Synthesis and anticancer activity evaluation of novel oxacalix[2]arene[2]pyrimidine derivatives

  • Tonghui Huang
  • Xin Wu
  • Tianya Liu
  • Lin An
  • Xiaoxing YinEmail author
Original Research


A series of novel oxacalix[2]arene[2]pyrimidine derivatives were synthesized, and their antitumor activities against HeLa, MCF7, HepG2, and A549 human cancer cell lines were evaluated using an MTT assay. Some of the synthesized compounds exhibited considerable anti-proliferative activity against the human cancer cell lines. Compound 5l, which contains an ethanolamine moiety, exhibited the strongest inhibitory activity against HepG2 with an IC50 value of 12.37 μM. Moreover, a cell apoptosis assay indicated that the anti-proliferative activity of 5l might be attributed to its induction of apoptosis. Our report highlights the potential anticancer efficacy of novel oxacalix[2]arene[2]pyrimidines.


Oxacalix[2]arene[2]pyrimidine Ethanolamine Anticancer Apoptosis 



This study was funded by the grants from Natural Science Foundation of Jiangsu Province (BK20171184; BK20170258), Jiangsu Planned Projects for Postdoctoral Research Funds (1701132C), Technology Plan Projects of Xuzhou (KC17091), and Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX18-2203).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2019_2321_MOESM1_ESM.pdf (1 mb)
Supplementary Information


  1. Addepalli Y, Yang XH, Zhou MH, Reddy DP, Zhang SL, Wang Z, He Y (2018) Synthesis and anticancer activity evaluation of novel azacalix[2]arene[2]pyrimidines. Eur J Med Chem 151:214–225CrossRefPubMedGoogle Scholar
  2. An L, Han LL, Zheng YG, Peng XN, Xue YS, Gu XK, Sun J, Yan CG (2016) Synthesis, X-ray crystal structure and anti-tumor activity of calix[n]arene polyhydroxyamine derivatives. Eur J Med Chem 123:21–30CrossRefPubMedGoogle Scholar
  3. Arafa ESA, Abdelazeem AH, Arab HH, Omar HA (2014) OSU-CG5, a novel energy restriction mimetic agent, targets human colorectal cancer cells in vitro. Acta Pharmacol Sin 35:394–400CrossRefPubMedCentralGoogle Scholar
  4. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca Cancer J Clin 68:394–424CrossRefPubMedGoogle Scholar
  5. Buldenkoa VM, Kobzara OL, Trusha VV, Drapailob AB, Kalchenkob VI, Vovka AI (2017) Sulfonyl-bridged calix[4]arene as an inhibitor of protein tyrosine phosphatases. FUJC 5:144–151Google Scholar
  6. Caio JM, Esteves T, Carvalho S, Moiteiro C, Felix V (2014) Azacalix[2]arene[2]triazine-based receptors bearing carboxymethyl pendant arms on nitrogen bridges: synthesis and evaluation of their coordination ability towards copper(II). Org Biomol Chem 12:589–599CrossRefPubMedGoogle Scholar
  7. Chhajed M, Shrivastava AK, Taile V (2014) Synthesis of 5-arylidine amino-1,3,4-thiadiazol-2-[(N-substituted benzyol)]sulphonamides endowed with potent antioxidants and anticancer activity induces growth inhibition in HEK293, BT474 and NCI-H226 cells. Med Chem Res 23:3049–3064CrossRefPubMedGoogle Scholar
  8. Dings RPM, Chen XM, Hellebrekers DMEI, van Eijk LI, Zhang Y, Hoye TR, Griffioen AW, Mayo KH (2016) Design of nonpeptidic topomimetics of antiangiogenic proteins with antitumor activities. J NatlCancer I 98:932–936CrossRefGoogle Scholar
  9. Dings RPM, Levine JI, Brown SG, Astorgues-Xerri L, MacDonald JR, Hoye TR, Raymond E, Mayo KH (2013) Polycationic calixarene PTX013, a potent cytotoxic agent against tumors and drug resistant cancer. Invest New Drug 31:1142–1150CrossRefGoogle Scholar
  10. Dings RPM, Miller MC, Nesmelova I, Astorgues-Xerri L, Kumar N, Serova M, Chen XM, Raymond E, Hoye TR, Mayo KH (2014) Antitumor agent calixarene 0118 targets human galectin-1 as an allosteric inhibitor of carbohydrate binding. J Med Chem 55:5121–5129CrossRefGoogle Scholar
  11. Elkamhawy A, Paik S, Hassan AHE, Lee YS, Roh EJ (2017) Hit discovery of 4-amino-N-(4-(3-(trifluoromethyl)phenoxy)pyrimidin-5-yl)benzamide: a novel EGFR inhibitor from a designed small library. Bioorg Chem 75:393–405CrossRefPubMedGoogle Scholar
  12. Fa SX, Wang LX, Wang DX, Zhao L, Wang MX (2014) Synthesis, structure, and fullerene-complexing property of azacalix[6]aromatics. J Org Chem 79:3559–3571CrossRefPubMedGoogle Scholar
  13. Galal SA, Khattab M, Shouman SA, Ramadan R, Kandil OM, Kandil OM, Tabll A, El Abd YS, El-Shenawy R, Attia YM, El-Rashedy AA, El Diwani HI (2018) Part III: Novel checkpoint kinase 2 (Chk2) inhibitors; design, synthesis and biological evaluation of pyrimidine-benzimidazole conjugates. Eur J Med Chem 146:687–708CrossRefPubMedGoogle Scholar
  14. Gao GR, Li MY, Lv YC, Cao SF, Tong LJ, Wei LX, Ding J, Xie H, Duan WH (2016) Design, synthesis and biological evaluation of biphenylurea derivatives as VEGFR-2 kinase inhibitors (II). Chin Chem Lett 27:200–204CrossRefGoogle Scholar
  15. Geretto M, Ponassi M, Casale M, Pulliero A, Cafeo G, Malagreca F, Profumo A, Balza E, Bersimbaev R, Kohnke FH, Rosano C, Izzotti A (2018) A novel calix[4]pyrrole derivative as a potential anticancer agent that forms genotoxic adducts with DNA. Sci Rep-UK 8:11075CrossRefGoogle Scholar
  16. Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N, Sarkar S (2014) Drug resistance in cancer: an overview. Cancers 6:1769–1792CrossRefPubMedPubMedCentralGoogle Scholar
  17. Huang SL, Li RH, LaMontagne KR, Greenberger LM, Connolly PJ (2011) 4-Aminopyrimidine-5-carbaldehyde oximes as potent VEGFR-2 inhibitors. Part II. Bioorg Med Chem Lett 21:1815–1818CrossRefPubMedGoogle Scholar
  18. Johnson TW, Gallego RA, Edwards MP (2018) Lipophilic efficiency as an important metric in drug design. J Med Chem 61:6401–6420CrossRefPubMedGoogle Scholar
  19. Kamchonwongpaisan S, Quarrell R, Charoensetakul N, Ponsinet R, Vilaivan T, Vanichtanankul J, Tarnchompoo B, Sirawaraporn W, Lowe G, Yuthavong Y (2004) Inhibitors of multiple mutants of Plasmodium falciparum dihydrofolate reductase and their antimalarial activities. J Med Chem 47:673–680CrossRefPubMedGoogle Scholar
  20. Kaur R, Kaur P, Sharma S, Singh G, Mehndiratta S, Bedi PMS, Nepali K (2015) Anti-cancer pyrimidines in diverse scaffolds: a review of patent literature. Recent Pat Anti-Cancer Drug Discov 10:23–71CrossRefGoogle Scholar
  21. Kraljevic TG, Klik M, Kralj M, Martin-Kleiner I, Jurmanovic S, Milic A, Padovan J, Raic-Malic S (2012) Synthesis, cytostatic activity and ADME properties of C-5 substituted and N-acyclic pyrimidine derivatives. Bioorg Med Chem Lett 22:308–312CrossRefPubMedGoogle Scholar
  22. Kumar B, Sharma P, Gupta VP, Khullar M, Singh S, Dogra N, Kumar V (2018) Synthesis and biological evaluation of pyrimidine bridged combretastatin derivatives as potential anticancer agents and mechanistic studies. Bioorg Chem 78:130–140CrossRefPubMedGoogle Scholar
  23. Li JT, Wang DX, Zhao L, Wang MX (2014) Synthesis of functionalized azacalix[3]aromatics from azacalix[4]pyrimidine: unexpected macrocyclic transannular reactions. Tetrahedron Lett 55:3259–3262CrossRefGoogle Scholar
  24. Liu I, Li SL, Li XL, Min Z, Yin L, Yang JJ, Zhang YM, He XR (2018) Synthesis of NSAIDs-Se derivatives as potent anticancer agents. Med Chem Res 27:2071–2078CrossRefGoogle Scholar
  25. Liu XP, Liu SC, Chen JR, He L, Meng XY, Liu SQ (2016) Baicalein suppresses the proliferation of acute T-lymphoblastic leukemia Jurkat cells by inhibiting the Wnt/beta-catenin signaling. Ann Hematol 95:1787–1793CrossRefPubMedGoogle Scholar
  26. Moty SGA, Hussein MA, Aziz SAA, Abou-Salim MA (2016) Design and synthesis of some substituted thiazolo[3,2-a]pyrimidine derivatives of potential biological activities. Saudi Pharm J 24:119–132CrossRefPubMedGoogle Scholar
  27. Mutihac L, Lee JH, Kim JS, Vicens J (2011) Recognition of amino acids by functionalized calixarenes. Chem Soc Rev 40:2777–2796CrossRefPubMedGoogle Scholar
  28. Olgen S (2018) Overview on anticancer drug design and development. Curr Med Chem 25:1704–1719CrossRefPubMedGoogle Scholar
  29. Pelizzaro-Rocha KJ, de Jesus MB, Ruela-de-Sousa RR, Nakamura CV, Reis FS, de Fatima A, Ferreira-Halder CV (2013) Calix[6]arene bypasses human pancreatic cancer aggressiveness: downregulation of receptor tyrosine kinases and induction of cell death by reticulum stress and autophagy. Bba-Mol Cell Res 1833:2856–2865Google Scholar
  30. Preetam A, Nath M (2015) An eco-friendly Pictet–Spengler approach to pyrrolo- and indolo[1,2-a]quinoxalines using p-dodecylbenzenesulfonic acid as an efficient Bronsted acid catalyst. RSC Adv 5:21843–21853CrossRefGoogle Scholar
  31. Soares MN, Gascon TM, Fonseca FLA, Ferreira KS, Bagatin IA (2014) Evaluation of the biological effects of 5-Cl-8-oxyquinolinepropoxycalix[4]arene and 8-oxyquinolinepropoxycalix[4]arene in vitro and in vivo. Mater Sci Eng C-Mater 40:260–266CrossRefGoogle Scholar
  32. Steed JW (2015) Supramolecular chemistry as an underpinning concept. Supramol Chem 27:731–733CrossRefGoogle Scholar
  33. Tantry SJ, Markad SD, Shinde V, Bhat J, Balakrishnan G, Gupta AK, Ambady A, Raichurkar A, Kedari C, Sharma S, Mudugal NV, Narayan A, Kumar CNN, Nanduri R, Bharath S, Reddy J, Panduga V, Prabhakar KR, Kandaswamy K, Saralaya R, Kaur P, Dinesh N, Guptha S, Rich K, Murray D, Plant H, Preston M, Ashton H, Plant D, Walsh J, Alcock P, Naylor K, Collier M, Whiteaker J, McLaughlin RE, Mallya M, Panda M, Rudrapatna S, Ramachandran V, Shandil R, Sambandamurthy VK, Mdluli K, Cooper CB, Rubin H, Yano T, Iyer P, Narayanan S, Kavanagh S, Mukherjee K, Balasubramanian V, Hosagrahara VP, Solapure S, Ravishankar S, Hameed PS (2017) Discovery of imidazo[1,2-a]pyridine ethers and squaramides as selective and potent inhibitors of mycobacterial adenosine triphosphate (ATP) synthesis. J Med Chem 60:1379–1399CrossRefPubMedGoogle Scholar
  34. Vineis P, Wild CP (2014) Global cancer patterns: causes and prevention. Lancet 383:549–557CrossRefPubMedGoogle Scholar
  35. Yao DH, Zhou YX, Zhu LJ, Ouyang L, Zhang J, Jiang YN, Zhao YQ, Sun DJ, Yang SL, Yu Y, Wang JH (2017) Design, synthesis and structure–activity relationship studies of a focused library of pyrimidine moiety with anti-proliferative and anti-metastasis activities in triple negative breast cancer. Eur J Med Chem 140:155–171CrossRefPubMedGoogle Scholar
  36. Zadmard R, Schrader T (2006) DNA recognition with large calixarene dimers. Angew Chem Int Ed 45:2703–2706CrossRefGoogle Scholar
  37. Zhang N, Yu ZM, Yang XH, Hu P, He Y (2018) Synthesis of novel ring-contracted artemisinin dimers with potent anticancer activities. Eur J Med Chem 150:829–840CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Tonghui Huang
    • 1
    • 2
  • Xin Wu
    • 1
  • Tianya Liu
    • 3
  • Lin An
    • 1
  • Xiaoxing Yin
    • 1
    Email author
  1. 1.Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityXuzhouPeople’s Republic of China
  2. 2.Xuzhou Medical University Science ParkXuzhouPeople’s Republic of China
  3. 3.Department of PharmacyThe Affiliated Hospital of Xuzhou Medical UniversityXuzhouPeople’s Republic of China

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