Glutathione S‐transferase omega 1 (GSTO1) contributes to the inactivation of a wide range of drug compounds via conjugation to glutathione during phase reactions. Chemotherapy‐induced GSTO1 expression in breast cancer cells leads to chemoresistance and promotes metastasis. In search of novel GSTO1 inhibitors, we identified S2E, a thia‐Michael adduct of sulfonamide chalcone with low LC₅₀ (3.75 ± 0.73 μm) that binds to the active site of GSTO1, as revealed by molecular docking (glide score: −8.1), cellular thermal shift assay and fluorescence quenching assay (K_b ≈ 10 × 10⁵ mol·L⁻¹). Docking studies confirmed molecular interactions between GSTO1 and S2E, and identified the hydrogen bond donor Val‐72 (2.14 Å) and hydrogen bond acceptor Ser‐86 (2.77 Å). Best pharmacophore hypotheses could effectively map S2E and identified the 4‐methyl group of the benzene sulfonamide ring as crucial to its anti‐cancer activity. Lack of a thiophenyl group in another analog, 2e, reduced its efficacy as observed by cytotoxicity and pharmacophore matching. Furthermore, GSTO1 inhibition by S2E, along with tamoxifen, led to a significant increase in apoptosis and decreased migration of aggressive MDA‐MB‐231 cells, as well as significantly decreased migration, invasion and mammosphere formation in sorted breast cancer stem cells (CSCs, CD24⁻/CD44⁺). GSTO1 silencing in breast CSCs also significantly increased apoptosis and decreased migration. Mechanistically, GSTO1 inhibition activated the c‐Jun N‐terminal kinase stress kinase, inducing a mitochondrial apoptosis signaling pathway in breast CSCs via the pro‐apoptotic proteins BAX, cytochrome c and cleaved caspase 3. Our study elucidated the role of the GSTO1 inhibitor S2E as a potential therapeutic strategy for preventing chemotherapy‐induced breast CSC‐mediated cancer metastasis and recurrence.

The synthesis of highly functionalized piperidines has been strategically accessed via organo-catalytic three components (in situ five components) reaction of an amine, aldehyde and 1,3-dicarbonyl compound. This imine based multi-component reaction was realized using fully green L-proline nitrate as recyclable room temperature ionic liquid. Recycling of the catalyst was possible up to five runs without loss of catalyst activity. Smaller E-factor (0.255) and process mass intensity (PMI = 3.35), high atom-economy (AE = 89.5%) and reaction mass efficiency (RME = 79.66%) demonstrates the higher environmental compatibility and sustainability of this protocol. DFT calculations showed that the L-proline catalyzed reaction proceeds by three pathways; (i) via proline enamine pathway, (ii) proline mediated aniline enamine pathway or (iii) the pathway involving iminium activation of the aldehyde to provide the Knoevenagel product.

Zn(OTf)₂-mediated expeditious and solvent-free synthesis of propargylamines via A³ coupling of aldehydes, amines, and phenylacetylene has been described. The described protocol proceeds effectively with variety of substituted benzaldehydes, enolizable aldehyde, and formaldehyde. Recyclability of the catalyst, low catalyst loading, and use of inexpensive catalyst are the key features of the present protocol.