Synthesis and mechanistic studies of a novel homoisoflavanone inhibitor of endothelial cell growth

Halesha D. Basavarajappa, Bit Lee, Xiang Fei, Daesung Lim, Breedge Callaghan, Julie A. Mund, Jamie Case, Gangaraju Rajashekhar, Seung Yong Seo, Timothy W. Corson

Research output: Contribution to journalArticle

22 Scopus citations


Preventing pathological ocular angiogenesis is key to treating retinopathy of prematurity, diabetic retinopathy and agerelated macular degeneration. At present there is no small molecule drug on the market to target this process and hence there is a pressing need for developing novel small molecules that can replace or complement the present surgical and biologic therapies for these neovascular eye diseases. Previously, an antiangiogenic homoisoflavanone was isolated from the bulb of a medicinal orchid, Cremastra appendiculata. In this study, we present the synthesis of a novel homoisoflavanone isomer of this compound. Our compound, SH-11052, has antiproliferative activity against human umbilical vein endothelial cells, and also against more ocular disease-relevant human retinal microvascular endothelial cells (HRECs). Tube formation and cell cycle progression of HRECs were inhibited by SH-11052, but the compound did not induce apoptosis at effective concentrations. SH-11052 also decreased TNF-α induced p38 MAPK phosphorylation in these cells. Intriguingly, SH-11052 blocked TNF-α induced IκB-α degradation, and therefore decreased NF-κB nuclear translocation. It decreased the expression of NF-κB target genes and the pro-angiogenic or pro-inflammatory markers VCAM-1, CCL2, IL8, and PTGS2. In addition SH-11052 inhibited VEGF induced activation of Akt but not VEGF receptor autophosphorylation. Based on these results we propose that SH-11052 inhibits inflammation induced angiogenesis by blocking both TNF-α and VEGF mediated pathways, two major pathways involved in pathological angiogenesis. Synthesis of this novel homoisoflavanone opens the door to structure-activity relationship studies of this class of compound and further evaluation of its mechanism and potential to complement existing antiangiogenic drugs.

Original languageEnglish (US)
Article numbere95694
JournalPloS one
Issue number4
StatePublished - Apr 21 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Fingerprint Dive into the research topics of 'Synthesis and mechanistic studies of a novel homoisoflavanone inhibitor of endothelial cell growth'. Together they form a unique fingerprint.

  • Cite this

    Basavarajappa, H. D., Lee, B., Fei, X., Lim, D., Callaghan, B., Mund, J. A., Case, J., Rajashekhar, G., Seo, S. Y., & Corson, T. W. (2014). Synthesis and mechanistic studies of a novel homoisoflavanone inhibitor of endothelial cell growth. PloS one, 9(4), [e95694].