Abstract The microbial transformation of artemisinic acid (1) using cell culture of endophytic fungus Trichothecium roseum was investigated. Previously, we have reported two major metabolites, 3β-hydroxyartemisinic acid (2) and 3β,15-dihydroxyartemisinic acid (3) from the biotransformation of artemisinic acid by the fungus T. roseum CIMAPN1. Here in the present paper, we obtained a new minor compound 4 (5.2% in yield) along with compounds 2 and 3 through scale-up of biotransformation process of artemisinic acid using the same fungus. The structure of compound 4 was established as 3-oxoartemisinic acid on the basis of its IR, ESI-MS, HRMS, 1 D (1H and 13C, DEPT), and 2 D (COSY, HSQC, HMBC) NMR spectral data analysis. The possible reaction mechanism of the formation of 3-oxoartemisinic acid from artemisinic acid was proposed. Furthermore, all the three metabolites along with the artemisinic acid were evaluated for their antifungal activity against the three fungal strains Candida albicans (ATCC 14053), Candida albicans clinical isolates and Candida kefyr (ATCC 204093). 3-Oxoartemisinic acid was the most active (4 to 16 times more potent than artemisinic acid) with MIC ranges from 125 to 500 µg/mL among all tested compounds. This study suggested that the artemisinic acid molecule has a great potential to be exploited for further biotransformation by the different fungi and can produce chemically diverse molecules with better biological activity.

中文翻译：

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真菌 Trichothecium roseum 对青蒿酸的生物转化及其代谢物的抗念珠菌活性

摘要 研究了利用内生真菌玫瑰红毛霉细胞培养物对青蒿酸 (1) 的微生物转化。此前，我们报道了两种主要代谢物，3β-羟基青蒿酸 (2) 和 3β,15-二羟基青蒿酸 (3)，它们来自真菌 T. roseum CIMAPN1 对青蒿酸的生物转化。在本文中，我们通过使用相同的真菌扩大青蒿酸的生物转化过程，获得了一种新的次要化合物 4（产率 5.2%）以及化合物 2 和 3。通过IR、ESI-MS、HRMS、1D（1H和13C，DEPT）和2D（COSY、HSQC、HMBC）NMR谱数据分析，确定化合物4的结构为3-氧代青蒿酸。提出了青蒿酸生成3-氧代青蒿酸的可能反应机理。此外，评估了所有三种代谢物以及青蒿酸对三种真菌菌株白色念珠菌 (ATCC 14053)、白色念珠菌临床分离株和克菲尔念珠菌 (ATCC 204093) 的抗真菌活性。在所有测试化合物中，3-氧代青蒿酸的活性最强（比青蒿酸强 4 到 16 倍），MIC 范围为 125 到 500 µg/mL。该研究表明，青蒿酸分子具有被不同真菌进一步生物转化的巨大潜力，并且可以产生具有更好生物活性的化学多样化分子。在所有测试化合物中，3-氧代青蒿酸的活性最强（比青蒿酸强 4 到 16 倍），MIC 范围为 125 到 500 µg/mL。该研究表明，青蒿酸分子具有被不同真菌进一步生物转化的巨大潜力，并且可以产生具有更好生物活性的化学多样化分子。在所有测试化合物中，3-氧代青蒿酸的活性最强（比青蒿酸强 4 到 16 倍），MIC 范围为 125 到 500 µg/mL。该研究表明，青蒿酸分子具有被不同真菌进一步生物转化的巨大潜力，并且可以产生具有更好生物活性的化学多样化分子。