Abstract Biological modification of natural products is an important approach to improve the pharmacological properties. 4′-d-β-Demethylepipodophyllotoxin (4′-d-β-DMEP), a typical natural lignin, is used as the aglycon of topoisomerase inhibitor etoposide (VP-16). In this study, 4′-d-β-DMEP was isomerized into the novel product 4′-d-α-DMEP with 43.09% conversion by P. purpurogenum ACCC 32170. 4′-d-α-DMEP was largely produced extracellularly in the late fermentation stage, which was accompanied with the decrease of dry cell weight and the increase of culture pH. A constitutively expressed cytosolic enzyme was involved in the transformation and functioned when culture pH ranged from 7.0–10.0. The IC50 value of 4′-d-α-DMEP was around 0.80 μM against tumor cells MCF-7, which was significantly reduced by 11.27 and 17.34 times than 4′-d-β-DMEP (i.e., 9.82 μM) and VP-16 (i.e., 14.67 μM). This study provided the novel podophyllotoxin derivative with higher anti-tumor activity and microbial transformation process, which would promote transferring lignans into the clinic trial.

中文翻译：

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紫原青霉通过4'-去甲基表鬼臼毒素生物转化产生具有更高抗肿瘤活性的新型鬼臼毒素衍生物

摘要 天然产物的生物修饰是改善其药理特性的重要途径。4'-d-β-Demethylepipodophyllotoxin (4'-d-β-DMEP) 是一种典型的天然木质素，用作拓扑异构酶抑制剂依托泊苷 (VP-16) 的苷元。在本研究中，4'-d-β-DMEP 被 P. purpurogenum ACCC 32170 异构化为新产品 4'-d-α-DMEP，转化率为 43.09%。4'-d-α-DMEP 主要在细胞外产生发酵后期，伴随着细胞干重的降低和培养物pH值的升高。组成型表达的胞质酶参与转化并在培养 pH 值范围为 7.0-10.0 时起作用。4'-d-α-DMEP 对肿瘤细胞 MCF-7 的 IC50 值约为 0.80 μM，比 4'-d-β-DMEP（即 9. 82 μM) 和 VP-16 (即 14.67 μM)。该研究提供了具有更高抗肿瘤活性和微生物转化过程的新型鬼臼毒素衍生物，这将促进木脂素进入临床试验。