Skip to main content
SpringerLink
Log in

Synthesis and biological evaluation of novel 1,3-diphenylurea quinoxaline derivatives as potent anticancer agents

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

A series of 1,3-diphenylurea quinoxaline derivatives were synthesized and characterized by 1H, 13C NMR, and HR-ESI-MS analyses. In vitro cytotoxicity of the synthesized compounds was evaluated by MTT assay against MGC-803, H460, T-24, HeLa, HepG2, and SMMC-7721 human cancer cell lines. The results showed that most of the compounds exhibited effective cytotoxicity to the tested cancer cell lines. The mechanism of action of the two best active quinoxaline derivatives, compounds 2d and 2g was also investigated. They may be potent anticancer agents.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Chen W, Zheng R, Zhang S, Zeng H, Xia C, Zuo T, et al. Cancer incidence and mortality in China, 2013. Cancer Lett. 2017;401:63–71. https://doi.org/10.1016/j.canlet.2017.04.024.

    Article  PubMed  CAS  Google Scholar 

  2. Feng RM, Zong YN, Cao SM, Xu RH. Current cancer situation in China: good or bad news from the 2018 Global Cancer Statistics? Cancer Commun. 2019;39:22 https://doi.org/10.1186/s40880-019-0368-6.

    Article  Google Scholar 

  3. Tariq S, Somakala K, Amir M. Quinoxaline: An insight into the recent pharmacological advances. Eur J Med Chem. 2018;143:542–57. https://doi.org/10.1016/j.ejmech.2017.11.064.

    Article  PubMed  CAS  Google Scholar 

  4. Qi J, Dong H, Huang J, Zhang S, Niu L, Zhang Y, et al. Synthesis and biological evaluation of N-substituted 3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic acid derivatives as tubulin polymerization inhibitors. Eur J Med Chem. 2018;143:8–20. https://doi.org/10.1016/j.ejmech.2017.08.018.

    Article  PubMed  CAS  Google Scholar 

  5. Acharya BR, Chatterjee A, Ganguli A, Bhattacharya S, Chakrabarti G. Thymoquinone inhibits microtubule polymerization by tubulin binding and causes mitotic arrest following apoptosis in A549 cells. Biochimie. 2014;97:78–91. https://doi.org/10.1016/j.biochi.2013.09.025.

    Article  PubMed  CAS  Google Scholar 

  6. Kamal A, Reddy NV, Nayak VL, Reddy VS, Prasad B, Nimbarte VD, et al. Synthesis and biological evaluation of benzo[b]furans as inhibitors of tubulin polymerization and inducers of apoptosis. ChemMedChem. 2014;9:117–28. https://doi.org/10.1002/cmdc.201300366.

    Article  PubMed  CAS  Google Scholar 

  7. Perez-Perez MJ, Priego EM, Bueno O, Martins MS, Canela MD, Liekens S. Blocking blood flow to solid tumors by destabilizing tubulin: an approach to targeting tumor growth. J Med Chem. 2016;59:8685–711. https://doi.org/10.1021/acs.jmedchem.6b00463.

    Article  PubMed  CAS  Google Scholar 

  8. Tantak MP, Klingler L, Arun V, Kumar A, Sadana R, Kumar D. Design and synthesis of bis(indolyl)ketohydrazide-hydrazones: identification of potent and selective novel tubulin inhibitors. Eur J Med Chem. 2017;136:184–94. https://doi.org/10.1016/j.ejmech.2017.04.078.

    Article  PubMed  CAS  Google Scholar 

  9. Horio T, Murata T. The role of dynamic instability in microtubule organization. Front Plant Sci. 2014;5:511 https://doi.org/10.3389/fpls.2014.00511.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Prota AE, Bargsten K, Zurwerra D, Field JJ, Diaz JF, Altmann KH, et al. Molecular mechanism of action of microtubule-stabilizing anticancer agents. Science. 2013;339:587–90. https://doi.org/10.1126/science.1230582.

    Article  PubMed  CAS  Google Scholar 

  11. Stanton RA, Gernert KM, Nettles JH, Aneja R. Drugs that target dynamic microtubules: a new molecular perspective. Med. Res Rev. 2011;31:443–81. https://doi.org/10.1002/med.20242.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Montana M, Correard F, Khoumeri O, Esteve MA, Terme T, Vanelle P. Synthesis of new quinoxalines containing an oxirane ring by the TDAE strategy and in vitro evaluation in neuroblastoma cell lines. Molecules. 2014;19:14987–98. https://doi.org/10.3390/molecules190914987.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lan J, Huang L, Lou H, Chen C, Liu T, Hu S, et al. Design and synthesis of novel C14-urea-tetrandrine derivatives with potent anti-cancer activity. Eur J Med Chem. 2018;143:1968–80. https://doi.org/10.1016/j.ejmech.2017.11.007.

    Article  PubMed  CAS  Google Scholar 

  14. Sun S, He Z, Huang M, Wang N, He Z, Kong X, et al. Design and discovery of thioether and nicotinamide containing sorafenib analogues as multikinase inhibitors targeting B-Raf, B-RafV600E and VEGFR-2. Bioorg Med Chem. 2018;26:2381–91. https://doi.org/10.1016/j.bmc.2018.03.039.

    Article  PubMed  CAS  Google Scholar 

  15. Zhan WH, Li YY, Huang WP, Zhao YJ, Yao ZG, Yu SY, et al. Design, synthesis and antitumor activities of novel bis-aryl ureas derivatives as Raf kinase inhibitors. Bioorg Med Chem. 2012;20:4323–9. https://doi.org/10.1016/j.bmc.2012.05.051.

    Article  PubMed  CAS  Google Scholar 

  16. Xu Z, Yang F, Wei D, Liu B, Chen C, Bao Y, et al. Long noncoding RNA-SRLR elicits intrinsic sorafenib resistance via evoking IL-6/STAT3 axis in renal cell carcinoma. Oncogene. 2017;36:1965–77. https://doi.org/10.1038/onc.2016.356.

    Article  PubMed  CAS  Google Scholar 

  17. Li M, Su Y, Zhang F, Chen K, Xu X, Xu L, et al. A dual-targeting reconstituted high density lipoprotein leveraging the synergy of sorafenib and antimiRNA21 for enhanced hepatocellular carcinoma therapy. Acta Biomaterialia. 2018;75:413–26. https://doi.org/10.1016/j.actbio.2018.05.049.

    Article  PubMed  CAS  Google Scholar 

  18. Busschaert N, Kirby IL, Young S, Coles SJ, Horton PN, Light ME, et al. Squaramides as potent transmembrane anion transporters. Angew Chem Int Ed Engl. 2012;51:4426–30. https://doi.org/10.1002/anie.201200729.

    Article  PubMed  CAS  Google Scholar 

  19. Chen JN, Wang XF, Li T, Wu DW, Fu XB, Zhang GJ, et al. Design, synthesis, and biological evaluation of novel quinazolinyl-diaryl urea derivatives as potential anticancer agents. Eur J Med Chem. 2016;107:12–25. https://doi.org/10.1016/j.ejmech.2015.10.045.

    Article  PubMed  CAS  Google Scholar 

  20. Rodriguez R, Miller KM, Forment JV, Bradshaw CR, Nikan M, Britton S, et al. Small-molecule-induced DNA damage identifies alternative DNA structures in human genes. Nat Chem Biol. 2012;8:301–10. https://doi.org/10.1038/nchembio.780.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Chtchigrovsky M, Eloy L, Jullien H, Saker L, Segal-Bendirdjian E, Poupon J, et al. Antitumor trans-N-heterocyclic carbene-amine-Pt(II) complexes: synthesis of dinuclear species and exploratory investigations of DNA binding and cytotoxicity mechanisms. J Med Chem. 2013;56:2074–86. https://doi.org/10.1021/jm301780s.

    Article  PubMed  CAS  Google Scholar 

  22. Wei JH, Chen ZF, Qin JL, Liu YC, Li ZQ, Khan TM, et al. Water-soluble oxoglaucine-Y(III), Dy(III) complexes: in vitro and in vivo anticancer activities by triggering DNA damage, leading to S phase arrest and apoptosis. Dalton Trans. 2015;44:11408–19. https://doi.org/10.1039/c5dt00926j.

    Article  PubMed  CAS  Google Scholar 

  23. Qin QP, Qin JL, Meng T, Lin WH, Zhang CH, Wei ZZ, et al. High in vivo antitumor activity of cobalt oxoisoaporphine complexes by targeting G-quadruplex DNA, telomerase and disrupting mitochondrial functions. Eur J Med Chem. 2016;124:380–92. https://doi.org/10.1016/j.ejmech.2016.08.063.

    Article  PubMed  CAS  Google Scholar 

  24. Kastan MB, Bartek J. Cell-cycle checkpoints and cancer. Nature. 2004;432:316–23. https://doi.org/10.1038/nature03097.

    Article  PubMed  CAS  Google Scholar 

  25. Bhalla KN. Microtubule-targeted anticancer agents and apoptosis. Oncogene. 2003;22:9075–86. https://doi.org/10.1038/sj.onc.1207233.

    Article  PubMed  CAS  Google Scholar 

  26. Jordan MA, Wilson L. Microtubules as a target for anticancer drugs. Nat Rev Cancer. 2004;4:253–65. https://doi.org/10.1038/nrc1317.

    Article  PubMed  CAS  Google Scholar 

  27. Dumontet C, Jordan MA. Microtubule-binding agents: a dynamic field of cancer therapeutics. Nat Rev Drug Discov. 2010;9:790–803. https://doi.org/10.1038/nrd3253.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Zeng L, Chen Y, Liu J, Huang H, Guan R, Ji L, et al. Ruthenium(II) complexes with 2-phenylimidazo[4,5-f][1,10]phenanthroline derivatives that strongly combat cisplatin-resistant tumor cells. Sci Rep. 2016;6:19449. https://doi.org/10.1038/srep19449.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Chen ZF, Qin QP, Qin JL, Liu YC, Huang KB, Li YL, et al. Stabilization of G-quadruplex DNA, inhibition of telomerase activity, and tumor cell apoptosis by organoplatinum(II) complexes with oxoisoaporphine. J Med Chem. 2015;58:2159–79. https://doi.org/10.1021/jm5012484.

    Article  PubMed  CAS  Google Scholar 

  30. Lu CD, Altieri DC, Tanigawa N. Expression of a novel antiapoptosis gene, survivin, correlated with tumor cell apoptosis and p53 accumulation in gastric carcinomas. Cancer Res. 1998;58:1808–12.

    PubMed  CAS  Google Scholar 

  31. Bhattacharjee RN, Park KS, Kumagai Y, Okada K, Yamamoto M, Uematsu S, et al. VP1686, a Vibrio type III secretion protein, induces toll-like receptor-independent apoptosis in macrophage through NF-kappaB inhibition. J Biol Chem. 2006;281:36897–904. https://doi.org/10.1074/jbc.M605493200.

    Article  PubMed  CAS  Google Scholar 

  32. Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res. 2009;15:1126–32. https://doi.org/10.1158/1078-0432.CCR-08-0144.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Qin JL, Qin QP, Wei ZZ, Yu YC, Meng T, Wu CX, et al. Stabilization of c-myc G-Quadruplex DNA, inhibition of telomerase activity, disruption of mitochondrial functions and tumor cell apoptosis by platinum(II) complex with 9-amino-oxoisoaporphine. Eur J Med Chem. 2016;124:417–27. https://doi.org/10.1016/j.ejmech.2016.08.054.

    Article  PubMed  CAS  Google Scholar 

  34. Gou Y, Wang J, Chen S, Zhang Z, Zhang Y, Zhang W, et al. α-N-heterocyclic thiosemicarbazone Fe(III) complex: Characterization of its antitumor activity and identification of anticancer mechanism. Eur J Med Chem. 2016;123:354–64. https://doi.org/10.1016/j.ejmech.2016.07.041.

    Article  PubMed  CAS  Google Scholar 

  35. Noh J, Kwon B, Han E, Park M, Yang W, Cho W, et al. Amplification of oxidative stress by a dual stimuli-responsive hybrid drug enhances cancer cell death. Nat Commun. 2015;6:6907 https://doi.org/10.1038/ncomms7907.

    Article  PubMed  CAS  Google Scholar 

  36. Hong Y, Sengupta S, Hur W, Sim T. Identification of novel ROS inducers: quinone derivatives tethered to long hydrocarbon chains. J Med Chem. 2015;58:3739–50. https://doi.org/10.1021/jm501846y.

    Article  PubMed  CAS  Google Scholar 

  37. Smiley ST, Reers M, Mottola-Hartshorn C, Lin M, Chen A, Smith TW, et al. Intracellular heterogeneity in mitochondrial membrane potentials revealed by a J-aggregate-forming lipophilic cation JC-1. Proc Natl Acad Sci USA. 1991;88:3671–5. https://doi.org/10.1073/pnas.88.9.3671.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Hoye AT, Davoren JE, Wipf P, Fink MP, Kagan VE. Targeting mitochondria. Acc Chem Res. 2008;41:87–97. https://doi.org/10.1021/ar700135m.

    Article  PubMed  CAS  Google Scholar 

  39. Fromenty B, Pessayre D. Impaired mitochondrial function in microvesicular steatosis effects of drugs, ethanol, hormones and cytokines. J Hepatol. 1997;26:43–53. https://doi.org/10.1016/s0168-8278(97)80496-5.

    Article  PubMed  CAS  Google Scholar 

  40. Wang X. The expanding role of mitochondria in apoptosis. Genes Dev. 2001;15:2922–33.

    PubMed  CAS  Google Scholar 

  41. Salvesen GS, Riedl SJ. Caspase mechanisms. Adv Exp Med Biol. 2008;615:13–23. https://doi.org/10.1007/978-1-4020-6554-5_2.

    Article  PubMed  CAS  Google Scholar 

  42. Green D, Kroemer G. The central executioners of apoptosis: caspases or mitochondria? Trends Cell Biol. 1998;8:267–71. https://doi.org/10.1016/s0962-8924(98)01273-2.

    Article  PubMed  CAS  Google Scholar 

  43. Carvallo-Chaigneau F, Trejo-Solis C, Gomez-Ruiz C, Rodriguez-Aguilera E, Macias-Rosales L, Cortes-Barberena E, et al. Casiopeina III-ia induces apoptosis in HCT-15 cells in vitro through caspase-dependent mechanisms and has antitumor effect in vivo. Biometals. 2008;21:17–28. https://doi.org/10.1007/s10534-007-9089-4.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge the financial support from the Science and Technology Project of Guangxi (No. AB18221005), Science and Technology Major Project of Guangxi (No. AA17204058-21), Guangxi Key Laboratory of Special Non-wood Forest Cultivation & Utilization (No.18-A-04-01).

Author information

Author notes

  1. These authors contributed equally: Gui-Zhen Li, Xi-Lin Ouyang

Authors and Affiliations

  1. Guangxi Key Laboratory of Special Non-wood Forest Cultivation and Utilization, Guangxi Zhuang Autonomous Region Forestry Research Institute, 530022, Nanning, P. R. China

    Gui-Zhen Li, Yao Gu & Li Yang

  2. Department of Pharmacy, Gannan Healthcare Vocational College, 341000, Ganzhou, P. R. China

    Xi-Lin Ouyang

  3. State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmaceutical Sciences, Guangxi Normal University, 541004, Guilin, P. R. China

    Zu-Yu Mo, Xiao-Lin Cao, Hai-Tao Tang & Ying-Ming Pan

Authors
  1. Gui-Zhen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xi-Lin Ouyang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zu-Yu Mo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yao Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiao-Lin Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Li Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hai-Tao Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ying-Ming Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Li Yang.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, GZ., Ouyang, XL., Mo, ZY. et al. Synthesis and biological evaluation of novel 1,3-diphenylurea quinoxaline derivatives as potent anticancer agents. Med Chem Res 30, 1496–1511 (2021). https://doi.org/10.1007/s00044-021-02745-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-021-02745-2

Keywords

Search

Navigation