Synthesis of C12‐Keto Saxitoxin Derivatives with Unusual Inhibitory Activity Against Voltage‐Gated Sodium Channels

A novel series of C12‐keto‐type saxitoxin (STX) derivatives bearing an unusual nonhydrated form of the ketone at C12 has been synthesized, and their Na V ‐inhibitory activity has been evaluated in a cell‐based assay as well as whole‐cell patch‐clamp recording. Among these compounds, 11‐benzylidene STX ( 3 a ) showed potent inhibitory activity against neuroblastoma Neuro 2A in both cell‐based and electrophysiological analyses, with EC 50 and IC 50 values of 8.5 and 30.7 n m , respectively. Interestingly, the compound showed potent inhibitory activity against tetrodotoxin‐resistant subtype of Na V 1.5, with an IC 50 value of 94.1 n m . Derivatives 3 a – d and 3 f showed low recovery rates from Na V 1.2 subtype (ca 45–79 %) compared to natural dcSTX ( 2 ), strongly suggesting an irreversible mode of interaction. We propose an interaction model for the C12‐keto derivatives with Na V in which the enone moiety in the STX derivatives 3 works as Michael acceptor for the carboxylate of Asp 1717 .