Structural Design, Synthesis, and Preliminary Biological Evaluation of Novel Dihomooxacalix[4]arene-Based Anti-tumor Agents.

Calixarene and its derivatives have extensively served as promising anti-tumor agents. Previously, we have synthesized a series of calix[n]arene polyhydroxyamine derivatives ( = 4, 6, 8) and found that 5,11,17,23--butyl-25,27-bis [N-(2-hydroxyethyl)aminocarbonylmethoxyl] calix[4]arene displayed significant effect toward SKOV3, A549, SW1990, HeLa, Raji, and MDA-MB-231 cancer cells. In the present work, we find a replacement of calix[4]arene bone and synthesized 19 novel structurally related dihomooxacalix[4]arene amide derivatives to optimize its efficacy. Their abilities to induce cytotoxicity in human lung carcinoma (A549) cells, breast cancer (MCF-7) cells, cervical cancer (HeLa) cells, hepatocellular carcinoma (HepG2) cells, as well as human umbilical vein endothelial (HUVEC) cells are evaluated . Encouraging results show that the majority of dihomooxacalix[4]arene amide derivatives are effective at inhibiting A549 cell proliferation with the corresponding IC ranging from 0.6 to 20.1 μM. In particular, compounds , , and explore markedly increased potency (IC value is 2.0 ± 0.5 μM, 0.7 ± 0.1 μM, and 1.7 ± 0.4 μM) over the cytotoxicity profiles of control , whose IC value is 2.8 ± 0.3 μM. More interestingly, also demonstrates the perfect cytotoxic effect against MCF-7, HeLa, and HepG2 cells with IC values of 1.0 ± 0.1 μM, 0.8 ± 0.2 μM, and 2.7 ± 0.4 μM. In addition, the results proved that our synthesized has much lower toxicity (41%) to normal cells at a concentration of 10 μM than that of (90%). To reveal the mechanisms, the key indicators including the cell cycle and apoptosis are observed by the flow cytometry analysis in MCF-7 cells. The results demonstrate that both and can induce the MCF-7 cell cycle arrest in G0/G1 phase and cell apoptosis. Therefore, our finding proves that the dihomooxacalix[4]arene amide derivatives are convenient platforms for potential supramolecular anticancer agents.