Carmela De Risi

Pharmacological profiles of presynaptic nociceptin/orphanin FQ receptors modulating 5‐hydroxytryptamine and noradrenaline release in the rat neocortex

The pharmacological profiles of presynaptic nociceptin/orphanin FQ (N/OFQ) peptide receptors (NOP) modulating 5‐hydroxytryptamine (5‐HT) and noradrenaline (NE) release in the rat neocortex were characterized in a preparation of superfused synaptosomes challenged with 10 mM KCl. N/OFQ concentration‐dependently inhibited K+‐evoked [3H]‐5‐HT and [3H]‐NE overflow with similar potency (pEC50 ∼7.9 and ∼7.7, respectively) and efficacy (maximal inhibition ∼40%). N/OFQ (0.1 μM) inhibition of [3H]‐5‐HT and [3H]‐NE overflow was antagonized by selective NOP receptor antagonists of peptide ([Nphe1]N/OFQ(1‐13)NH2 and UFP‐101; 10 and 1 μM, respectively) and non‐peptide (J‐113397 and JTC‐801; both 0.1 μM) nature. Antagonists were routinely applied 3 min before N/OFQ. However, a 21 min pre‐application time was necessary for J‐113397 and JTC‐801 to prevent N/OFQ inhibition of [3H]‐NE overflow. The NOP receptor ligand [Phe1ψ(CH2‐NH)Gly2]N/OFQ(1‐13)NH2 ([F/G]N/OFQ(1‐13)NH2; 3 μM) did not affect K+‐evoked [3H]‐NE but inhibited K+‐evoked [3H]‐5‐HT overflow in a UFP‐101 sensitive manner. [F/G]N/OFQ(1‐13)NH2 antagonized N/OFQ actions on both neurotransmitters. The time‐dependency of JTC‐801 action was studied in CHO cells expressing human NOP receptors. N/OFQ inhibited forskolin‐stimulated cAMP accumulation and JTC‐801, tested at different concentrations (0.1–10 μM) and pre‐incubation times (0, 40 and 90 min), antagonized this effect in a time‐dependent manner. The Schild‐type analysis excluded a competitive type of antagonism. We conclude that presynaptic NO receptors inhibiting 5‐HT and NE release in the rat neocortex have similar pharmacological profiles. Nevertheless, they can be differentiated pharmacologically on the basis of responsiveness to [F/G]N/OFQ(1‐13)NH2 and time‐dependent sensitivity towards non‐peptide antagonists.

Synthetic Routes to Chiral Nonracemic and Racemic Dihydro- And Tetrahydrothiophenes

Natural and man-made organosulfur compounds play important roles in biological and medicinal chemistry. Among the various classes of organic sulfur compounds, dihydroand especially tetrahydrothiophenes have attracted particular attention because of the widespread occurrence as ring system motifs in natural and nonnatural products displaying a broad spectrum of biological activities. Tetrahydrothiophene-based compounds include the essential coenzyme biotin 1, a water-soluble vitamin involved in important biological functions, and the potent α-glucosidase inhibitors salacinol 2 6 and kotalanol 3, isolated from several Salacia plant species. Recently, the related compounds salaprinol 4 and ponkoranol 5 were isolated from Salacia prinoides, and significant efforts to prepare these cyclic sulfonium salts and synthetic analogues, including 6 and 7, have been made in the past few years (Figure 1). Further representative compounds are the 40-thioadenosine derivative 8, a highly potent and selective A3 adenosine receptor antagonist; the 40-thiocytidine nucleoside 9, active against HSV-1 and HSV-2; the cholecystokinin type-B receptor antagonist tetronothiodin 10; and (R)-tetrahydrothiophen-3-ol 11, 18 a pivotal intermediate to obtain the potent antibacterial Sulopenem 12 (Figure 2). The field of applications of tetrahydrothiophenes is impressively wide in scope: these compounds have been employed as templates to assist and control various chemical transformations, including asymmetric hydrogenation, catalytic asymmetric epoxidation, and catalytic intramolecular cyclopropanation. Moreover, adsorption of tetrahydrothiophene on gold has emerged as a powerful tool to obtain self-assembled monolayers (SAMs), which can be used to control physical and chemical properties of surfaces for various technological purposes. The dihydrothiophene ring system is a common structural feature of many bioactive compounds, some of which are shown in Figure 3. In particular, (S)-ethyl 4-amino-4,5-dihydrothiophene-2-carboxylate 13 inhibits copper amine oxidases (CAOs), the unnatural L-nucleoside 14 displays potent anti-HIV activity without significant toxicity, and 4,5-dihydrothiophene-3-carbonitrile 15 exhibits antibacterial and antifungal properties. Interestingly, it has been demonstrated that calicheamicin becomes active Figure 1.

Recent Developments in General Methodologies for the Synthesis of α-Ketoamides

The α-ketoamide motif is widely found in many natural products and drug candidates with relevant biological activities. Furthermore, α-ketoamides are attractive candidates to synthetic chemists due to the ability of the motif to access a wide range of functional group transformations, including multiple bond-forming processes. For these reasons, a vast array of synthetic procedures for the preparation of α-ketoamides have been developed over the past decades, and the search for expeditious and efficient protocols continues unabated. The aim of this review is to give an overview of the diverse methodologies that have emerged since the 1990s up to the present. The different synthetic routes have been grouped according to the way the α-ketoamide moiety has been created. Thus, syntheses of α-ketoamides proceeding via C(2)-oxidation of amide starting compounds are detailed, as are amidation approaches installing the α-ketoamide residue through C(1)-N bond formation. Also discussed are the methodologies centered on C(1)-C(2) σ-bond construction and C(2)-R/Ar bond-forming processes. Finally, the literature regarding the synthesis of α-ketoamide compounds by palladium-catalyzed double-carbonylative amination reactions is discussed.

A new synthetic approach to 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-benzimidazol-2-one(J-113397), the first non-peptide ORL-1 receptor antagonist..

An efficient approach to 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-benzimidazol-2-one (J-113397) 1, the first non-peptide ORL-1 receptor antagonist described in literature, is outlined. After construction of the piperidine framework through Dieckmann cyclization of the Michael adduct 8 of cyclooctylmethylamine to methyl acrylate, condensation with o-phenylendiamine produced the beta-enamino ester 2, which has been conveniently used to construct the benzimidazolone substituent at C-4. Catalytic hydrogenation of intermediate 11 followed by base-promoted cis--trans isomerization of the key compound 12 led to the formation of ester 13, which was converted to the racemic title compound by LiAlH(4) reduction. The pure enantiomers were obtained by chiral preparative HPLC separation using a derivatized cellulose-based stationary phase.

Diastereoselective synthesis of β-amino-α-hydroxy phosphonates via oxazaborolidine catalyzed reduction of β-phthalimido-α-keto phosphonates

Abstract Reduction of β-phthalimido-α-keto phosphonates, obtained through an Arbuzov reaction between the appropriate acid chloride and triethyl phosphite, with boranes and oxazaborolidine as catalyst, afforded β-phthalimido-α-hydroxy phosphonates in good yields and high diastereoselectivity. Deprotection of the amino group gave the title compounds.

A unified asymmetric approach to substituted hexahydroazepine and 7-azabicyclo[2.2.1]heptane ring systems from D(−)-quinic acid: Application to the formal synthesis of (−)-balanol and (−)-epibatidine

3,4-O-Isopropylidene-3(R),4(S)-dihydroxycyclohexanone 7, a chiron easily prepared through a five step sequence from D(-)-quinic acid 1, has been efficiently utilized as the starting building block for the enantioselective syntheses of (3R,4S)-N-p-toluenesulfonyl-3,4-epoxy-hexahydroazepine 17 and (1R,4S)-N-tert-butoxycarbonyl-7-azabicyclo[2.2.1]heptan-2-one 43, advanced intermediates already taken to (-)-balanol and (-)-epibatidine respectively. While the nitrogen atom ring-insertion via Beckmann rearrangement was the key step for the construction of the hexahydroazepine ring of 17, a regio- and stereospecific intramolecular nucleophilic ring opening of an intermediate cyclic sulfate featured the approach to the substituted 7-azabicyclo[2.2.1]heptane nucleus of 43.

Polymer-bound 4-benzylsulfonyl-1-triphenylphosphoranylidene-2-butanone as a tool for the solid-phase synthesis of substituted piperidin-4-one derivatives.

Abstract An efficient method for the construction of 2-substituted-piperidin-4-one derivatives on solid support has been developed using polymer-bound 4-benzylsulfonyl-1-triphenylphosphoranylidene-2-butanone as a convenient precursor for substituted divinyl ketones in the heterocyclization reaction with amines. The resin was released in a recyclable sulfinate form.

Enantioselective approach to 7-azabicyclo[2.2.1]heptane ring systems using D-(−)-quinic acid as the chiral educt: Application to the formal synthesis of (+)-epibatidine

By utilizing D-(−)-quinic acid as the chiral starting material the optically pure 7-[(1,1-dimethylethoxy)carbonyl]-7-azabicyclo[2.2.1.]heptan-2-one 2, an advanced intermediate already taken to (+)-epibatidine 1, a non-opioid analgesic isolated from Ecuadorian poison frogs, was synthetized through a facile, regioselective intramolecular nucleophilic ring opening of a cyclic sulfate moiety.

Enantiodivergent synthesis of 2-hydroxymethyl-3-hydroxy-4-nitro-pyrrolidines through tandem Michael-Henry reaction using L-serine as the chiral educt

Abstract By utilizing L-serine, both enantiomers of all trans 2-hydroxymethyl-3-hydroxy-4-nitro-pyrrolidine were efficiently prepared through tandem Michael-Henry methodology. Their stereochemistry has been assigned through conversion of one of them to trans 2-hydroxymethyl-3-hydroxypyrrolidine, a naturally occurring compound recently isolated from Castanospermum australe.

Enantioselective synthesis of (−)-meroquinene through tandem Michael reaction methodology.

Abstract An enantioselective approach to the synthesis of non natural (−)-meroquinene 1 based on sequential inter- and intramolecular Michael reaction between (L)-menthyl N-benzyl-5-amino-2E-pentenoate 3 and 1-acetyloxy-4-methoxymethyloxy-2-nitrobutane 10b , acting as surrogate of 2-nitro-1,3-butadiene 4 , is described. The heterocyclization process led to the formation of the piperidine ring system 12 , obtained as an unseparable 80:20 mixture of diastereomers at the newly created chiral centres at C-3 and C-4, which became easily separable by column chromatography after transformation of the nitrogen protective benzyl group into the corresponding carbamates 14 and 15 . Both compounds, after elaboration of the chain geminal to the nitro group into a vinyl appendage. underwent regio- and stereo-selective removal of the nitro group by palladium-catalyzed displacement with hydride generated by formate to give the precursor 19 , easily converted by treatment with hydrochloric acid to 1 , isolated as hydrochloride.