A small oxazine compound as an anti-tumor agent: A novel pyranoside mimetic that binds to VEGF, HB-EGF, and TNF-alpha

作者：Basappa; Murugan Sengottuvelan; Kavitha Chandagirikoppal V; Purushothaman Anurag; Nevin Kottayath G; Sugahara Kazuyuki; Rangappa Kanchugarakoppal S^*

来源：Cancer Letters, 2010, 297(2): 231-243.

DOI：10.1016/j.canlet.2010.05.016

• Tumor metastases
• Heparin
• Growth factors
• Oxazines
• Sugar mimetics

A novel pyranoside mimetic compound, DMBO (2-(2,6-difluorophenyl)-5-(4-methoxyphenyl)-1-oxa-3-azaspiro[5.5]undecane), was designed and synthesized. The sugar mimicking behavior of DMBO was addressed by its ability to bind several growth factors/cytokines such as vascular endothelial growth factor (VEGF), heparin-binding epidermal growth factor-like growth factor (HB-EGF), and tumor necrosis factor (TNF)-alpha as demonstrated by the recently developed surface plasmon resonance assay. DMBO exhibited strong anti-proliferation activity in vitro against tumor cells including a highly metastatic murine osteosarcoma cell line LM8G7 that secretes VEGF as well as two human ovarian cell lines, OVSAHO and SKOV-3, which secrete TNF-alpha and HB-EGF respectively. Furthermore, DMBO inhibited the metastatic activity to the mouse liver of LM8G7 cells injected from a lateral tail vein, and affected the heparan-degrading activity of LM8G7 cells. Here, we report that DMBO acts as a human heparanase inhibitor in vitro possibly as a substrate mimetic. DMBO also inhibited the migration and invasion of LM8G7 cells and angiogenic events such as endothelial cell proliferation, migration and capillary tube-like formation in vitro. More prominently, the administration of DMBO with heparin resulted in synergistic anti-tumor effects in mouse model of osteosarcoma. These preclinical data shows the potential anti-cancer effects of DMBO.

• 出版日期2010-11-28