Novel Pseudopterosin Analog Elicits New Modality for Use in Wound Repair

Abstract

The pseudopterosins are known to be anti‐inflammatory agents (Look, et. al. 1986, PNAS, 83, 6238‐6240), eliciting a reduction in neutrophil infiltration in PMA induced mouse ears and more recently, mediators in acceleration of wound healing. A new pseudopterosin semi‐synthetic analog has been developed which resists glycoside cleavage in the cell via a C‐glycoside linkage. This new compound has been used for the study of cell proliferation effects in HUVEC‐C cell lines. Binding studies indicate that this compound binds to adenosine A2a and A3 receptors with an IC50/hill coefficient of 20 μM/1.2 and 10 μM/2.3 respectively in overexpressed HEK‐293 cells (Zhong, et. al. 2008, J.Org.Chem., 73, 7011‐7016). Although an understanding of the direct molecular mechanism of action has been unknown to this point we will report a tentative theory to explain pseudopterosin effects on wound repair. Modulation of inflammation and cell division/angiogenesis can be important factors in accelerating the wound healing response. Data suggests that Pseudopterosin‐A c‐glycoside elicits a 35% increase in cell proliferation with an ED50 of 3.7 μM over 48 hours in treated HUVEC‐C cell lines. We believe that this effect is mediated by modulation of an adenosine receptor which may act to stimulate the expression and release of growth factors, key to cell division (Ethier et al. 1993, Amer. J. of Phys., 265, H131‐H138). An increase in growth factor expression and release can be potentially important in treatment of chronic wounds since high bacterial and protease loads in wound site act to increase the breakdown of endogenous growth factors. This data suggests that pseudopterosin mediated wound repair may follow two routes; a reduction in inflammatory response, and an increase in cell proliferation. We gratefully acknowledge the U.S. Army Medical Research Program (Grant No. W81XWH‐06‐1‐0089) for its support of this research.