4.7 Article

Biotransformation of artemisinic acid to bioactive derivatives by endophytic Penicillium oxalicum B4 from Artemisia annua L

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PHYTOCHEMISTRY
卷 185, 期 -, 页码 -

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PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phytochem.2021.112682

关键词

Penicillium oxalicum; Trichocomaceae; Biotransformation; Artemisinic acid; Endophyte; Cytotoxicity; Nitric oxide

资金

  1. National Natural Science Foundation of China [81273487, 81773696, 82073955]
  2. Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD)

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By co-culturing with endophytic fungi, artemisinic acid was biotransformed to produce various new metabolites, some of which exhibited stronger cytotoxic activity against human cancer cells and demonstrated potential therapeutic value.
As a biosynthetic precursor of the antimalarial drug artemisinin, artemisinic acid (AA) is abundant in Artemisia annua L. with a content of 8-10-fold higher than artemisinin, but less effective. In this study, the biotransformation of AA was carried out with an endophytic fungus Penicillium oxalicum B4 to extend its utility. After 10-day-culture of the endophyte with AA at 2 mg/mL, eight biotransformation metabolites were isolated from the culture broth, including five undescribed metabolites, namely 3 alpha,14-dihydroxyartemisinic acid, 14-hydroxy-3-oxo-artemisinic acid, 15-hydroxy-3-oxo-artemisinic acid, 12, 15-artemisindioic acid and 1,2,3,6-tetradehydro-12, 15-artemisindioic acid. The fungal enzymes possess the selective capacity to hydroxylate, carbonylate and ketonize the allyl group of AA. The major biotransformation metabolite was the hydroxylated product 3-alpha-hydroxyartemisinic acid (33.3%) in the cultures of early stage (day 1-6), whereas most of the other biotransformation products were synthesized in the later stage (day 8-10). Compared with AA, some metabolites (3 alpha,14-dihydroxyartemisinic acid, 15-hydroxy-3-oxo-artemisinic acid and 1,2,3,6-tetradehydro-12, 15-artemisindioic acid) possessed stronger cytotoxic activity to the human colon carcinoma cell line (LS174T) and promyelocytic leukemia cell line (HL-60). The metabolites 12, 15-artemisindioic acid and 3-alpha-hydroxyartemisinic acid exhibited significant inhibitory activity to the lipopolysaccharide-induced nitrite production of RAW 264.7 cells at 10.00 mu M and 2.50 mu M, respectively. The results demonstrated the potential of fungal endophytes on biotransforming AA to its bioactive derivatives.

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