Binding of ciguatera toxins to the voltage‐gated Kv1.5 potassium channel in the open state. Docking of gambierol and molecular dynamics simulations of a homology model

Ciguatera poisoning is a toxinological syndrome from ingestion of seafood contaminated by dinoflagellate toxins which has serious social and economic consequences from the Indo‐Pacific to the Caribbean. These polyannealed ethereal‐ring toxins, which comprise ciguatoxins, maitotoxin, and gambierol, are known to affect ion channels. Reported here are the first indications at molecular level as to the mode of interaction of these toxins with ion channels. The study concerns gambierol, an eight‐ring ladder polyether which is known to affect TRPV1‐type of thermal and pain sensation channels, as well as to inhibit voltage‐gated currents in K⁺ channels of mouse taste cells. Automated docking of gambierol on a homology model of the voltage‐gated Kv1.5 potassium ion channel in implicit solvent is followed by molecular dynamics (MD) simulation of the complex in a POPC membrane solvated with water. It is found that gambierol binds to the internal helices of the channel, unequally to the different subunits of the tetramer. Such unequal binding is a novel observation that should stimulate and aid developing a much demanded medical treatment of ciguatera poisoning. Copyright © 2008 John Wiley & Sons, Ltd.     

The role of neutron activation analysis and radioanalytical methods in dose-effect relationship studies for the setting of trace metal protection criteria

In order to prepare scientifically accurate health protection criteria documents for trace metals integrated multidisciplinary research is necessary. In particular, the rational for structuring the documents should be based primarily on the two major questions of exposure and response. Unfortunately, in a majority of cases there is a paucity of relevant data to the establishment of dose-effect relationships. This work intends to show the role that neutron activation analysis and radiotracers with very high specific radioactivity have in solving problems relevant for establishing dose-effect relationships for trace metals. Typical applications in the different research areas involved in the preparation of the protection criteria, from source and exposure to levels and forms of trace metals in humans, are presented.     

Rogiolol Acetate: A Novel β-Chamigrene-Type Sesquiterpene Isolated from a Marine Sponge

The marine sponge Spongia zimocca SCHMIDT , 1862, collected in front of the torrent II Rogiolo, south of Livorno, contains the sesquiterpene rogiolol acetate (= (+)-(2R,3S,6R,8R,9R)-2,8-dibromo-9-chloro-1,1,9-trimethyl-5-methylidenespiro[5.5]undec-3-yl acetate; (+)- 3a ), which represents the first chamigrane isolated from a sponge. Although compounds of this class are common in red seaweeds of the genus Laurencia, and our sponge actually contains 9-bromochamigrene and a variety of other metabolites of nearby growing Laurencia sp., (+)- 3a is unique to our sponge.     

Cavernicolin-1 and cavernicolin-2, epimeric dibromolactams from the mediterranean sponge aplysina (venongia) cavernicola

Cavernicolin-1 and Cavernicolin-2, two epimeric compounds having a γ-lactam ring fused to a dibromocyclohexenone ring, have been isolated from the Mediterranean sponge $\text{Aplysina}$$\text{(Verongia)}$$\text{cavernicola}$.     

Synthesis of the Alleged Natural Monoterpenoid α-Santolinenone

Authentic α-santolinenone ( = (+)-(4R)-1(7)-p-menthen-2-one; (+)- 1 ) is made available for the the first time in 30% overall yield from (+)-(4R)-p-menthene ((+)- 2 ) via the diastereoisomeric allylic alcohols (+)- 4a /(+)- 4b , which are oxidized to (+)- 1 with Ag₂CO₃/Celite. Yields are good, except for the last stage; indeed, only alcohol (+)- 4a , with equatorial OH-group, undergoes oxidation, and (+)- 1 is partly substracted via a hetero Diels-Alder dimerization giving a mixture of the diastereoisomeric dihydropyrans (+)- 5a /(+)- 5b . When Cr(VI) reagents ae used, (+)- 4a /(+)- 4b mainly give phellandral ( 6 ) and carvotanacetone ( 7 ), NnO₂ reacts too sluggishly with (+)- 4a /(+)- 4b . A camphor pyrolyzate, previously thought to be 1 must be a different compound, probably 7 .     

Conformational Preferences and Absolute Configuration of Agelastatin A,a Cytotoxic Alkaloid of the Axinellid Sponge Agelas dendromorpha from the Coral Sea,via combined molecular modelling,NMR, and exciton splitting for diamide and hydroxyamide derivatives

The absolute configuration of agelastatin A ( 1 ), the major, strongly cytotoxic alkaloid of the axinellid sponge Agelas dendromorpha from the Coral Sea, is proposed here to be (5aS,5bS,8aS,9aR), as deduced from combined molecular-mechanics calculations and a novel application of exciton splitting to the bis[4-(dimethylamino)benzoyl] compounds (–)- 9 and (–)- 13 , derivatives of a diamide and a hydroxyamide, respectively. The position of the conformational equilibrium of A 1 could be finely tuned by slight molecular changes. The minor analogue, agelastatin B ( 3 ), was isolated as the trimethyl derivative (–)- 4 .     

Chiroptical studies of labile or difficult to resolve molecules generated by chiral laser photochemistry.1. (1S,5R-1-methoxybicyclo[3.2.0] hepta-3,6-dien-2-one

The optical activity of (1$\text{S}$,5$\text{R}$-1-methoxybicyclo[3.2.0]hepta-3,6-dien-2-one ($\text{1}$) is determined by partial photoresolution of the racemate with circularly polarized laser light; although a rearranged, optically active product was also formed, isolation of the $\text{1}$ enantiomers was note required.     

Photoinduced Double Addition of Acetylene to 3-Oxocyclopent-1-ene-1-carbonitrile or 3-oxocyclopent-1-enyl acetate leading to 2,3-dihydro-1H-inden-1-one and other rearranged products

UV Irradiation of 3-oxocyclopent-1-enyl acetate ( 17 ) and acetylene in MeCN at 0° gives, besides the product of normal enone-alkyne [2 + 2] cycloaddition (cis-4-oxobicyclo[3.2.0] hept-6-en-1-yl acetate, 18 ) and its product of oxa-di-π-methane rearrangement (5-oxotricyclo[4.1.0.0^2,7]hept-2-yl acetate, 19 ), unexpected products of further addition of a molar equivalent of acetylene. These are indanone ( = 2,3-dihydro-1H-inden-1-one, 16 ), in 21% yield, cis-1-cisoid-1,2-cis-2- ( 20 ) and cis-1-transoid-1,2-cis-2-7-oxotricyclo[4.3.0.0^2,5]non-3-en-1-yl acetate ( 21 ), 4-oxo-7-‘exo’-vinyltricyclo[3.2.0.0^2,6]hept-2-yl acetate ( 22 ), cis-4-oxo-6-‘endo’- ( 23 ) and cis-4-oxo-6-‘exo’-vinylbicyclo[3.2.0]hept-1-yl acetate ( 24 ), and cis-4-oxo-7-‘exo’-vinylbicyclo[3.2.0]hept-1-yl acetate ( 25 ). At least in part, indanone must be formed via intermediates 20 and 21 . In fact, on heating a 9:1 mixture 20/21 , indanone is obtained quantitatively. With 3-oxocyclopent-1-ene-1-carbonitrile ( 15 ) in place of 17 , indanone is formed in lower (8%) yield besides much tars.