AUTHOR=An Lin , Wang Chan , Han Lili , Liu Jiadong , Huang Tonghui , Zheng Youguang , Yan Chaoguo , Sun Jing 

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

JOURNAL=Frontiers in Chemistry

VOLUME=7

YEAR=2019

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2019.00856

DOI=10.3389/fchem.2019.00856

ISSN=2296-2646

ABSTRACT=<p>Calixarene and its derivatives have extensively served as promising anti-tumor agents. Previously, we have synthesized a series of calix[n]arene polyhydroxyamine derivatives (<italic>n</italic> = 4, 6, 8) and found that 5,11,17,23-<italic>tetra-tert</italic>-butyl-25,27-bis [N-(2-hydroxyethyl)aminocarbonylmethoxyl] calix[4]arene <bold>(CLX-4)</bold> 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 <bold>4A−4S</bold> 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 <italic>in vitro</italic>. Encouraging results show that the majority of dihomooxacalix[4]arene amide derivatives are effective at inhibiting A549 cell proliferation with the corresponding IC<sub>50</sub> ranging from 0.6 to 20.1 μM. In particular, compounds <bold>4A</bold>, <bold>4D</bold>, and <bold>4L</bold> explore markedly increased potency (IC<sub>50</sub> value is 2.0 ± 0.5 μM, 0.7 ± 0.1 μM, and 1.7 ± 0.4 μM) over the cytotoxicity profiles of control <bold>CLX-4</bold>, whose IC<sub>50</sub> value is 2.8 ± 0.3 μM. More interestingly, <bold>4A</bold> also demonstrates the perfect cytotoxic effect against MCF-7, HeLa, and HepG2 cells with IC<sub>50</sub> 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 <bold>4A</bold> has much lower toxicity (41%) to normal cells at a concentration of 10 μM than that of <bold>4D</bold> (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 <bold>4A</bold> and <bold>4D</bold> 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.</p>