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

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 IC 50 ranging from 0.6 to 20.1 µM. In particular, compounds 4A, 4D, and 4L explore markedly increased potency (IC 50 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 IC 50 value is 2.8 ± 0.3 µM. More interestingly, 4A also demonstrates the perfect cytotoxic effect against MCF-7, HeLa, and HepG2 cells with IC 50 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.

Exploring the Expanding Frontiers: The Promising Role of Supramolecules in Advancing Cancer and Infectious Disease Therapy

“…They found that some of the calixarenes were able to prevent breast cancer development cancer cells and induce apoptosis in these cells. Another study investigated the activity of calixarenes against human colon cancer cells and found that the compounds were able to inhibit the growth of these cells and induce apoptosis through the caspase pathway 29,30 . In addition to their ability to induce apoptosis, calixarenes also have the potential to enhance the efficacy of other anti-cancer agents.…”

Controllable self-assembly of thiophene-based π-conjugated molecule and further construction of pillar[5]arene-based host-guest white-light emission system

“…Pillar [n]arenes (Ogoshi et al, 2008;Xiao et al, 2018;Duan et al, 2020;Wang et al, 2020;Wang et al, 2022b) are the fifth generation of macrocyclic hosts following crown ethers (An et al, 2021), cyclodextrins (Zhou et al, 2021), calixarenes (An et al, 2019;Guo et al, 2020b) and cucurbiturils (Yan et al, 2021). They are oligo-cyclic compounds obtained by methylene bridged p-methoxylbenzene (Zhang et al, 2019;Lou and Yang, 2021).…”

Efficient and Selective Antitumor Agents Based on Cationic Calixarenes: Synthesis, Characterization, and Antiproliferative Properties

“…Recently, calixarenes have been proven to be good building scaffolds for the synthesis of anticancer agents in the literature (Rouge et al, 2010;Nimse ve Kim, 2013;Santos et al, 2015;Yousaf et al, 2015;Naseer et al, 2017;Yilmaz et al, 2020;An et al, 2021;Zhou et al, 2021). Due to their multiple derivatization possibilities, different functional groups that have anti-tumor properties can easily be incorporated at their lower/upper rim (de Fátima et al, 2009;Rodik et al, 2009;Dings et al, 2013;Saluja ve Sekhon, 2013;Läppchen et al, 2015;Yousaf et al, 2015;An et al, 2016;An et al, 2019;Rego ve ark., 2019).…”