Department of Chemistry, Roger Adams Laboratory, University of Illinois, Urbana, IL, USA.
Department of Chemistry, Boston College, Chestnut Hill, MA, USA.
Nat Chem. 2019 Jun;11(6):521-532. doi: 10.1038/s41557-019-0261-6. Epub 2019 May 13.
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.
天然产物的化学多样化为创造具有丰富立体化学和结构多样性的小分子提供了一种强大而通用的方法。由此产生的化合物具有与大多数筛选库中的化合物不同的物理化学性质，因此是生物发现的绝佳来源。在此，我们对二萜天然产物培洛霉素进行了一系列反应，旨在通过少数几个合成步骤来创造环系统多样性。这一努力得到了一组以前未报道过的环系统的化合物，提供了一组新的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。生物评估鉴定了新型化合物 ferroptocide，这是一种小分子，可迅速而强烈地诱导癌细胞发生铁死亡。靶标鉴定工作和 CRISPR 敲除研究表明，ferroptocide 是硫氧还蛋白的抑制剂，硫氧还蛋白是细胞抗氧化系统的关键组成部分。ferroptocide 在乳腺癌的小鼠模型中正向调节免疫系统，将成为研究促铁死亡剂治疗癌症的用途的有用工具。
