Human epidermal growth factor receptor 2 (HER2)-positive breast cancer exhibits early relapses, poor prognoses, and high recurrence rates. Herein, a JNK-targeting compound has been developed that may be of utility in HER2-positive mammary carcinoma. The design of a pyrimidine-and coumarin-linked structure targeting JNK was explored and the lead structure PC-12 [4-(3-((2-((4-chlorobenzyl)thio) pyrimidin-4-yl)oxy)propoxy)-6-fluoro-2H-chromen-2-one (5d)] was observed to selectively inhibit the proliferation of HER2-positive BC cells. The compound PC-12 exerted DNA damage and induced apoptosis in HER-2 positive BC cells more significantly compared to HER-2 negative BC cells. PC-12 induced PARP cleavage and down-regulated the expression of IAP-1, BCL-2, SURVIVIN, and CYCLIN D1 in BC cells. In silico and theoretical calculations showed that PC-12 could interact with JNK, and in vitro studies demonstrated that it enhanced JNK phosphorylation through ROS generation. Overall, these findings will assist the discovery of new compounds targeting JNK for use in HER2-positive BC cells.

The present study explores the comprehensive investigations of two methoxy-oriented chalcone structures (HK1 and HK2), each featuring distinct halogen substituents (chlorine and bromine). The crystals of the derivatives were grown and confirmed via single-crystal X-ray diffraction (XRD), revealing that HK1 crystallizes in the orthorhombic system with the space group Pbca, while HK2 crystallizes in the monoclinic system with the space group P2₁/c. Intermolecular interactions, such as hydrogen bonding, π–π stacking, and van der Waals forces, were examined for their role in molecular assembly. Hirshfeld surface analysis and enrichment ratio provided further insights into these intermolecular interactions within the lattice. Density functional theory (DFT) calculations using the B3LYP functional and 6-311++G (d,p) basis set was employed to explore the electronic structure and physicochemical properties. Quantum theory of atoms in molecules (QTAIM) and non-covalent interaction (NCI) analyses elucidated the topology of these compounds. In silico biological studies of the derivatives were also carried out, focusing on their inhibitory potential targeting monoamine oxidase (MAO-A and MAO-B) enzymes. Drug-likeness was evaluated through ADME-T profiling predictions, followed by molecular docking and dynamics simulations to determine the favorable binding configurations within the MAOs. Dynamics simulations over a 100 ns period confirmed the stability of the ligand–protein complexes. Overall, the present study offers a deeper understanding of the structural intricacies of the reported molecules by providing valuable insights into their chemical and biological properties through molecular interactions.

Telomere shortening and the induction of senescence and/or cell death may result from inhibition of telomerase activity in cancer cells. Herein, the properties of carbazole–triazole compounds targeting telomerase in human breast cancer cells are explored. All derivatives were evaluated for loss of viability in MCF-7 breast cancer cells, with compound 5g identified as the most potent within the examined series. Green synthesis was employed using water, a reusable nano-Fe₂O₃-catalyzed reaction, and an electrochemical method for the synthesis of tetrahydrocarbazole and triazoles. The crystal data of compound 4 is also reported. Furthermore, in silico analysis predicted that compound 5g may target human telomerase. Molecular docking analysis of compound 5g towards hTERT predicted a binding affinity of −6.74 kcal/mol. In flow cytometry assays, compound 5g promoted apoptosis and cell cycle arrest in the G2-M phase. Finally, compound 5g inhibited the enzymatic activity of telomerase in human breast cancer cells. In conclusion, a green synthesized series of carbazole–triazoles that target telomerase in cancer cells is reported.