Diverse compounds from pleuromutilin lead to a thioredoxin inhibitor and inducer of ferroptosis
Diverse compounds from pleuromutilin lead to a thioredoxin inhibitor and inducer of ferroptosis
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DOI：
10.1038/s41557-019-0261-6
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发表时间：
2019-06-01
期刊：
影响因子：
21.8
通讯作者：
Hergenrother, Paul J.
中科院分区：
文献类型：
--
作者：
Llabani, Evijola;Hicklin, Robert W.;Hergenrother, Paul J.
天然产物的化学多样性为产生立体化学丰富且结构多样的小分子提供了一种稳健且通用的方法。由此产生的化合物具有不同于大多数筛选收集物的理化特性，因此是生物发现的极好来源。在此，我们对二萜天然产物截短侧耳素进行反应序列，重点是在几个合成步骤中产生环系统多样性。这一努力导致了一系列具有以前未报道的环系统的化合物，提供了一组结构多样且高度复杂的化合物，适合在各种不同的环境中进行筛选。生物学评价鉴定了新型化合物ferropotocide，一种快速和强烈诱导癌细胞ferropototic死亡的小分子。靶点鉴定工作和CRISPR敲除研究表明，杀铁蛋白是硫氧还蛋白的抑制剂，硫氧还蛋白是细胞中抗氧化系统的关键组分。在乳腺癌的小鼠模型中，杀铁剂积极地调节免疫系统，并且将是研究促铁剂用于治疗癌症的效用的有用工具。
The chemical diversification of natural products provides a robust and general method for the creation of stereochemically rich and structurally diverse small molecules. The resulting compounds have physicochemical traits different from those in most screening collections, and as such are an excellent source for biological discovery. Herein, we subject the diterpene natural product pleuromutilin to reaction sequences focused on creating ring system diversity in few synthetic steps. This effort resulted in a collection of compounds with previously unreported ring systems, providing a novel set of structurally diverse and highly complex compounds suitable for screening in a variety of different settings. Biological evaluation identified the novel compound ferroptocide, a small molecule that rapidly and robustly induces ferroptotic death of cancer cells. Target identification efforts and CRISPR knockout studies reveal that ferroptocide is an inhibitor of thioredoxin, a key component of the antioxidant system in the cell. Ferroptocide positively modulates the immune system in a murine model of breast cancer and will be a useful tool to study the utility of pro-ferroptotic agents for treatment of cancer.