Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Structure-activity relationships of natural quinone vegfrecine analogs with potent activity against VEGFR-1 and -2 tyrosine kinases


A series of analogs of vegfrecine, a natural quinone vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, was synthesized via oxidative amination of 2,5-dihydroxybenzamide with functionalized arylamine followed by ammonolysis and substitution of the quinone ring. The inhibitory activities of the analogs against the VEGFR-1 and -2 tyrosine kinases were assayed in vitro with the aim to identify a compound suitable to treat cancer and inflammatory diseases. Alterations of the functionality of the phenyl group, substitution of the quinone ring, and oxidative cyclization of the 1-carboxamide-2-aminoquinone moiety to form an isoxazole quinone ring were examined. Introduction of halo- and alkyl-substituents at the 5′-position of the phenyl ring resulted in potent inhibition of the VEGFR-1 and -2 tyrosine kinases. In particular, structural modification at C-5′ on the phenyl ring was shown to significantly affect the selectivity of the inhibition between the VEGFR-1 and -2 tyrosine kinases. Compound 8, 5′-methyl-vegfrecine, showed superior selectivity toward the VEGFR-2 tyrosine kinase over the VEGFR-1 tyrosine kinase.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2
Scheme 1


  1. 1.

    Carmeliet P, et al. Role of tissue factor in embryonic blood vessel development. Nature. 1996;383:73–5.

    CAS  Article  Google Scholar 

  2. 2.

    Ferrara N, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996;380:439–42.

    CAS  Article  Google Scholar 

  3. 3.

    Mustonen T, Alitalo K. Endothelial receptor tyrosine kinases involved in angiogenesis. J Cell Biol. 1995;129:895–8.

    CAS  Article  Google Scholar 

  4. 4.

    Risau W. Mechanisms of angiogenesis. Nature. 1997;386:671–4.

    CAS  Article  Google Scholar 

  5. 5.

    Costa C, Incio J, Soares R. Angiogenesis and chronic inflammation: cause or consequence? Angiogenesis. 2007;10:149–66.

    Article  Google Scholar 

  6. 6.

    Elshabrawy HA, Chen Z, Volin MV, Ravella S, Virupannavar S, Shahrara S. The pathogenic role of angiogenesis in rheumatoid arthritis. Angiogenesis. 2015;18:433–48.

    CAS  Article  Google Scholar 

  7. 7.

    Dorrell M, Uusitalo-Jarvinen H, Aguilar E, Friedlander M. Ocular neovascularization: basic mechanisms and therapeutic advances. Surv Ophthalmol. 2007;52:S3–19.

    Article  Google Scholar 

  8. 8.

    Creamer D, Sullivan D, Bicknell R, Barker J. Angiogenesis in psoriasis. Angiogenesis. 2002;5:231–6.

    CAS  Article  Google Scholar 

  9. 9.

    Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002;29 Suppl 16:15–8.

    CAS  Article  Google Scholar 

  10. 10.

    Eichmann A, Marcelle C, Breant C, Le Douarin NM. Two molecules related to the VEGF receptor are expressed in early endothelial cells during avian embryonic development. Mech Dev. 1993;42:33–48.

    CAS  Article  Google Scholar 

  11. 11.

    Jakeman LB, Winer J, Bennett GL, Altar CA, Ferrara N. Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues. J Clin Investig. 1992;89:244–53.

    CAS  Article  Google Scholar 

  12. 12.

    Kaipainen A, et al. The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells. J Exp Med. 1993;178:2077–88.

    CAS  Article  Google Scholar 

  13. 13.

    Yamane A, et al. A new communication system between hepatocytes and sinusoidal endothelial cells in liver through vascular endothelial growth factor and Flt tyrosine kinase receptor family (Flt-1 and KDR/Flk-1). Oncogene. 1994;9:2683–90.

    CAS  PubMed  Google Scholar 

  14. 14.

    Adams J, Huang P, Patrick D. A strategy for the design of multiplex inhibitors for kinase-mediated signalling in angiogenesis. Curr Opin Chem Biol. 2002;6:486–92.

    CAS  Article  Google Scholar 

  15. 15.

    Boyer SJ. Small molecule inhibitors of KDR (VEGFR-2) kinase: an overview of structure activity relationships. Curr Top Med Chem. 2002;2:973–1000.

    CAS  Article  Google Scholar 

  16. 16.

    Sun L, McMahon G. Inhibition of tumor angiogenesis by synthetic receptor tyrosine kinase inhibitors. Drug Discov Today. 2000;5:344–53.

    CAS  Article  Google Scholar 

  17. 17.

    Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K. Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res. 2000;60:203–12.

    CAS  PubMed  Google Scholar 

  18. 18.

    Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem. 1994;269:26988–95.

    CAS  Article  Google Scholar 

  19. 19.

    Adini A, Kornaga T, Firoozbakht F, Benjamin LE. Placental growth factor is a survival factor for tumor endothelial cells and macrophages. Cancer Res. 2002;62:2749–52.

    CAS  PubMed  Google Scholar 

  20. 20.

    Hiratsuka S, Maru Y, Okada A, Seiki M, Noda T, Shibuya M. Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis. Cancer Res. 2001;61:1207–13.

    CAS  PubMed  Google Scholar 

  21. 21.

    Luttun A, et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med. 2002;8:831–40.

    CAS  Article  Google Scholar 

  22. 22.

    Lyden D, et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med. 2001;7:1194–201.

    CAS  Article  Google Scholar 

  23. 23.

    Sawano A, et al. Flt-1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood. 2001;97:785–91.

    CAS  Article  Google Scholar 

  24. 24.

    Choi ST, Kim JH, Seok JY, Park YB, Lee SK. Therapeutic effect of anti-vascular endothelial growth factor receptor I antibody in the established collagen-induced arthritis mouse model. Clin Rheumatol. 2009;28:333–7.

    Article  Google Scholar 

  25. 25.

    De Bandt M, et al. Blockade of vascular endothelial growth factor receptor I (VEGF-RI), but not VEGF-RII, suppresses joint destruction in the K/BxN model of rheumatoid arthritis. J Immunol. 2003;171:4853–9.

    Article  Google Scholar 

  26. 26.

    Shibuya M. Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1, a dual regulator for angiogenesis. Angiogenesis. 2006;9:225–30. discussion 231.

    CAS  Article  Google Scholar 

  27. 27.

    Wu Y, et al. Anti-vascular endothelial growth factor receptor-1 antagonist antibody as a therapeutic agent for cancer. Clin Cancer Res. 2006;12:6573–84.

    CAS  Article  Google Scholar 

  28. 28.

    Yin B, Fang DM, Zhou XL, Gao F. Natural products as important tyrosine kinase inhibitors. Eur J Med Chem. 2019;182:111664.

  29. 29.

    Pan CC, et al. Angiostatic actions of capsicodendrin through selective inhibition of VEGFR2-mediated AKT signaling and disregulated autophagy. Oncotarget. 2017;8:12675–85.

    Article  Google Scholar 

  30. 30.

    Shen S, Xu X, Liu Z, Liu J, Hu L. Synthesis and structure-activity relationships of boswellic acid derivatives as potent VEGFR-2 inhibitors. Bioorg Med Chem. 2015;23:1982–93.

    CAS  Article  Google Scholar 

  31. 31.

    Kimura Y, Sumiyoshi M, Baba K. Anti-tumor actions of major component 3’-O-acetylhamaudol of Angelica japonica roots through dual actions, anti-angiogenesis and intestinal intraepithelial lymphocyte activation. Cancer Lett. 2008;265:84–97.

    CAS  Article  Google Scholar 

  32. 32.

    Li Q, et al. Screening bioactive compounds from Ligusticum chuanxiong by high density immobilized human umbilical vein endothelial cells. Anal Bioanal Chem. 2015;407:5783–92.

    CAS  Article  Google Scholar 

  33. 33.

    Hailat MM, Ebrahim HY, Mohyeldin MM, Goda AA, Siddique AB, El, et al. The tobacco cembranoid (1S,2E,4S,7E,11E)-2,7,11-cembratriene-4,6-diol as a novel angiogenesis inhibitory lead for the control of breast malignancies. Bioorg Med Chem. 2017;25:3911–21.

    CAS  Article  Google Scholar 

  34. 34.

    Lu K, Basu S. The natural compound chebulagic acid inhibits vascular endothelial growth factor A mediated regulation of endothelial cell functions. Sci Rep. 2015;5:9642.

    CAS  Article  Google Scholar 

  35. 35.

    Nosaka C, et al. Vegfrecine, an inhibitor of VEGF receptor tyrosine kinases isolated from the culture broth of Streptomyces sp. J Nat Prod. 2013;76:715–9.

    CAS  Article  Google Scholar 

  36. 36.

    Adachi H, et al. Microbial metabolites and derivatives targeted at inflammation and bone diseases therapy: chemistry, biological activity and pharmacology. J Antibiot. 2018;71:60–71.

    CAS  Article  Google Scholar 

  37. 37.

    Niedermeyer THJ, Mikolasch A, Lalk M. Nuclear Amination catalyzed by fungal laccases: Reaction products of p-hydroquinones and primary aromatic amines. J Org Chem. 2005;70:2002–8.

    CAS  Article  Google Scholar 

  38. 38.

    Itokawa T, et al. Antiangiogenic effect by SU5416 is partly attributable to inhibition of Flt-1 receptor signaling. Mol Cancer Ther. 2002;1:295–302.

    CAS  PubMed  Google Scholar 

  39. 39.

    Diazgarcia MA, et al. Synthesis and 2nd-order nonlinear-optical properties of substituted aminobenzoquinones. J Mater Chem. 1995;5:385–7.

    CAS  Article  Google Scholar 

  40. 40.

    Chen SP, Li XM, Wan SB, Jiang T. Synthesis of novel benzoxazinone compounds as epidermal growth factor receptor (Egfr) tyrosine kinase inhibitors. Synth Commun. 2012;42:2937–46.

    CAS  Article  Google Scholar 

  41. 41.

    Stahl P, Kissau L, Mazitschek R, Giannis A, Waldmann H. Natural product derived receptor tyrosine kinase inhibitors: identification of IGF1R, Tie-2, and VEGFR-3 inhibitors. Angew Chem Int Ed. 2002;41:1174–8.

    CAS  Article  Google Scholar 

Download references


We thank Dr. Masatomi Iijima and Dr. Isao Momose for mass spectral determinations.

Author information



Corresponding author

Correspondence to Hayamitsu Adachi.

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.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Adachi, H., Nosaka, C., Atsumi, S. et al. Structure-activity relationships of natural quinone vegfrecine analogs with potent activity against VEGFR-1 and -2 tyrosine kinases. J Antibiot 74, 734–742 (2021).

Download citation


Quick links