Synthesis of Ascorbic Acid Derivatives with Different Types of C8 Straight Acyl Chain and Their Neurite Outgrowth-Enhancing Activities

Abstract

We previously reported that 2-O-α-D-glucopyranosyl-6-O-octanoyl-L-ascorbic acid, having a C₈ straight acyl chain, at a concentration of 100 μM remarkably enhanced nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells after being metabolized to L-ascorbic acid (AA) as an active form by esterase and α-glucosidase. In this study, to examine the structure-activity relationship of 6-O-substituted AA derivatives with a C₈ straight acyl chain for neurite outgrowth-promoting activity, we synthesized AA derivatives 1-4 and compared their activities for promoting NGF-induced neurite outgrowth in PC12 cells. AA derivatives 1-4 showed neurite outgrowth-enhancing activity at 100 μM, while AA derivative 2 also showed the enhancing activity at 3 μM. Furthermore, AA derivative 2 as well as AA enhanced NGF-induced neurite outgrowth after being incorporated into PC12 cells via sodium-dependent vitamin C transporter as an anion transporter. The results suggested that AA derivative 2 has neurite outgrowth-enhancing activity in its intact form at a low concentration (3 μM) and that AA derivatives 1-4 showed their activities in the form of AA, a metabolite of these derivatives, at a higher concentration (100 μM).

Keywords: C8 straight acyl chain; Nerve growth factor; Neurite outgrowth-enhancing activity; PC12 cell; ascorbic acid derivative.