimensional structure as artemisin. The team has succeeded in creating a lead compound that exhibits antimalarial activity comparable to that of artemisinin drugs from the synthesized compound group (joint research with Kitasato University, submission of a paper). The 6-aza-artemisinin group in which a benzyl group was linked to nitrogen exhibited a superior in vivo therapeutic effect than artemisinin. By introducing elements that deviate from the framework of biosynthesis into the fused ring skeleton, we succeeded in de novo chemical synthesis of a group of natural product analogs with promising antimalarial activity. Furthermore, this project is designing and synthesizing analog groups in which the 3, 6 and 9 positions of artemisinin are modified and various substituents are introduced into the three directions of the tetracyclic skeleton.
Apr 2016 — Mar 2018
$56,393
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