School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland.
J Nat Prod. 2023 Jun 23;86(6):1620-1631. doi: 10.1021/acs.jnatprod.2c01068. Epub 2023 Jun 12.
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 (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.
真菌代谢产物是开发新型抗癌药物未被充分利用的资源。本综述将重点介绍在包括（愚人帽）在内的蘑菇中发现的有前景的真菌肾毒素奥来毒素。将重点介绍其历史意义、结构特征和相关的毒理学机制。还讨论了该化合物及其代谢物的分析、合成和化疗潜力的色谱方法。尽管奥来毒素对近端肾小管细胞的特殊选择性已得到充分证明，但它在肾组织中的毒性机制仍存在争议。在这里，最常提出的假设将根据分子结构、摄入后的症状及其特征性的潜伏期进行详细描述。奥来毒素及其相关物质的色谱分析仍然具有挑战性，而由于对活性代谢物作用的不确定性，对该化合物的生物学评估也很复杂。这限制了对该分子进行结构优化的努力；尽管有许多已建立的合成方法，但关于如何优化奥来毒素的结构以用于治疗用途的发表材料很少。尽管存在这些障碍，奥来毒素在转移性透明细胞肾细胞癌的临床前研究中产生了有希望的数据，这导致 2022 年初宣布在人类中进行 I/II 期试验。
