Preparation and in vitro bioactivity evaluation of N-heterocyclic-linked dihomooxacalix[4]arene derivatives.

Based on the superior prospects of calixarenes-based agents and N-heterocyclic pharmacophores in biomedical applications, 14 new dihomooxacalix[4]arene N-heterocyclic (pyridine, quinoline, and thiazole) derivatives 4a-4n were efficiently synthesized from the parent compound, namely, p-tert-butyldihomooxacalix[4]arene 1; they were further investigated by using their IR, 1H NMR, 13C NMR, and HRMS spectra. Among these derivatives, the crystal and molecular structures of 2-aminomethyl-pyridine-substituted dihomooxacalix[4]arene 4f (obtained from methanol) have been determined by X-ray diffraction. In the case of the inhibition assay of cell growth, we evaluated the effects on four select tumor cell lines (MCF-7, HepG2, SKOV3, and HeLa), as well as the normal cell lines of HUVEC, using paclitaxel as the positive control drug. It was found that the derivatives 4d-4f, 4i, 4k, and 4l could inhibit tumoral activity up to varying degrees. Mechanistically, the cell cycle analysis demonstrated that dihomooxacalix[4]arene N-heterocyclic derivatives could induce apoptosis of MCF cells. In addition, the results of the western blot and immunofluorescence studies revealed the upregulation of the protein expression levels of Bax and cleaved caspase-3, as well as the downregulation of Bcl-2, which are in good agreement with the corresponding inhibitory potencies. Therefore, these findings suggest that N-heterocyclic derivatives based on the dihomooxacalix[4]arene scaffold are promising candidates for use against cancer.

Synthesis, X-ray crystal structure and anti-tumor activity of calix[n]arene polyhydroxyamine derivatives.

Calixarene-based compounds are highly effective therapeutic agents against cancer. This study aims to prepare a series of calix [n]arene (n = 4, 6, 8) polyhydroxyamine derivatives (3a-3m) and to study their potential antitumor activities. The single crystal structure of calixs[4]arene derivative 3a was determined through X-ray diffraction. We assessed the ability of the prepared calix [n]arene polyhydroxyamine derivatives to induce cytotoxicity in six cancer cell lines by performing cancer cell growth inhibition assays. Results demonstrated that compounds 3a-3d achieved IC50 values ranging from 1.6 µM to 11.3 µM. Among the different compounds, 3a and 3b exerted the strongest cytotoxic effect in inhibiting the growth of SKOV3 cells. In relation to the underlying mechanisms of cytotoxic effects, cell cycle analysis revealed that the exposure of SKOV3 cells to 3a induced cell cycle arrest in the G0/G1 phase, suggesting a reduction in DNA synthesis. Immunofluorescent staining indicated that the protein expression levels of caspase-3 and p53 in cells significantly increased, whereas that of Bcl-2 was effectively suppressed. Meanwhile, no significant changes in Bax were observed in SKOV3 cells. These results highlight that calixarene 3a can be further studied as a potential anticancer agent.