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. 2019 Dec 13:7:856.
doi: 10.3389/fchem.2019.00856. eCollection 2019.

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

Lin An  1   2 , Chan Wang  1   2 , Lili Han  3 , Jiadong Liu  1   2 , Tonghui Huang  1   2 , Youguang Zheng  1   2 , Chaoguo Yan  4 , Jing Sun  4
Affiliations

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

Lin An et al. Front Chem. .

Abstract

Calixarene and its derivatives have extensively served as promising anti-tumor agents. Previously, we have synthesized a series of calix[n]arene polyhydroxyamine derivatives (n = 4, 6, 8) and found that 5,11,17,23-tetra-tert-butyl-25,27-bis [N-(2-hydroxyethyl)aminocarbonylmethoxyl] calix[4]arene (CLX-4) 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 4A-4S 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 in vitro. Encouraging results show that the majority of dihomooxacalix[4]arene amide derivatives are effective at inhibiting A549 cell proliferation with the corresponding IC50 ranging from 0.6 to 20.1 μM. In particular, compounds 4A, 4D, and 4L explore markedly increased potency (IC50 value is 2.0 ± 0.5 μM, 0.7 ± 0.1 μM, and 1.7 ± 0.4 μM) over the cytotoxicity profiles of control CLX-4, whose IC50 value is 2.8 ± 0.3 μM. More interestingly, 4A also demonstrates the perfect cytotoxic effect against MCF-7, HeLa, and HepG2 cells with IC50 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 4A has much lower toxicity (41%) to normal cells at a concentration of 10 μM than that of 4D (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 4A and 4D 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.

Keywords: X-ray diffraction; biological evaluation; calixarene; dihomooxacalix[4]arene; structural optimization; supramolecular chemotherapy.

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Figures

Figure 1
Figure 1
The chemical structures of calix[4]arene-based anti-tumor agents.
Figure 2
Figure 2
Structural optimization design of dihomooxacalix[4]arene amide derivatives.
Scheme 1
Scheme 1
Synthetic routes for dihomooxacalix[4]arene amide derivatives 4A–4S. Reagents and conditions: (i) BrCH2COOC2H5, K2CO3, acetone, reflux; (ii) NH2CH2CH2OH or NH(CH2CH2OH)2, ethanol/toluene, reflux; (iii) NH2(CH2)nNH2 (n = 4, 6), methanol, rt; (iv) NH2(CH2)nNH2(n = 2, 3, 4), ethanol, reflux; (v) NH2R, ethanol; (vi) NH2CH2CH2OH, dichloromethane; (vii) NH2R, rt.
Figure 3
Figure 3
Single crystal structures of dihomooxacalix[4]arene-based compounds (hydrogen atoms on the skeletons were omitted for clarity) (A) amide derivative 4L; (B) amide derivative 4N.
Figure 4
Figure 4
Cytotoxicity effects of dihomooxacalix[4]arene-based compounds. Cell viability of cells (A) A549 cells, (B) HeLa cells, (C) MCF-7 cells, and (D) HepG2 cells were measured in the presence of various concentration of dihomooxacalix[4]arene amide derivatives and CLX-4.
Figure 5
Figure 5
Effect of 4A and 4D on the cell cycle of MCF-7 cells. Flow cytometric analyses of MCF-7 cells show that 4A (A), 4D (B) treatment induces G0/G1 arrest in MCF-7.
Figure 6
Figure 6
Effect of 4A and 4D on apoptosis in MCF-7 cells. Flow cytometric analyses of MCF-7 cells after Annexin IV staining show that compared to controls (A), 4A exposure (B) and 4D exposure (C) result in apoptosis in MCF-7 cells in a concentration. Data are reported as mean ± SD. *P < 0.001, compared to the control group.
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References

    1. Ali Y., Muhamad Bunnori N., Susanti D., Muhammad Alhassan A., Abd Hamid S. (2018). Synthesis, in-vitro and in silico studies of azo-based calix[4]arenes as antibacterial agent and neuraminidase inhibitor: a new look into an old scaffold. Front. Chem. 6, 210–219. 10.3389/fchem.2018.00210 - DOI - PMC - PubMed
    1. An L., Han L. L., Zheng Y. G., Peng X. N., Xue Y. S., Gu X. K., et al. (2016). Synthesis, x-ray crystal structure and anti-tumor activity of calix[n]arene polyhydroxyamine derivatives. Eur.J. Med. Chem. 123, 21–30. 10.1016/j.ejmech.2016.07.016 - DOI - PubMed
    1. An L., Wang J. W., Wang C., Zhou S. S., Sun J., Yan C. G. (2018). 2, 3-Ethylene-bridged dihomooxacalix [4] arenes: synthesis, X-ray crystal structures and highly selective binding properties with anions. New J. Chem. 42, 10689–10696. 10.1039/C8NJ01284A - DOI
    1. Bauer D., Andrae B., Gaß P., Trenz D., Becker S., Kubik S. (2019). Functionalisable acyclic cucurbiturils. Org. Chem. Front. 6, 1555–1560. 10.1039/C9QO00156E - DOI
    1. Böhmer V. (2010). Calixarenes, macrocycles with (almost) unlimited possibilities. Angew. Chem, Int. Ed. Engl. 34, 713–745. 10.1002/anie.199507131 - DOI