Design of ROS-Triggered Sesquiterpene Lactone SC Prodrugs as TrxR1 Covalent Inhibitors for the Treatment of Non-Small Cell Lung Cancer

Thioredoxin reductase 1 (TrxR1) is an important therapeutic
target
for nonsmall cell lung cancer (NSCLC) treatment due to its overexpression
in NSCLC cells. In this work, to address the deficiency that sesquiterpene
lactone containing α-methylene-γ-lactone moiety was rapidly
metabolized by endogenous nucleophiles, series of novel thioether
derivatives were designed and synthesized based on a reactive oxygen
species (ROS)-triggered prodrug strategy. Among them, prodrug 5u exhibited potent cytotoxicity against NSCLC cells and better
release rates in response to ROS. The active compound 6a released from 5u covalently binds to Cys475 and Sec498
sites on TrxR1, resulting in inhibition on TrxR1 activity, which led
to redox homeostasis disorder, and caused apoptosis and ferroptosis.
Moreover, prodrug 5u exhibited significant antitumor
efficiency in nude mice and NSCLC organoids. Our results deliver ROS-triggered
prodrug 5u as a novel TrxR1 inhibitor for the treatment
of NSCLC and provide a promising strategy of ROS-activated prodrug
for covalent compounds in cancer therapy.