New bis-norditerpene by biotransformation of favelines from Cnidoscolus quercifolius using Umbelopsis isabellina as biocatalyst

IF 2.5 3区医学 Q3 CHEMISTRY, MEDICINAL

Fitoterapia Pub Date : 2025-05-08 DOI:10.1016/j.fitote.2025.106605

Sovannychloé Nai , Thomas Gaslonde , Julia Krystyańczuk , Séverine Amand , Laurent Picot , Carlos Arthur Gouveia Veloso , Didier Buisson , Marie-Christine Lallemand , Raimundo Gonçalves de Oliveira Junior

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Abstract

Favelines, tricyclic benzylcycloheptene diterpenes predominantly found in Cnidoscolus quercifolius, have demonstrated significant cytotoxic activity against human cancer cell lines, including melanoma. In this study, we employed a combinatorial approach to screen microbial strains for biotransformation, focusing on regioselective oxidation of the cyclohexyl ring in the faveline core structure. This strategy, applied directly to the crude plant extract, enabled the rapid identification of Umbelopsis isabellina as the active strain. Subsequent preparative biotransformation yielded a novel bis-norditerpene, 14-hydroxy-isofavelol (3). The new compound exhibited moderate cytotoxic activity (IC₅₀ = 68.8 μM) against chemoresistant human melanoma A2058 cells, which are resistant to dacarbazine but sensitive to vemurafenib. Compound 3 enhanced the cytotoxic effect of vemurafenib, reducing its IC₅₀ from 24.8 to 9.63 μM. This work demonstrates the utility of microbial biotransformation for generating new bioactive natural product derivatives and highlights the potential of 14-hydroxy-isofavelol as a chemosensitizing agent in melanoma therapy.

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以深黄伞为生物催化剂，从槲皮刺槐中提取亚麻碱生物转化新的双北二萜

Favelines是一种三环苄基环戊烯二萜，主要存在于槲皮针孔菌中，已经证明对人类癌细胞系（包括黑色素瘤）具有显著的细胞毒活性。在这项研究中，我们采用组合方法筛选微生物菌株进行生物转化，重点关注faveline核心结构中环己基环的区域选择性氧化。该方法直接应用于植物粗提取物中，可快速鉴定为活性菌株。随后的制备性生物转化产生了一种新的双去二萜，14-羟基异avelol(3)。新化合物对化学耐药的人类黑色素瘤A2058细胞具有中等的细胞毒活性（IC₅₀= 68.8 μM），该细胞对达卡巴胺具有抗性，但对vemurafenib敏感。化合物3增强了vemurafenib的细胞毒作用，使其IC₅₀从24.8 μM降至9.63 μM。这项工作证明了微生物转化在产生新的生物活性天然产物衍生物方面的效用，并强调了14-羟基异非韦洛作为黑色素瘤治疗化学增敏剂的潜力。

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来源期刊

Fitoterapia 医学-药学

CiteScore

5.80

自引率

2.90%

发文量

198

审稿时长

1.5 months

期刊介绍： Fitoterapia is a Journal dedicated to medicinal plants and to bioactive natural products of plant origin. It publishes original contributions in seven major areas: 1. Characterization of active ingredients of medicinal plants 2. Development of standardization method for bioactive plant extracts and natural products 3. Identification of bioactivity in plant extracts 4. Identification of targets and mechanism of activity of plant extracts 5. Production and genomic characterization of medicinal plants biomass 6. Chemistry and biochemistry of bioactive natural products of plant origin 7. Critical reviews of the historical, clinical and legal status of medicinal plants, and accounts on topical issues.