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

Abstract

An ovel series of C12-keto-type saxitoxin (STX) derivatives bearinga nu nusualn onhydrated form of the ketone at C12 has been synthesized,a nd their Na V -inhibitory activity has been evaluated in ac ell-based assay as well as whole-cell patch-clamp recording. Among these compounds, 11-benzylidene STX (3a)s howedp otent inhibitory activity againstn euroblastoma Neuro2Ai nboth cell-baseda nd electrophysiological analyses,w ithE C 50 and IC 50 valueso f8 .5 and 30.7 nm,r espectively.I nterestingly,t he compound showed potent inhibitory activity against tetrodotoxin-resistant subtype of Na V 1.5, with an IC 50 value of 94.1 nm.D erivatives 3a-d and 3f showedl ow recovery rates from Na V 1.2 subtype (ca4 5-79 %) comparedt on atural dcSTX (2), strongly suggesting an irreversible mode of interaction. We propose an interaction model for the C12-ketod erivatives with Na V in which the enonem oiety in the STX derivatives 3 worksa sM ichaela cceptorf or the carboxylateo fA sp 1717 .

First Identification of 12β-Deoxygonyautoxin 5 (12α-Gonyautoxinol 5) in the Cyanobacterium Dolichospermum circinale (TA04) and 12β-Deoxysaxitoxin (12α-Saxitoxinol) in D. circinale (TA04) and the Dinoflagellate Alexandrium pacificum (Group IV) (120518KureAC)

“…These toxins are produced by some species of freshwater cyanobacteria and marine dinoflagellates [ 5 , 6 ]. Due to their potent physiological effects and unique structures, chemical and biological aspects of STX and its analogues have been studied intensively by chemists and pharmacologists [ 7 , 8 ]. The first biosynthetic study of STX was a feeding experiment conducted by Shimizu et al [ 9 ], in which stable isotope-labeled acetic acid and amino acids were used as essential substrates for PST-producing cyanobacteria and dinoflagellates.…”

Hydrogenated Graphene Improves Neuronal Network Maturation and Excitatory Transmission

“…We additionally measured electrical resistivity and water contact angles (WCA) of Gr and HGr, as both properties strongly influence the substrate interactions and functional behavior of neuronal cells. [24,64] Graphene FETs were fabricated on SiO 2 (285 nm)/Si substrates as shown in the inset of Figure 2a. As shown in the resistivity versus gate voltage curves of the Gr and HGr devices (Figure 2a), the charge neutrality point of Gr before hydrogenation was ≈60 V, in agreement with the fact that the as-grown Gr is generally p-doped due to polymer residue, adsorbed and trapped molecules and charged impurities from the SiO 2 substrate, as previously reported.…”

“…However, after hydrogenation, the WCA of HGr dramatically decreased to 48.4 and 40.7° on SiO 2 and PET, respectively, consistent with previous results indicating that the sp 3 bonds in the HGr lead to a strong interaction between graphene and water. [64,68] Thus, the possibility exists that the electrical conductivity and chemical functional groups of HGr are beneficial for enhancing the interactions with neurons due to charge transfer and enhanced adhesion. [69] Survival and adhesion of rat primary cortical neurons grown onto the two kinds of graphene supports were investigated after 14 days.…”

Synthetic Approaches to Zetekitoxin AB, a Potent Voltage-Gated Sodium Channel Inhibitor

“…IC50 (mean ± SD) (nM). Next, they further synthesized 11-substituted STX analogs 33b-f, and elucidated their subtype selectivity towards Na V 1.2, 1.5, and 1.7, using the whole-cell patch-clamp recording method (Figure 8, Table 5) [92]. They found that 11-fluorobenzylidene STX (33c) showed selective and potent inhibitory activity against Na V 1.2 (IC 50 = 7.7 ± 1.6 nM), compared to the other subtypes tested.…”