Medicinal Chemistry Research

, Volume 28, Issue 10, pp 1694–1703 | Cite as

New pyranoquinoline derivatives as vascular-disrupting anticancer agents

  • Florian Schmitt
  • Rainer Schobert
  • Bernhard BiersackEmail author
Original Research


A series of new 4-aryl-pyranoquinoline derivatives with a focus on meta-nitro and meta-halophenyl derivatives were prepared and investigated for their structure-dependent antiproliferative effects on a panel of six human cancer cell lines. The compounds were highly active with nanomolar IC50 values. Some of them even exceeded the activities of known analogs such as LY290181 in vitro while not affecting non-malignant fibroblasts. These most active derivatives led to an increase of reactive oxygen species in cancer cells and to a disruption of their microtubular cytoskeleton by inhibiting tubulin polymerization. They also displayed vascular-disrupting activity in ovo as assessed by chorioallantoic membrane assays.


Pyranoquinoline Anticancer agents Tubulin polymerization inhibitors Vascular-disrupting agents 



We thank Madeleine Gold and Kerstin Hannemann (Organic Chemistry 1, University of Bayreuth) for technical assistance.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2019_2406_MOESM1_ESM.docx (17.6 mb)
Supplementary material


  1. Afzal O, Kumar S, Haider MR, Ali MR, Kumar R, Jaggi M, Bawa S (2015) A review on anticancer potential of bioactive heterocycle quinoline. Eur J Med Chem 97:871–910CrossRefGoogle Scholar
  2. Birch KA, Heath WF, Hermeling RN, Johnston CM, Stramm L, Dell C, Smith C, Williamson JR, Reifel-Miller A (1996) LY290181, an inhibitor of diabetes-induced vascular dysfunction, blocks protein kinase C-stimulated transcriptional activation through inhibition of transcription factor binding to a phorbol response element. Diabetes 45:642–650CrossRefGoogle Scholar
  3. Dgachi Y, Sokolov O, Luzet V, Godyn J, Panek D, Bonet A, Martin H, Iriepa I, Moraleda I, García-Iriepa C, Janockova J, Richert L, Soukup O, Malawska B, Chabchoub F, Marco-Contelles J, Ismaili L (2017) Tetrahydropyranodiquinolin-8-amines as new, non hepatoxic, antioxidant, and acetylcholinesterase inhibitors for Alzheimer’s disease therapy. Eur J Med Chem 126:576–589CrossRefGoogle Scholar
  4. El-Agrody AM, Al-Ghamdi AM (2011) Synthesis, of novel 4H-pyrano[3,2-h]quinoline derivatives. ARKIVOC 11:134–146Google Scholar
  5. El-Agrody AM, Abd-Rabboh HSM, Al-Ghamdi AM (2013) Synthesis, antitumor activity, and structure-activity relationship of some 4H-pyrano[3,2-h]quinoline and 7H-pyrimidino[4’,5’:6,5]pyrano[3,2-h]quinoline derivatives. Med Chem Res 22:1339–1355CrossRefGoogle Scholar
  6. Fouda AM (2017) Halogenated 2-amino-4H-pyrano[3,2-h]quinolone-3-carbonitriles as antitumor agents and structure-activity relationships of the 4-, 6-, and 9-positions. Med Chem Res 26:302–313CrossRefGoogle Scholar
  7. Gold M, Mujahid Y, Ahmed K, Kostrhunova H, Kasparkova J, Brabec V, Biersack B, Schobert R (2019) A new 4-(pyridinyl-4H-benzo[g]chromene-5,10-dione ruthenium(II) complex inducing senescence in 518A2 melanoma cells. J Biol Inorg Chem.
  8. Isanbor C, O’Hagan D (2006) Fluorine in medicinal chemistry: A review of anticancer agents. J Fluor Chem 127:303–319CrossRefGoogle Scholar
  9. Kemnitzer W, Drewe J, Jiang S, Zhang H, Zhao J, Crogan-Grundy C, Xu L, Lamothe S, Gourdeau H, Denis R, Tseng B, Kasibhatla S, Cai SX (2007) Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 3. Structure – activity relationships of fused rings at the 7,8-positions. J Med Chem 50:2858–2864CrossRefGoogle Scholar
  10. Kumar S, Bawa S, Gupta H (2009) Biological activities of quinoline derivatives. Mini-Rev Med Chem 9:1648–1654CrossRefGoogle Scholar
  11. Lau ATY, Wang Y, Chiu JF (2008) Reactive oxygen species: current knowledge and applications in cancer research. J Cell Biochem 104:657–667CrossRefGoogle Scholar
  12. Lippert III JW (2007) Vascular disrupting agents. Bioorg Med Chem 15:605–615CrossRefGoogle Scholar
  13. Mahal K, Biersack B, Schobert R (2013) New oxazole-bridged combretastatin A-4 analogues as potential vascular-disrupting agents. Int J Clin Pharm Ther 51:41–43CrossRefGoogle Scholar
  14. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63CrossRefGoogle Scholar
  15. Nitzsche B, Gloesenkamp C, Schrader M, Ocker M, Preissner R, Lein M, Zakrzewicz A, Hoffmann B, Höpfner M (2010) Novel compounds with antiangiogenic and antiproliferative potency for growth control of testicular germ cell tumours. Br J Cancer 103:18–28CrossRefGoogle Scholar
  16. Pérez-Pérez M-J, Priego E-M, Bueno O, Martins MS, Canela M-D, Liekens S (2016) Blocking blood flow to solid tumors by destabilizing tubulin: an approach to targeting tumor growth. J Med Chem 59:8685–8711CrossRefGoogle Scholar
  17. Rafinejad A, Fallah-Tafti A, Tiwari R, Shirazi AN, Mandal D, Shafiee A, Parang K, Foroumadi A, Akbarzadeh T (2012) 4-Aryl-4H-naphthopyrans derivatives: one-pot synthesis, evaluation of Src kinase inhibitory and anti-proliferative activities. DARU J Pharm Sci 20:100CrossRefGoogle Scholar
  18. Schmitt F, Kasparkova J, Brabec V, Begemann G, Schobert R, Biersack B (2018) New (arene)ruthenium(II) complexes of 4-aryl-4H-naphthopyrans with anticancer and anti-vascular activities. J Inorg Biochem 184:69–78CrossRefGoogle Scholar
  19. Schmitt F, Gold M, Rothemund M, Andronache I, Biersack B, Schobert R, Mueller T (2019) New naphthopyran analogues of LY290181 as potential tumor vascular-disrupting agents. Eur J Med Chem 163:160–168CrossRefGoogle Scholar
  20. Smith W, Bailey JM, Billingham MEJ, Chandrasekhar S, Dell CP, Harvey AK, Hicks CA, Kingston AE, Wishart GN (1995) The anti-rheumatic potential of a series of 2,4-di-substituted-4H-naphthol[1,2-b]pyran-3-carbonitriles. Bioorg Med Chem Lett 5:2783–2788CrossRefGoogle Scholar
  21. Thorpe PE (2002) Vascular targeting agents as cancer therapeutics. Clin Cancer Res 10:415–427CrossRefGoogle Scholar
  22. Thumar NJ, Patel MP (2009) Synthesis and in vitro antimicrobial evaluation of 4H-pyrazolopyran, -benzopyran and naphthopyran derivatives of 1H-pyrazole. Arkivoc 13:363–380Google Scholar
  23. Tron GC, Pirali T, Sorba G, Pagliai F, Busacca S, Genazzani AA (2006) Medicinal chemistry of combretastatin A4: present and future directions. J Med Chem 49:3033–3044CrossRefGoogle Scholar
  24. Upadhyay KD, Dodia NM, Khunt RC, Chaniara RS, Shah AK (2018) Synthesis and biological screening of pyrano[3,2-c]quinolone analogues as anti-inflammatory and anticancer agents. ACS Med Chem Lett 9:283–288CrossRefGoogle Scholar
  25. Wiernicki TR, Bean JS, Dell C, Williams A, Wood D, Kauffman RF, Singh JP (1996) Inhibition of vascular smooth muscle cell proliferation and arterial intimal thickening by a novel antiproliferative naphthopyran. J Pharm Exp Ther 278:1452–1459Google Scholar
  26. Wood D, Panda D, Wiernicki TR, Wilson L, Jordan MA, Singh JP (1997) Inhibition of mitosis and microtubule function through direct tubulin binding by a novel antiproliferative naphthopyran LY290181. Mol Pharm 52:427–444CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Organic Chemistry LaboratoryUniversity of BayreuthBayreuthGermany

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