- Elongation of the Hydrophobic Chain as a Molecular Switch: Discovery of Capsaicin Derivatives and Endogenous Lipids as Potent Transient Receptor Potential Vanilloid Channel 2 Antagonists
-
The transient receptor potential vanilloid type-2 (TRPV2) protein is a nonselective Ca2+ permeable channel member of the TRPV subfamily, still considered an orphan TRP channel due to the scarcity of available selective and potent pharmacological tools and endogenous modulators. Here we describe the discovery of novel synthetic long-chain capsaicin derivatives as potent TRPV2 antagonists in comparison to the totally inactive capsaicin, the role of their hydrophobic chain, and how the structure-activity relationships of such derivatives led, through a ligand-based approach, to the identification of endogenous long-chain fatty acid ethanolamides or primary amides acting as TRPV2 antagonists. Both synthetic and endogenous antagonists exhibited differential inhibition against known TRPV2 agonists characterized by distinct kinetic profiles. These findings represent the first example of both synthetic and naturally occurring TRPV2 modulators with efficacy in the submicromolar/low-micromolar range, which will be useful for clarifying the physiopathological roles of this receptor, its regulation, and its targeting in pathological conditions.
- Schiano Moriello, Aniello,López Chinarro, Silvia,Novo Fernández, Olalla,Eras, Jordi,Amodeo, Pietro,Canela-Garayoa, Ramon,Vitale, Rosa Maria,Di Marzo, Vincenzo,De Petrocellis, Luciano
-
p. 8255 - 8281
(2018/09/25)
-
- Properties of unusual phospholipids. III: Synthesis, monolayer investigations and DSC studies of hydroxy octadeca(e)noic acids and diacylglycerophosphocholines derived therefrom
-
Diacylglycerophosphocholines containing (R)-3-, (R)-12-, (R)-17-hydroxy octadeca(e)noic acids and the corresponding racemates were synthesized and purified to homogeneity. The influence of the position of the hydroxy group on the monolayer packing properties of these fatty acids and their phosphatidylcholines was studied by Langmuir techniques and 1,2-di-[(R)-12-hydroxy-octadec-cis-9-enyl]-sn-glycero-3-phosphocholine displayed the largest lift-off area (330 A2/molecule). This result was in line with the thermotropic phase behavior of these phospholipids, as measured by differential scanning calorimetry (DSC): the gel- to liquid-crystalline phase transition temperature (T(m))passed through a minimum of -15.1°C for 1,2-di-[(R)-12-hydroxy-octadec-cis-9-enyl]-sn-glycero-3-phosphocholine.
- Negelmann, Lars,Pisch, Sandra,Bornscheuer, Uwe,Schmid, Rolf D.
-
p. 117 - 134
(2007/10/03)
-
- Intramolecular Cyclization of (ω-Carboxyalkyl)sulfonium Salts. A Novel Synthesis of Macrocyclic Lactones
-
A useful method for the synthesis of macrocyclic lactones using (ω-carboxyalkyl)sulfonium salts was developed.Base-catalyzed intramolecular cyclization of (ω-carboxyalkyl)diphenylsulfonium salts 2 gave simple macrocyclic lactones in high yields at high dilution conditions. (ω-Carboxyalkyl)alkylphenylsulfonium salts 8 afforded simple macrocyclic lactone 6a and alkyl carboxylates 9.The reactions of (ω-carboxyalkyl)dialkylsulfonium salts 10 gave only esters without lactonization product 6a.The cyclization of S-(ω-carboxyalkyl)thiolanium salts 3 and S-(ω-carboxyalkyl)-2-methylthiolanium salts 4 took place readily under similar conditions to afford sulfur-containing macrocyclic lactones 13 and 15, respectively, in good yields.To investigate the reaction mechanism, sulfonium salt 25, having an optically active carbon atom, was prepared.The intramolecular cyclization of 25 took place with an inversion of configuration at chiral carbon atom to give ricinelaidic acid lactone (26; optical purity 66percent).
- Matsuyama, Haruo,Nakamura, Takako,Kamigata, Nobumasa
-
p. 5218 - 5223
(2007/10/02)
-
- Tin-mediated esterification in macrolide synthesis
-
A neutral and relatively simple new method for effecting internal macrocyclic esterification of omega -hydroxycarboxylic acids, based on a tin 'template-driven' extrusion process, is discussed and its application to the synthesis (macrocyclization step) of the macrolide antibiotics zearalenone, ingramycin, and nodusmicin detailed. An efficient, formal total synthesis of pyrenophorin using this technique is also presented. Attempts to extend the methodology to include the macrocyclization of omega -bromo carboxylic acids or omega -mercapto carboxylic acids were unsuccessful. However, although beta - and omega -amino carboxylic acids preferentially gave way to polymer formation, 4-,5, and 6-amino carboxylic acids readily condensed to give the corresponding five-, six-, and seven-membered lactams in excellent yields. For example, in this way, the bridged lactam 1-azabicyclo- left bracket 3. 3. 1 right bracket nonan-2-one was prepared in 77% yield as compared to the previously reported yield of less than 2%.
- Steliou,Poupart
-
p. 7130 - 7138
(2007/10/02)
-
- Ethylaluminum Dichloride Catalyzed Ene Reactions of Aldehydes with Nonnucleophilic Alkenes
-
Ethylaluminum dichloride, which is a strong Lewis acid and a proton scavenger, catalyzes the ene reactions of aliphatic aldehydes with nonnucleophilic alkenes.Higher aldehydes give good yields of ene adducts with terminal alkenes.Formaldehyde gives good yields of adducts with electron-deficient alkenes.This reaction has been used for the synthesis of recifeiolide, ricinelaidic acid, and the insect pheromones (E,E)-8,10-dodecadienyl acetate and (E)-9,11-dodecadienyl acetate.
- Snider, Barry B,Phillips, Gary B.
-
p. 464 - 469
(2007/10/02)
-
- Preparation of Macrocyclic Lactones by Ring Closure of Cesium Carboxylates
-
A series of ω-halo fatty acids, the longest being 16-iodohexadecanoic acid, was prepared by oxidation of the corresponding ketones with m-chloroperbenzoic acid in boiling chloroform, followed by ring opening usually with hydrogen iodide in acetic acid at 100 deg C.Solutions of these acids in dimethylformamide (DMF) at concentrations of 5E-3 - 5E-2 M were treated with an equivalent amount of dry Cs2CO3.The solutions were stirred at 40 deg C overnight.Workup of the reaction mixture produced a mixture of (macro)cyclic lactone (macrolide) and its dimer (dilide).For the case of 16-iodohexanoic acid the lactone was isolated in 85percent yield.Yields for other large ring macrolides were also excellent.It was demonstrated that substitution by carboxylate on a secondary halide also goes well to afford the corresponding macrolide with no detectable amount of elimination.The effects of ring size, concentration, and solvent on the ring closure of the cesium carboxylates formed in situ were investigated.DMF is the best solvent of those investigated for the ring closure.Cesium carboxylates also undergo more readily ring closure and in far better yield than the carboxylates of lithium, sodium, potassium, rubidium, silver, thallium, magnesium, strontium, or barium.The S-lactone of ricinelaidic acid was prepared optically pure in 80percent yield from optically pure mesylate of R-ricinelaidic acid, which was treated with cesium carbonate in dry DMF.This demonstrates that the ring closure proceeds with the anticipated SN2 inversion at the hydroxyl-bearing carbon atom.With the same approach optically pure S-zearalenone was protected and subjected to ring opening, and the hydroxyl group was activated as mesylate.Some racemization was found to occur in the ring-opening step.On treatment of this material with dry cesium carbonate in DMF, the desired ring closure took place in 80percent yield to provide an excess of the protected R enantiomer of zearalenone.On the basis of these results, some speculations are made concerning the action of cesium in promoting ring closure to macrocyclic lactones.
- Kruizinga, Wim H.,Kellogg, Richard M.
-
p. 5183 - 5189
(2007/10/02)
-