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

• Published in: European journal of medicinal chemistry 2016-11, Vol.123, p.21-30
• Main Authors: An, Lin, Han, Li-Li, Zheng, You-Guang, Peng, Xian-Na, Xue, Yun-Sheng, Gu, Xiao-Ke, Sun, Jing, Yan, Chao-Guo
• Format: Article
• Language: English
• Subjects: Animals; Anti-tumor activity; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Calix[n]arene; Calixarenes - chemical synthesis; Calixarenes - chemistry; Calixarenes - pharmacology; Caspase 3 - drug effects; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Crystallography, X-Ray; Cytostatic Agents - chemical synthesis; Cytostatic Agents - chemistry; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Polyhydroxyamine derivative; Structure-Activity Relationship; Tumor Suppressor Protein p53 - drug effects
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.07.016

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. [Display omitted] •Novel calix[n]arene (n = 4, 6, 8) polyhydroxyamine derivatives (3a–3m) were designed and afforded, including a single crystal of 3a.•Cell viability assay were evaluated in the six cell lines (A549, SKOV3, SW1990, Hela, Raji and MDA-MB-231).•Calix[4]arenes 3a–3d indicated good anti-tumor activity with IC50 values ranging from1.6 μM to 11.3 μM.•Cell cycle analysis and immunofluorescent staining indicated that 3a can be further studied as a potential anticancer agent.