A facile and efficient method for the synthesis of 3-[(4nitrophenyl)thio]-substituted 4-methylene-1-pyrrolines is described. When treated with 4-nitrobenzenesulfenyl chloride in refluxing acetonitrile, Npropargylic β-enaminones produced α-sulfenylated N-propargylic β-enaminones, which, in the presence of sodium hydride or cesium carbonate, underwent nucleophilic cyclization to afford 4-methylene-3-[(4-nitrophenyl)thio]-1-pyrrolines in good to high yields. It was shown for the first time that on N-propargylic β-enaminone systems, α-sulfenylation dominates over the formation of thiirenium ion. This one-pot two-step process was found to be general for a variety of N-propargylic β-enaminones and demonstrated good tolerance to a diversity of aromatic and heteroaromatic groups with electron-withdrawing and electron-donating substituents. This process is also applicable to the cyclization of internal alkyne-tethered N-propargylic β-enaminones. The enrichment of 1-pyrroline core with an aryl sulfide moiety might exhibit potential for the synthesis of molecules of pharmacological interest.

Breast cancer is one of the most common cancers worldwide and the discovery of new cytotoxic agents is needed. Enaminones are regarded to be a significant structural motif that is found in a variety of pharmacologically active compounds however the number of studies investigating the anticancer activities of N-propargylic β-enaminones (NPEs) is limited. Herein we investigated the potential cytotoxic and apoptotic effects of 23 different NPEs (1-23) on human breast cancer cells. Cytotoxicity was evaluated via MTT assay. Apoptotic cell death and cell cycle distributions were investigated by flow cytometry. CM-H2DCFDA dye was used to evaluate cellular ROS levels. Expression levels of Bcl-2, Bax, p21, and Cyclin D1 were measured by quantitative real-time PCR. ADME properties were calculated using the ADMET 2.0 tool. NPEs 4, 9, 16, and 21 showed selective cytotoxic activity against breast cancer cells with SI values >2. NPEs induced apoptosis and caused significant changes in Bcl-2 and Bax mRNA levels. The cell cycle was arrested at the G0/G1 phase and levels of p21 and Cyclin D1 were upregulated in both breast cancer cells.ROS levels were significantly increased by NPEs, suggesting that the cytotoxic and apoptotic effects of NPEs were mediated by ROS. ADME analysis revealed that NPEs showed favorable distributions in both breast cancer cell lines, meaning good lipophilicity values, low unfractionated values, and high bioavailability. Therefore, these potential anticancer compounds should be further validated by in vivo studies for their appropriate function in human health with a safety profile, and a comprehensive drug interaction study should be performed.

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Heterocyclic compounds have emerged as promising and appealing scaffolds for developing effective antitumor agents. Here, the effects of synthesized 24 different 1‐pyrroline derivatives (PDs) containing substituted aryl sulfide moiety were investigated on human breast cancer cell lines. The viability of cells was assessed via MTT assay. Reactive oxygen species (ROS) generation was analyzed via fluorescent dye CM‐H2DCFDA. Apoptotic cells were determined via flow cytometry. Endoplasmic reticulum (ER) stress‐associated protein levels were analyzed via western blot analysis. Four of the PDs (PD‐12, ‐14, ‐16 and ‐17) had great cytotoxic selectivity against breast cancer cells. Apoptotic cell death was induced by PDs via the generation of ROS. PDs significantly increased the GRP78, p‐PEAK, p‐eIF2α, and CHOP protein levels indicating ER stress in breast cancer cells. These results imply that newly synthesized PDs may be potential anticancer agents as they selectively inhibit breast cancer cells.