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 mol­ecular system displays a planar conformation between the phenyl and imidazo[1,2-a] pyridine rings. Weak C—H⋯π and π–π inter­actions as well as short contacts consolidate the three-dimensional network structure.

2‐(4‐methylphenoxy)‐N‐(4‐(4‐bromophenyl) thiazol‐2‐yl) acetamide compound was obtained via a multistep synthesis sequence processes, which is characterized by 1H NMR, 13C NMR and its three‐dimensional structure has been confirmed by single crystal X‐ray diffraction method. The supramolecular structure of the molecule revealed the stability of crystal packing with diverse intermolecular interactions. Density functional theory calculations (DFT) at B3LYP 6–311++G(d,p) level has been used to predict the molecular geometry and were in good agreement with the experimental data. Moreover, the theoretical calculations were carried out to appraise the electronic structure, vibrational spectra, natural bond orbital analysis, molecular electrostatic potential, frontier molecular orbitals and global reactivity descriptors. Raman spectra with fluorescence effect was examined with visible and near IR excitation wavelengths. Hirshfeld surface and energy framework analysis revealed the important intermolecular contacts and interaction energies. The antioxidant activity of this synthesized compound was predicted by in silico docking study on human peroxiredoxin 5 protein. The potential antioxidant activity was investigated by 1,1‐diphenyl‐1‐picrylhydrazyl (DPPH) free radical screening and compared with standard drug ascorbic acid.

The design and development of a small molecule named NPB [3-{(4(2,3-dichlorophenyl)piperazin-1-yl}{2-hydroxyphenyl)methyl}-N-cyclopentylbenzamide], which specifically inhibited the phosphorylation of BAD at Ser99 in human carcinoma cells has been previously reported. Herein, the synthesis, characterization, and effect on cancer cell viability of NPB analogs, and the single-crystal X-ray crystallographic studies of an example compound (4r), which was grown via slow-solvent evaporation technique is reported. Screening for loss of viability in mammary carcinoma cells revealed that compounds such as 2[(4(2,3-dichlorophenyl)piperazin-1-yl][naphthalen-1-yl]methyl)phenol (4e), 5[(4(2,3-dichlorophenyl)piperazin-1-yl][2-hydroxyphenyl)methyl)uran-2-carbaldehyde (4f), 3[(2-hydroxyphenyl][4(p-tolyl)piperazin-1-yl)methyl)benzaldehyde (4i), and NPB inhibited the viability of MCF-7 cells with IC50 values of 5.90, 3.11, 7.68, and 6.5 µM, respectively. The loss of cell viability was enhanced by the NPB analogs synthesized by adding newer rings such as naphthalene and furan-2-carbaldehyde in place of N-cyclopentyl-benzamide of NPB. Furthermore, these compounds decreased Ser99 phosphorylation of hBAD. Additional in silico density functional theory calculations suggested possibilities for other analogs of NPB that may be more suitable for further development.

Small molecules are being used to inhibit cyclin dependent kinase (CDK) enzymes in cancer treatment. There is evidence that CDK is a drug-target for cancer therapy across many tumor types because it catalyzes the transfer of the terminal phosphate of ATP to a protein that acts as a substrate. Herein, the identification of pyranopyrazoles that were CDK inhibitors was attempted, whose synthesis was catalyzed by nano-zirconium dioxide via multicomponent reaction. Additionally, we performed an in-situ analysis of the intermediates of multicomponent reactions, for the first-time, which revealed that nano-zirconium dioxide stimulated the reaction, as estimated by Gibbs free energy calculations of spontaneity. Functionally, the novel pyranopyrazoles were tested for a loss of cell viability using human breast cancer cells (MCF-7). It was observed that compounds 5b and 5f effectively produced loss of viability of MCF-7 cells with IC50 values of 17.83 and 23.79 µM, respectively. In vitro and in silico mode-of-action studies showed that pyranopyrazoles target CDK1 in human breast cancer cells, with lead compounds 5b and 5f having potent IC50 values of 960 nM and 7.16 μM, respectively. Hence, the newly synthesized bioactive pyranopyrazoles could serve as better structures to develop CDK1 inhibitors against human breast cancer cells.