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 .
We have developed a versatile synthetic method for the construction of spirocyclic guanidines in moderate yields by intramolecular dearomative oxidative cyclization of guanidino phenols using the hypervalent iodine reagent 4‐chloro‐1‐(diacetoxyiodo)benzene in 2,2,3,3‐tetrafluoro‐1‐propanol.
N-Acyl isoxazolidines were obtained in moderate to good yields by intramolecular hydroamination of N-alkoxyamides in the presence of a ruthenium photocatalyst. In this reaction, the N-alkoxyamide anion generated by deprotonation undergoes photocatalyzed single-electron-transfer (SET) oxidation to generate the corresponding radical, which cyclizes to afford the isoxazolidine ring. Notably, this method was applicable to a macrocyclic substrate, affording the corresponding 12-membered macrocycle-containing product.
Voltage-gated sodium channels (NaVs) are membrane proteins that are involved in the generation and propagation of action potentials in neurons. Recently, the structure of a complex made of a tetrodotoxin-sensitive (TTX-s) NaV subtype with saxitoxin (STX), a shellfish toxin, was determined. STX potently inhibits TTX-s NaV, and is used as a biological tool to investigate the function of NaVs. More than 50 analogs of STX have been isolated from nature. Among them, zetekitoxin AB (ZTX) has a distinctive chemical structure, and is the most potent inhibitor of NaVs, including tetrodotoxin-resistant (TTX-r) NaV. Despite intensive synthetic studies, total synthesis of ZTX has not yet been achieved. Here, we review recent efforts directed toward the total synthesis of ZTX, including syntheses of 11-saxitoxinethanoic acid (SEA), which is considered a useful synthetic model for ZTX, since it contains a key carbon–carbon bond at the C11 position.
Saxitoxin (STX) is a potent neurotoxin that is biosynthesized
by
toxic dinoflagellates and accumulated in shellfish via the food chain.
STX and its various analogues are now monitored in shellfish by the
hygiene authorities in many countries with instrumental analytical
methods, which require calibration with standards. Unfortunately,
STX is registered as a chemical warfare agent in Schedule 1 of the
Chemical Weapons Convention, and this has made it difficult to import
calibration standards into some countries. We aimed to avoid violation
of the Chemical Weapons Convention and facilitate analyses by preparing
calibration standards based on unnatural nontoxic antipodal STXs (ent-STXs) with the same physicochemical properties as natural
STXs. Our findings demonstrate that the nontoxic ent-STXs can be safely utilized as alternative reference materials of
STXs in the routine monitoring program by the local authorities and
consequently can lead to reduced usage of STX.
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