Orellanine: From Fungal Origin to a Potential Future Cancer Treatment,Journal of Natural Products

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Orellanine: From Fungal Origin to a Potential Future Cancer Treatment
Journal of Natural Products ( IF 3.3 ) Pub Date : 2023-06-12 , DOI: 10.1021/acs.jnatprod.2c01068
Mark J Lyons ₁ , Carsten Ehrhardt ₁ , John J Walsh ₁

Affiliation

Fungal metabolites represent an underutilized resource in the development of novel anticancer drugs. This review will focus on the promising fungal nephrotoxin orellanine, found in mushrooms including Cortinarius orellanus (Fools webcap). Emphasis will be placed on its historical significance, structural features, and associated toxicomechanics. Chromatographic methods for analysis of the compound and its metabolites, its synthesis, and chemotherapeutic potential are also discussed. Although orellanine’s exceptional selectivity for proximal tubular cells is well documented, the mechanics of its toxicity in kidney tissue remains disputed. Here, the most commonly proposed hypotheses are detailed in the context of the molecule’s structure, the symptoms seen following ingestion, and its characteristic prolonged latency period. Chromatographic analysis of orellanine and its related substances remains challenging, while biological evaluation of the compound is complicated by uncertainty regarding the role of active metabolites. This has limited efforts to structurally refine the molecule; despite numerous established methods for its synthesis, there is minimal published material on how orellanine’s structure might be optimized for therapeutic use. Despite these obstacles, orellanine has generated promising data in preclinical studies of metastatic clear cell renal cell carcinoma, leading to the early 2022 announcement of phase I/II trials in humans.

中文翻译：

Orellanine：从真菌起源到未来潜在的癌症治疗

真菌代谢物是新型抗癌药物开发中未充分利用的资源。这篇综述将重点关注有前途的真菌肾毒素奥雷拉氨酸，这种毒素存在于包括Cortinarius orellanus (Fools webcap) 在内的蘑菇中。重点将放在其历史意义、结构特征和相关的毒理学上。还讨论了用于分析该化合物及其代谢物、其合成和化疗潜力的色谱方法。尽管奥来丙氨酸对近端肾小管细胞的特殊选择性已得到充分证明，但其在肾组织中的毒性机制仍存在争议。在这里，最常提出的假设详细介绍了分子的结构、摄入后出现的症状及其特征性的延长潜伏期。奥来丙氨酸及其相关物质的色谱分析仍然具有挑战性，而该化合物的生物学评估由于活性代谢物作用的不确定性而变得复杂。这限制了分子结构精炼的努力；尽管有许多已建立的合成方法，但关于如何优化奥来丙氨酸结构以用于治疗用途的公开材料却很少。尽管存在这些障碍，orellanine 在转移性透明细胞肾细胞癌的临床前研究中已经产生了有希望的数据，导致 2022 年初宣布进行人体 I/II 期试验。

更新日期：2023-06-12

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