Synthesis and Evaluation of a Novel Nonsteroidal-Specific Endothelial Cell Proliferation Inhibitor

Abstract

The identification of agents with specific antiproliferative or cytostatic activity against endothelial cells has significant value for the treatment of pathologies associated with angiogenesis, including solid tumors. Here, we describe a novel substituted dibenzo[b,d]pyran-6-one scaffold, exemplified by structures 9a and 10, and report preliminary in vitro activity data indicating that this scaffold is a promising lead for the development of specific inhibitors of endothelial cell proliferation.

The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer

“…In this study, we describe the biological activity of 8-(1-Hydroxy-ethyl)-2-methoxy-3-(4-methoxy-benzyloxy)-benzo[c]chromen-6-one (P529), a recently discovered drug that targets Akt, which has been shown to inhibit tumour angiogenesis, vascular permeability, and tumour growth, in a mouse model of glioblastoma (Xue et al, 2008). P529 is a derivative of 3-hydroxy dibenzo [b,d]pyran-6-one, which was designed to structurally mimic the antiangiogenic drug 2-methoxyestradiol (2ME 2 ) (Schmidt et al, 2003). 3-hydroxy dibenzo [b,d] pyran-6-one exhibits selective antiproliferative activity for endothelial cells (Schmidt et al, 2003).…”

“…P529 is a derivative of 3-hydroxy dibenzo [b,d]pyran-6-one, which was designed to structurally mimic the antiangiogenic drug 2-methoxyestradiol (2ME 2 ) (Schmidt et al, 2003). 3-hydroxy dibenzo [b,d] pyran-6-one exhibits selective antiproliferative activity for endothelial cells (Schmidt et al, 2003). We have shown in this study that P529 has a wide spectrum of antitumour efficacy in different tumour cell lines, and significantly enhances the effect of RT in prostate cancer both in vitro and in vivo.…”

“…Dibenzo [b,d]pyran-6-one derivatives have been shown to be potent inhibitors of endothelial cell growth, thus suggesting antiangiogenic properties (Schmidt et al, 2003). We, therefore, analysed the effect of P529 on HUVECs proliferation.…”

“…Because of the structural similarities between dibenzo[b,d]pyran-6-one derivatives and 2ME 2 (Schmidt et al, 2003), we examined whether P529 would bind to tubulin and whether this compound would affect tubulin polymerisation. The displacement of 5 mM [ 3 H]colchicine on 1 mM tubulin by P529 or positive control agents was expressed as rate of inhibition.…”

“…This drug is a derivative of 3-hydroxy dibenzo [b,d]pyran-6-one, which was previously described to share structural similarities with the potent antiangiogenic and antitumour compound 2-methoxyestradiol, and to exhibit selective antiproliferative activity for endothelial cells (Schmidt et al, 2003). Recently, benzochromenones were reported to differentially suppress the growth of certain tumour cell lines (Dai et al, 2007).…”