Fatty acid amide hydrolase (FAAH) is a promising target for modulating endocannabinoid and fatty ethanolamide signaling, which may have important therapeutic potential. We recently described new class of O-arylcarbamate inhibitors FAAH, including the cyclohexylcarbamic biphenyl-3-yl ester URB524 (half-maximal inhibitory concentration, IC50 = 63 nM), significant anxiolytic-like properties in rats. In present study, by introducing selected group substituents at meta para positions distal...

Fatty acid amide hydrolase (FAAH), an intracellular serine enzyme, participates in the deactivation of fatty ethanolamides such as endogenous cannabinoid anandamide, intestinal satiety factor oleoylethanolamide, and peripheral analgesic anti-inflammatory palmitoylethanolamide. In present study, we report on design, synthesis, structure−activity relationships (SAR) a novel class potent, selective, systemically active inhibitors FAAH activity, which have recently shown to exert potent...

We present the coupling of primary and secondary benzyl alcohols with indoles to form 3-benzylated H2O that is catalyzed, for first time, by a complex earth-abundant iron. This transformation accommodates variety substrates distinguished its operational simplicity, sustainability, high functional-group tolerance, amenability gram-scale synthesis. On basis preliminary experimental observations, we propose reaction proceeds through borrowing hydrogen process.

Organocatalytic asymmetric synthesis has evolved over the years and continues to attract interest of many researchers worldwide. Enantiopure noncanonical amino acids (ncAAs) are valuable building blocks in organic synthesis, medicinal chemistry, chemical biology. They employed elaboration peptides proteins with enhanced activities and/or improved properties compared their natural counterparts, as chiral catalysts, ligand design, for syntheses complex molecules, including products. The...

An efficient, one-pot reductive alkylation of indoles with N-protected aminoethyl acetals in the presence TES/TFA is reported. It represents first general method for direct synthesis tryptamine derivatives from and nitrogen-functionalized acetals. This convergent versatile approach employs safe inexpensive reagents, proceeds under mild conditions, tolerates several functional groups. The new procedure was efficiently applied to a gram-scale both luzindole, reference MT2-selective melatonin...

The selective C3-alkylation of indoles with N-protected ethanolamines involving the "borrowing hydrogen" strategy is described. This method provides convenient and sustainable access to several tryptamine derivatives.

Two types of adenosine receptor ligands were designed, i.e., 9H-purine and 1H-imidazo[4,5-c]pyridines, to obtain selective A(2A) antagonists, we report here their synthesis binding affinities for the four subtypes A(1), A(2A), A(2B) A(3). The design was carried out on basis molecular modeling a number potent antagonists described in literature. Three compounds (25b-d) showed an interesting affinity selectivity subtype. One them, ST1535...

Alkylcarbamic acid biphenyl-3-yl esters are a class of fatty amide hydrolase (FAAH) inhibitors that comprises cyclohexylcarbamic 3′-carbamoylbiphenyl-3-yl ester (URB597), compound with analgesic, anxiolytic-like and antidepressant-like properties in rat mouse models. Here, we extended the structure−activity relationships (SARs) for this compounds by replacing cyclohexyl ring parent (URB524) (FAAH IC50 = 63 nM) selected set substituents different size, shape, flexibility, lipophilicity....

Highly regioselective electrophilic substitution of indoles with N-acetylated α,β-dehydroalanine methyl ester, promoted by different transition metal salts was achieved. The orthogonal regioselectivity provides an efficient protocol toward highly functionalized 3-indolyl-α-amino acids. mechanism the reactions explored NMR studies.

A practical and efficient synthesis of 3-substituted hexahydropyrrolo[2,3-b]indole is described. The addition/cyclization indoles with alpha,beta-dehydroamino esters in the presence a Lewis acid provides adducts good yields stereoselectivities. This approach has been applied to concise esermethole employing an appropriately substituted indole N-acyl dehydroamino ester.

The synthetic efforts toward the concise synthesis of (-)-indolactam V from simple and commercially available starting materials using palladium- copper-catalyzed intramolecular N-arylation strategy for elaboration requisite nine-membered lactam ring as key step are described. incorporation a turn-inducing structural element along linear precursor was fundamental to achieve heterocyclization well obtain correct regio- chemoselectivity. stereoselective nature in C-N coupling cyclization...

A systematic modification of the caffeinyl core and substituents reference compound (E)-8-(3-chlorostyryl)caffeine led to 9-deazaxanthine derivative (E)-6-(4-chlorostyryl)-1,3,5,-trimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4-(3H,5H)-dione (17f), which acts as a dual human A2a antagonist/MAO-B inhibitor (Ki(A2A) = 260 nM; IC50(MAO-B) 200 IC50(MAO-A) 10 μM) dose dependently counteracts haloperidol-induced catalepsy in mice from 30 mg/kg by oral route. The is best balanced A2A reported date, it...

Abstract A copper‐based catalytic technique for the regioselective hydroboration and hydrosilylation of dehydroalanine derivatives has been developed. This method introduces synthetically versatile boron silicon groups, while simultaneously performing a anti‐Markovnikov hydrofunctionalization dehydroalanines dehydropeptides synthesis amino acids peptides bearing unnatural side‐chains. The products obtained were expediently converted into valuable nonproteinogenic acid building blocks...

Pd(II)-catalyzed cross-dehydrogenative coupling (CDC) of methyl N-phthaloyl dehydroalanine esters with simple aromatic hydrocarbons is reported. The reaction, which involves the cleavage two sp2 C–H bonds followed by C–C bond formation, stereoselectively generates highly valuable Z-dehydrophenylalanine skeletons in a practical, versatile, and atom economical manner. In addition, perfluorinated product was expediently converted into important nonproteinogenic amino acid building blocks...

Antitumor agents (−)-acylfulvene and (−)-irofulven are prepared in an approach that employs the powerful enyne ring-closing metathesis reaction to secure spiro-bicyclic AB rings. Other key features of this synthesis include efficient aldol-based introduction stereocenter at C2, a diazene-mediated reductive allylic transposition, metathesis/oxidation sequence.

We report our full account of the enantioselective total synthesis (−)-acylfulvene (1) and (−)-irofulven (2), which features metathesis reactions for rapid assembly molecular framework these antitumor agents. discuss application an Evans Cu-catalyzed aldol addition reaction using a strained cyclopropyl ketenethioacetal, (2) efficient enyne ring-closing cascade in challenging setting, (3) reagent IPNBSH late-stage reductive allylic transposition reaction, (4) final RCM/dehydrogenation...

A new and short synthesis of racemic cis-clavicipitic acid was achieved by taking advantage the double nucleophilic character indole-4-pinacolboronic ester. Key to success were an efficient selective C-3 indole Friedel–Crafts alkylation development unprecedented intramolecular rhodium-catalyzed 1,2-addition aryl pinacolboronic ester unactivated imine.

A Pd(II)-catalyzed intramolecular oxidative C–H/C–H cross-coupling has been developed for the direct construction of valuable polycyclic heteroarene scaffolds. From a retrosynthetic point view, strategic formation C–C bond via C(sp2)–H/C(sp2)–H dehydrogenative coupling across C3,N-linked biheterocyclic precursors may be useful in de novo syntheses indole-derived natural products and pharmaceuticals. The reaction exhibited good functional group/heterocycle tolerance, proposed mechanism...

Fatty acid amide hydrolase (FAAH) is a serine that catalyzes the intracellular hydrolysis of fatty ethanolamides such as anandamide and oleoylethanolamide. Targeting this enzyme may have important therapeutic potentials owing to multiple physiological roles these amides. Cyclohexylcarbamic biphenyl-3-yl ester (URB524) was one most promising FAAH inhibitors so far described. We report modulation electronic steric features proximal phenyl ring compound by introducing series substituents at...

A facile synthetic approach to the direct preparation of various novel unnatural boronated protected tryptophans using a regio- and chemoselective electrophilic substitution 4- 5-boronated indoles with N-protected dehydroalanine is described. The gram-scale synthesis two free tryptophan boronic acids also reported.

Abstract A Brønsted acid catalyzed bisindolization reaction with suitable α‐amido acetals that tolerates a wide range of indoles is reported. The method allows rapid access to the biologically relevant bisindolyl ethanamine scaffold in good excellent yields upon mild amide basic hydrolysis. In preliminary pharmacological studies, some these compounds display cytotoxic activity U937 cancer cells. marine natural alkaloid 2,2‐di(6′‐bromo‐3′‐indolyl)‐ethylamine was most active compound and could...

The rapid and expedient assembly of three new classes biheterocycles biological interest, viz. indole–imidazoles 4 , indole–pyrroles 6 indole–triazoles 8 was accomplished using different combinations tryptamines, 1,2‐diaza‐1,3‐dienes, aldehydes, and/or alkynes as readily available building blocks. Twenty‐six derivatives were thus prepared in excellent yields (up to 100 %). products screened for in‐vitro studies. Some these revealed promising anticancer activity against MCF7 Caco‐2 human...