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 Corson

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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
Article numbere95694
JournalPLoS One
Volume9
Issue number4
DOIs
StatePublished - Apr 21 2014

Fingerprint

Pathologic Neovascularization
Growth Inhibitors
Eye Diseases
Endothelial cells
Cell growth
angiogenesis
Vascular Endothelial Growth Factor A
endothelial cells
eye diseases
cell growth
Endothelial Cells
Retinopathy of Prematurity
Biological Therapy
Vascular Endothelial Growth Factor Receptor
synthesis
Vascular Cell Adhesion Molecule-1
Human Umbilical Vein Endothelial Cells
Macular Degeneration
complement
p38 Mitogen-Activated Protein Kinases

ASJC Scopus subject areas

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

Cite this

Synthesis and mechanistic studies of a novel homoisoflavanone inhibitor of endothelial cell growth. / Basavarajappa, Halesha D.; Lee, Bit; Fei, Xiang; Lim, Daesung; Callaghan, Breedge; Mund, Julie A.; Case, Jamie; Rajashekhar, Gangaraju; Seo, Seung Yong; Corson, Timothy.

In: PLoS One, Vol. 9, No. 4, e95694, 21.04.2014.

Research output: Contribution to journalArticle

Basavarajappa, HD, Lee, B, Fei, X, Lim, D, Callaghan, B, Mund, JA, Case, J, Rajashekhar, G, Seo, SY & Corson, T 2014, 'Synthesis and mechanistic studies of a novel homoisoflavanone inhibitor of endothelial cell growth', PLoS One, vol. 9, no. 4, e95694. https://doi.org/10.1371/journal.pone.0095694
Basavarajappa, Halesha D. ; Lee, Bit ; Fei, Xiang ; Lim, Daesung ; Callaghan, Breedge ; Mund, Julie A. ; Case, Jamie ; Rajashekhar, Gangaraju ; Seo, Seung Yong ; Corson, Timothy. / Synthesis and mechanistic studies of a novel homoisoflavanone inhibitor of endothelial cell growth. In: PLoS One. 2014 ; Vol. 9, No. 4.
@article{b7276c9321b94680bdbc837b6fa3960b,
title = "Synthesis and mechanistic studies of a novel homoisoflavanone inhibitor of endothelial cell growth",
abstract = "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.",
author = "Basavarajappa, {Halesha D.} and Bit Lee and Xiang Fei and Daesung Lim and Breedge Callaghan and Mund, {Julie A.} and Jamie Case and Gangaraju Rajashekhar and Seo, {Seung Yong} and Timothy Corson",
year = "2014",
month = "4",
day = "21",
doi = "10.1371/journal.pone.0095694",
language = "English",
volume = "9",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "4",

}

TY - JOUR

T1 - Synthesis and mechanistic studies of a novel homoisoflavanone inhibitor of endothelial cell growth

AU - Basavarajappa, Halesha D.

AU - Lee, Bit

AU - Fei, Xiang

AU - Lim, Daesung

AU - Callaghan, Breedge

AU - Mund, Julie A.

AU - Case, Jamie

AU - Rajashekhar, Gangaraju

AU - Seo, Seung Yong

AU - Corson, Timothy

PY - 2014/4/21

Y1 - 2014/4/21

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84899701416&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84899701416&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0095694

DO - 10.1371/journal.pone.0095694

M3 - Article

C2 - 24752613

AN - SCOPUS:84899701416

VL - 9

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 4

M1 - e95694

ER -