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A diselenide/disulfide unit was introduced into camptothecin (CPT), and two selenoprodrugs (e.g., CPT-Se3 and CPT-Se4) were identified to show improved potency in killing cancer cells and inhibiting tumor growth in vivo. Interestingly, the intrinsic fluorescence of CPT was severely quenched by the diselenide bond. Both the selenoprodrugs were activated by glutathione with a nearly complete recovery of CPT's fluorescence. The activation of prodrugs was accompanied by the production of selenol intermediates, which catalyzed the constant conversion of glutathione and oxygen to oxidized glutathione and superoxides. The diselenide unit is widely employed in constructing thiol-responsive materials. However, the selenol intermediates were largely ignored in the activation process prior to this study. Our work verified that integration of the diselenide unit may further enhance the parent drug's efficacy. Also, the discovery of the fluorescence quenching property of the diselenide/disulfide bond further shed light on constructing novel theranostic agents.

Upregulation of the selenoprotein thioredoxin reductase (TrxR) is of pathological significance in maintaining tumor phenotypes. Thus, TrxR inhibitors are promising cancer therapeutic agents. We prepared different amino-substituted phenylarsine oxides and evaluated their cytotoxicity and inhibition of TrxR. Compared with our reported p-substituted molecule (8), the o-substituted molecule (10) shows improved efficacy (nearly a fourfold increase) to kill leukemia HL-60 cells. Although the compounds 8 and 10 display similar potency to inhibit the purified TrxR, the o-substitution 10 exhibits higher potency than the p-substitution 8 to inhibit the cellular TrxR activity. Molecular docking results demonstrate the favorable weak interactions of the o-amino group with the TrxR C-terminal active site. Efficient inhibition of TrxR consequently induces the oxidative stress-mediated apoptosis of cancer cells. Silence of the TrxR expression sensitizes the cells to the arsenic compound treatment, further supporting the critical involvement of TrxR in the cellular actions of compound 10.

Clonorosins A (1) and B (2), two novel indole alkaloids featuring unprecedented 6/5/6/6/5 and 6/5/5 cores, together with seven known indole-linked 2,5-diketopiperazine alkaloids (3-9), were isolated from the soil-derived fungus Clonostachys rosea YRS-06. The new structures were proposed through HR-MS, NMR, and ECD spectroscopic data. They were established by comparing the calculated NMR, ECD, and specific rotation data with the experimental. To assist in determining the absolute configuration of the chiral carbon in the side chain of 2,5-diketopiperazine derivatives, flexible analogues 3i-3iv were synthesized and analyzed. 1 was active against Fusarium oxysporum with an MIC value of 50 μg/mL. 7 and 8 showed excellent activity against human HeLa and HepG2 cells with IC50 values of 0.12-0.60 μM.

Thioredoxin reductase (TrxR) is a pivotal regulator of redox homeostasis, while dysregulation of redox homeostasis is a hallmark for cancer cells. Thus, there is considerable potential to inhibit the aberrantly upregulated TrxR in cancer cells to discover selective cancer therapeutic agents. Nevertheless, the structural types of TrxR inhibitors presented currently are still relatively limited. We herein report that PACMA 31, previously reported to inhibit protein disulfide isomerase (PDI), is a potent TrxR inhibitor. PACMA 31 possesses a pharmacophore scaffold that is structurally different from the announced TrxR inhibitors and exhibits effective cytotoxicity against cervical cancer cells. Our results reveal that PACMA 31 selectively inhibits TrxR over the related glutathione reductase (GR) and in the presence of reduced glutathione (GSH). Further studies with mutant enzyme and molecular docking suggest that the propynamide fragment of PACMA 31 interacts covalently with the selenocysteine residue of TrxR. Moreover, PACMA 31 effectively and selectively curbs TrxR activity in cells and further stimulates the production of reactive oxygen species (ROS) at low micromolar concentrations, which in turn triggers the accumulation of oxidized thioredoxin (Trx) and GSSG in cells. Follow-up studies demonstrate that PACMA 31 targets TrxR in cells to induce oxidative stress-mediated cancer cell apoptosis. Our results provide a new structural type of TrxR inhibitor that may serve as a useful probe for investigating the biology of TrxR-implicated pathways, and uncover a new target of PACMA 31 that contributes to it becoming a candidate for cancer treatment.

The thioredoxin system is increasingly recognized as an important executor for maintaining cell redox homeostasis and regulating multiple cell signaling pathways. Targeting this system for cancer treatment has therefore attracted much attention.The authors focus on providing coverage and emphasizing the strategy of targeting the thioredoxin system to develop anticancer therapeutics in the past five years, especially from the perspective of discovering novel protein functions or new downstream regulatory pathways, and designing new therapeutic reagents. The authors also provide the readers with their expert perspectives for future development.The limited pharmacophore of inhibitors and the slow progress of clinical research partially restrict the development of anticancer drugs targeting the thioredoxin system, necessitating thus novel strategies to accelerate the system for treating cancer. Nevertheless, the synergistic targeting of thioredoxin system for cancer therapy is a promising strategy, particularly with regards to chemotherapy resistance and/or sensitization immunotherapy.

β-Lapachone as a natural novel anticancer candidate is under clinical trials. Previous studies suggested that β-lapachone works by redox activation to ablate cancer cells. However, it is still unclear whether thioredoxin reductase (TrxR), one of the key redox catalytic enzymes in cells, plays a role in the pharmacological effects of β-lapachone. Herein, we present that β-lapachone kills human promyelocytic leukemia HL-60 cells with preference over other cancer cells and normal cells. The follow-up studies demonstrate that β-lapachone induces the HL-60 cell apoptosis through inhibition of TrxR and further elevation of oxidative stress. Overexpression of the TrxR alleviates the efficiency of β-lapachone while knockdown of the enzyme increases the β-lapachone cytotoxicity, scientifically underpinning the correlation of the observed biological behaviors of β-lapachone to TrxR inhibition. The disclosure of the novel action mechanism of β-lapachone sheds light on understanding its capacity in interfering with cellular redox signaling and supports β-lapachone as an anticancer drug candidate.

Upregulation of the selenoprotein thioredoxin reductase (TrxR) is of pathological significance in maintaining tumor phenotypes. Thus, TrxR inhibitors are promising cancer therapeutic agents. We prepared different amino-substituted phenylarsine oxides and evaluated their cytotoxicity and inhibition of TrxR. Compared with our reported

Cysteine (Cys) plays a pivotal role in many physiological and pathological processes, including detoxification and protein synthesis. The abnormal levels of Cys are linked to many diseases. In this study, a novel red-emitting off-on fluorescent probe Cys-TCF was masterly constructed for discriminative detection of Cys. After a series of experimental assessment, Cys-TCF displayed higher selectivity and sensitivity for Cys over other biothilols with a low detection limit (0.04 μmol/L). More notably, the probe was also successfully applied to image Cys in live cells and live zebrafishes with low cytotoxicity.

The nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcription factor controlling a series of cytoprotective genes, is closely associated with scavenging the reactive oxygen species and maintaining the intracellular redox balance. Accumulating evidence has indicated that activation of Nrf2 is efficient to block or retard oxidative stress mediated neurodegenerative disorders. Small molecules that contribute directly or indirectly to the Nrf2 activation thus are promising therapeutic agents. Herein, we screened xanthohumol and its analogues, and two analogues (11 and 12) were disclosed to possess low cytotoxicity and rescue PC12 cells from the hydrogen peroxide or 6-hydroxydopamine induced injuries. Molecular mechanism studies demonstrated that compounds 11 and 12 are potent Nrf2 activators by promoting the nuclear accumulation of Nrf2 and enhancing the cellular antioxidant defense system. More importantly, genetically silencing the Nrf2 expression shuts down the observed cytoprotection conferred by both compounds, supporting the critical involvement of Nrf2 for the cellular actions of compounds 11 and 12.