Diverse compounds from pleuromutilin lead to a thioredoxin inhibitor and inducer of ferroptosis

Abstract

The chemical diversification of natural products provides a robust and general method for 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.

Recent Progress in Ferroptosis Inducers for Cancer Therapy

“…Compared with two available ferroptosis inducers, erastin and (1S, 3R)‐RSL3, ferroptocide is a more potent agent that can induce more quantitative cancer cells death and act more quickly. Moreover, ferroptocide has been proved effective in eliciting immune responses, where T and B cells contribute to the in vivo activity of ferroptocide in immunocompromised animal models …”

“…The N ‐ N moiety in ferroptocide could be replaced with CC, enabling functionalization of ferroptocide with minimal loss in its anticancer activity. For example, one of the fluorescent ferroptocide derivatives P30 (Figure J) has been used to monitor the subcellular localization in ES‐2 cells …”

“…In addition to the combination of multiple forms of RCDs for eradicating malignancies, the non‐apoptotic nature of ferroptosis also inspired research on the immunostimulatory property of ferroptosis inducers . One of the pioneer work described a biomimetic magnetosome nanoparticle (Pa‐M/Ti‐NCs) for ferroptosis/immunomodulation synergistic cancer therapy ( Figure ).…”

Modulation of ferroptosis sensitivity by TXNRD1 in pancreatic cancer cells

“…[10][11][12][13] This Cterminal selenocysteine operates alongside NADPH and FAD domains to reduce oxidized species. 14 The unique enzyme structure of TXNRD1, combined with the reactivity of its selenocysteine residue toward smallmolecule electrophiles, [15][16][17][18] warrants careful consideration when dissecting the function of TXNRD1 through genetic versus pharmacological inhibition. Inhibition of TXNRD1 has been previously explored as a therapeutic approach through which to kill cancer cells possessing a heightened dependence on resolving oxidative stress.…”

Synthetic biology based construction of biological activity-related library of fungal decalin-containing diterpenoid pyrones

“…Chemical synthesis, including divergent and diverted total syntheses, is a powerful strategy to produce bioactive natural product analogues and congeners 12,13 . A late-stage modification strategy is also a beneficial tool to generate natural product derivatives, such as diversity-oriented synthesis using natural products and their intermediate starting points [14][15][16][17] . However, the structural complexity and limited availability of natural products remain obstacles to synthesizing a large collection of natural products and their structural analogues in sufficient amounts.…”