Biotransformation of artemisinin to a novel derivative via ring rearrangement by Aspergillus niger.

Luo, Jiaer; Mobley, Rebecca; Woodfine, Sian; Drijfhout, Falko; Horrocks, Paul; Ren, Xiao-Dong; Li, Wen-Wu

Abstract

Artemisinin is a component part of current frontline medicines for the treatment of malaria. The aim of this study is to make analogues of artemisinin using microbial transformation and evaluate their in vitro antimalarial activity. A panel of microorganisms were screened for biotransformation of artemisinin (1). The biotransformation products were extracted, purified and isolated using silica gel column chromatography and semi-preparative HPLC. Spectroscopic methods including LC-HRMS, GC-MS, FT-IR, 1D and 2D NMR were used to elucidate the structure of the artemisinin metabolites.H-1 NMR spectroscopy was further used to study the time-course biotransformation. The antiplasmodial activity (IC50) of the biotransformation products of 1 against intraerythrocytic cultures of Plasmodium falciparum were determined using bioluminescence assays. A filamentous fungus Aspergillus niger CICC 2487 was found to possess the best efficiency to convert artemisinin (1) to a novel derivative, 4-methoxy-9,10-dimethyloctahydrofuro-(3,2-i)-isochromen-11(4H)-one (2) via ring rearrangement and further degradation, along with three known derivatives, compound (3), deoxyartemisinin (4) and 3-hydroxy-deoxyartemisinin (5). Kinetic study of the biotransformation of artemisinin indicated the formation of artemisinin G as a key intermediate which could be hydrolyzed and methylated to form the new compound 2. Our study shows that the anti-plasmodial potency of compounds 2, 3, 4 and 5 were ablated compared to 1, which attributed to the loss of the unique peroxide bridge in artemisinin (1). This is the first report of microbial degradation and ring rearrangement of artemisinin with subsequent hydrolysis and methoxylation by A.niger.

Citation

Luo, J., Mobley, R., Woodfine, S., Drijfhout, F., Horrocks, P., Ren, X., & Li, W. (2022). Biotransformation of artemisinin to a novel derivative via ring rearrangement by Aspergillus niger. Applied Microbiology and Biotechnology, 106, 2433-2444. https://doi.org/10.1007/s00253-022-11888-0

• Journal Article Type: Article
• Acceptance Date: Mar 19, 2022
• Publication Date: Mar 31, 2022
• Journal: Applied Microbiology and Biotechnology
• Print ISSN: 0175-7598
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 106
• Pages: 2433-2444
• DOI: https://doi.org/10.1007/s00253-022-11888-0
• Keywords: Biotransformation, Artemisinin, Kinetics, Aspergillus niger, Anti-plasmodial activity
• Publisher URL: https://link.springer.com/article/10.1007/s00253-022-11888-0#article-info