Cancer continues to be a leading cause of global mortality, highlighting the ongoing need for novel anticancer compounds that offer high efficacy with improved side effect profiles. In the present study, a series of 3H-1,2-dithiole-3-thione derivatives (DTT-S1-18) were synthesized as promising anticancer agents, and the structures of products were confirmed by spectral techniques. H2S-releasing experiments showed that most of the compounds released higher amounts of H2S slowly over time compared to standard ADT-OH. All compounds were tested for antiproliferative activity on HT-29, PC-3, MCF-7, and HUVEC cell lines. Compounds DTT-S6 (3-nitrophenyl derivative) and DTT-S8 (methionine derivative) have the lowest IC50 values of 41.6 and 38.9 & micro;M on the MCF-7 cell line, respectively. Based on the wound healing and colony formation assays performed in MCF-7 cells, the wound areas were not significantly changed after treatment with compounds DTT-S6 and DTT-S8, whereas compound DTT-S8 at double IC50 dose inhibited colony formation by 81.82%. In addition, molecular docking, MD simulations, MM/GBSA binding free energy calculations, and binary QSAR analyses were performed to explore the potential target interactions and predicted activity profiles of the synthesized compounds toward inflammation-related proteins, including COX-1, COX-2, 5-LOX, and iNOS, thereby supporting the development of mechanistic hypotheses for future validation. Furthermore, structure-activity relationship (SAR) analyses were conducted to correlate the structural characteristics of the synthesized compounds with their H2S releasing potential and biological profiles. Overall, this work integrates experimental anticancer evaluation with computational pathway and structure-based cancer/inflammation analyses to characterize novel DTT-based H2S donors. The findings identify particularly compound DTT-S8, as a promising in vitro anticancer candidate, while the computational results suggest a putative involvement of inflammation-related targets, particularly the COX-2/5-LOX axis, which requires direct biochemical and cellular validation.
Targeted protein degradation (TPD) has revolutionized drug discovery, with PROTACs leading the charge by catalytically eliminating disease-causing proteins. While conventional PROTACs degrade a single target, the complexity of diseases like cancer and neurodegeneration—marked by redundant and compensatory signaling networks—has spurred the rapid development of dual/multi-target PROTACs capable of simultaneously degrading two or more pathogenic proteins. This review systematically surveys recent advances (2023–2026) in this area, categorizing them into two classes: those targeting homologous proteins (e.g., CDKs, BCL-2/BCL-xL, HDACs, BAZ2A/BAZ2B) and those targeting distinct proteins across interconnected pathways (e.g., ERα/ARO, α-Syn/tau, BET/HDAC, PI3K/mTOR, FLT3/CHK1, CBP/BRD4, and others). For each, we critically analyze design strategies, structure–activity relationships, linker optimization, and E3 ligase selection. Despite remarkable progress—including the first dual degraders for non-kinase epigenetic regulators and protein aggregates—challenges persist in pharmacokinetics, off-target toxicity, and limited E3 ligase diversity. By consolidating key breakthroughs and practical SAR insights, this review provides a valuable resource for advancing next-generation multi-target degraders toward clinical translation for complex diseases.
Human rhinoviruses (HRVs) are major causative agents of the common cold and are strongly associated with asthma exacerbation, highlighting the need for effective antivirals. Because the viral 3 C protease (3Cpro) is essential for polyprotein processing and is highly conserved among HRV species, it represents an attractive therapeutic target. In this study, we performed structure-based virtual screening of 49,437 compounds against HRV-C 3Cpro using AutoDock Vina, followed by ADMET-based prioritization of the top hits. Docking analysis identified two lead compounds that favorably occupied the catalytic pocket and formed stabilizing interactions with key residues, including His40, Glu71, and Cys147, in comparison with the reference inhibitor rupintrivir. In 200-ns molecular dynamics simulations, both compounds stabilized the protease relative to the apo form, with compound 1 showing the lowest protein RMSD (1.21 ± 0.22 Å) and compound 2 producing the lowest Cys147 RMSF (0.48 Å). Both ligands also displayed lower ligand RMSD values than rupintrivir (compound 1: 1.49 ± 0.78 Å; compound 2: 2.01 ± 0.39 Å; rupintrivir: 4.83 ± 0.89 Å), indicating more persistent binding within the active site. MM/PBSA analysis further supported stronger effective binding for compound 1 (-23.59 ± 6.87 kcal/mol) and compound 2 (-25.25 ± 5.75 kcal/mol) than for rupintrivir (-19.43 ± 4.46 kcal/mol). Taken together, these results identify compounds 1 and 2 as promising non-covalent HRV 3Cpro inhibitor candidates for further experimental validation.
Aberrant activation of the Wnt/β-catenin signaling pathway is a hallmark of colorectal cancer, primarily driven by the interaction between β-catenin and T-cell factor 4 (Tcf4). Due to the large and shallow interface ( 4800 Å2) of this protein–protein interaction, it has historically been considered “undruggable.” However, emerging evidence highlights the presence of druggable hot spots within this interface. In this study, we employed a structure-based virtual screening approach to repurpose FDA-approved drugs targeting the β-catenin/Tcf4 interaction. Using physics-based molecular simulations and MM/GBSA binding free energy calculations, we identified Leucovorin (Folinic acid), Carbenicillin, and Ceforanide as promising candidate hit compounds with stable binding to critical hot spot residues (Asn430, Lys435, His470, Arg474, and Lys508) of β-catenin. Experimental validation using HT-29 colorectal cancer cells revealed that Carbenicillin and Ceforanide reduced the cell viability, impaired the colony formation, and exhibited superior anti-proliferative activity compared to the other candidates. These findings provide compelling evidence for the feasibility of targeting β-catenin/Tcf4 interactions using small molecules and suggest that Carbenicillin and Ceforanide may serve as promising repurposed candidates for therapeutic intervention in Wnt-driven malignancies.
An NH4I-mediated electrochemical three-component cascade reaction has been established for the preparation of trideuteromethylthiolated enaminones from primary amines, acetylacetone, and CD3SSO3Na. This simple protocol is readily applicable to gram-scale synthesis and late-stage modification of bioactive molecules. Preliminary biological screening of the prepared trideuteromethylthiolated enaminones identified compound 4l is capable of protecting cells from oxidative damage by initiating the activation of the Nrf2/HO-1 signaling pathway.
