The Pictet-Spengler Reaction Updates Its Habits.

The Pictet-Spengler reaction (P-S) is one of the most direct, efficient, and variable synthetic method for the construction of privileged pharmacophores such as tetrahydro-isoquinolines (THIQs), tetrahydro-ß-carbolines (THBCs), and polyheterocyclic frameworks. In the lustro (five-year period) following its centenary birthday, the P-S reaction did not exit the stage but it came up again on limelight with new features. This review focuses on the interesting results achieved in this period (2011-2015), analyzing the versatility of this reaction. Classic P-S was reported in the total synthesis of complex alkaloids, in combination with chiral catalysts as well as for the generation of libraries of compounds in medicinal chemistry. The P-S has been used also in tandem reactions, with the sequences including ring closing metathesis, isomerization, Michael addition, and Gold- or Brønsted acid-catalyzed N-acyliminium cyclization. Moreover, the combination of P-S reaction with Ugi multicomponent reaction has been exploited for the construction of highly complex polycyclic architectures in few steps and high yields. The P-S reaction has also been successfully employed in solid-phase synthesis, affording products with different structures, including peptidomimetics, synthetic heterocycles, and natural compounds. Finally, the enzymatic version of P-S has been reported for biosynthesis, biotransformations, and bioconjugations.

The Pictet-Spengler Reaction Still on Stage.

Today, in spite of being older than a century (born in 1911), the Pictet-Spengler two component reaction (PS-2CR) is still one of the most popular reactions, not only for the synthesis of tetrahydroisoquinolines (THIQs), tetrahydro-ß-carbolines (THBCs), or more complex structures containing these two privileged moieties, but also for the construction of novel scaffolds, available for structure-activity relationship (SAR) studies and/or for combinatorial libraries targeted at drug discovery. The prominence of the P-S cyclization is brought about by the inheritance from analogous enzyme-catalyzed reactions of the biogenetic pathways of natural products, mainly indole alkaloids, with a broad range of biological activities. This knowledge has been the starting point for the biomimetic synthesis or the bio-engineering production of pharmacologically important drugs. The long-lasting life of the P-S reaction depends on the discovery of its multiple facets, the modifications of its parameters and components, as well as the continuous renovation of solutions for the challenging stereochemical outcome of the transformation. This paper deals with an updated visit to the P-S reaction aiming to find the threads of the story without forgetting the numerous facets of the prism. It is organized as a theater piece, with a prologue and the main scene (namely, Act 1) where the readers can follow the parade of the two above-mentioned very recurring motifs (namely, THIQ and THBC) by moving from one step to another (a cyclization, an intramolecular attack, a stereoselective passage) to find the way out of the labyrinth of the P-S reaction.

Reaction of nitrosonium cation with resorc[4]arenes activated by supramolecular control: covalent bond formation.

Resorc[4]arenes 1 and 2, which previously proved to entrap NO(+) cation within their cavities under conditions of host-to-guest excess, were treated with a 10-fold excess of NOBF4 salt in chloroform. Kinetic and spectral UV-visible analyses revealed the formation of isomeric 1:2 complexes as a direct evolution of the previously observed event. Accordingly, three-body 1-(NO(+))2 and 2-(NO(+))2 adducts were built by MM and fully optimized by DFT calculations at the B3LYP/6-31G(d) level of theory. Notably, covalent nitration products 4, 5 and 6, 7 were obtained by reaction of NOBF4 salt with host 1 and 2, respectively, involving macrocycle ring-opening and insertion of a nitro group in one of the four aromatic rings. In particular, compounds 4 and 6, both containing a trans-double bond in the place of the methine bridge, were oxidized to aldehydes 5 and 7, respectively, after addition of water to the reaction mixture. Calculation of the charge and frontier orbitals of the aromatic donor (HOMO) and the NO(+) acceptor (LUMO) clearly suggests an ipso electrophilic attack by a first NO(+) unit on the resorcinol ring, mediated by the second NO(+) unit.

N-linked peptidoresorc[4]arene-based receptors as noncompetitive inhibitors for α-chymotrypsin.

This paper deals with the design, synthesis, and evaluation of a new series of receptors for protein surface recognition. The design of these agents is based around the attachment of four constrained dipeptide chains onto a central resorc[4]arene scaffold. By varying the sequence, nature, and stereochemistry of the chains we prepared anionically functionalized N-linked peptidoresorc[4]arenes 12, 13, and 17 by Pd/C-catalyzed hydrogenation of the corresponding benzyl esters 10, 11, and 16. From this family of receptors we have identified noncompetitive inhibitors of α-chymotrypsin (ChT), which function by binding to the surface of the enzyme in the neighborhood of the active site cleft (K(i) values ranging from 12.4 ± 5.1 µM for free carboxylic acid (+)-12b to 0.76 ± 0.14 µM for benzyl ester (-)-16a). For anionically functionalized receptors 12, 13, and 17 the ChT inhibition is based essentially on electrostatic interaction, and the bound enzyme can be released from the resorcarene surface by increasing the ionic strength, with its activity almost completely restored. For receptors with terminal benzyl ester groups (10 and 16) a hydrophobic network can be suggested.

Further antinociceptive properties of extracts and phenolic compounds from Plinia glomerata (Myrtaceae) leaves.

This study describes the antinociceptive activity of extracts (methanolic (ME) and acetonic (AE)) and two phenolic compounds, 3,4,3'-trimethoxyflavellagic acid (1) and 3,4,3'-trimethoxy flavellagic acid 4'-O-glucoside (2), from Plinia glomerata leaves, against different experimental models of pain in mice. When evaluated against writhing test, by i.p. route, ME and AE presented calculated ID(50) values (and respective confidence interval) of 3.28 (1.63-6.61) and 24.79 (16.57-37.09) mg/kg, respectively. Given by the oral route at 500 mg/kg, AE and ME extracts inhibited the abdominal constrictions by 60.5% and 35.3%, respectively. In the formalin test (10 mg/kg, i.p.), AE inhibited both phases of pain (45.6% in the first phase; 99.8% in the second phase) whereas ME inhibited 47.8% the first phase, and 92.6% the second phase. In the capsaicin test both extracts showed activity, with calculated ID(50) values of 6.56 (5.69-7.56) and 7.68 (4.94-11.93) mg/kg for AE and ME, respectively. When evaluated against the hot-plate test, both extracts demonstrated activity, but only in high doses. Compound 2, when evaluated against the formalin test (10 mg/kg, i.p.), inhibited both phases of pain (77.6%, first phase; 62%, second phase) whereas 1 inhibited only the first phase, with inhibition of 70%. When tested in the capsaicin and glutamate tests, at 10 mg/kg, i.p., 1 and 2 caused inhibitions of 41.5% and 37.9%, and 37.7% and 54.5%, respectively. These results confirm previous studies carried out by our research group regarding the antinociceptive properties of P. glomerata, stimulating other studies on mechanism of action as well as the determination of additional active principles in this plant.

Nitrosonium complexes of resorc[4]arenes: spectral, kinetic, and theoretical studies.

Resorc[4]arene octamethyl ethers 1-3, when treated with NOBF4 salt in chloroform, form very stable 1:1 nitrosonium (NO+) complexes, which are deeply colored. The complexation process is reversible, and the complexes dissociate and bleach upon addition of methanol or water, to give the starting macrocycles. Resorc[4]arenes 1 and 2 are in the same cone conformation, but with different side-chains, whereas 3 possesses a different conformation (chair), while bearing the same side-chain as 2. Kinetic and spectral UV-visible analysis revealed that NO+ interacts with resorc[4]arenes 1 and 2 both outside and inside their basket, leading to complexes with two absorption patterns growing at different rates, one featuring high-energy bands (HEB) within the near-UV zone, and the other one low-energy bands (LEB), attributed to charge-transfer interactions, within the visible range. The presence of ester carbonyl groups in 2 strongly drives the NO+ cation outside the resorcarene. Resorc[4]arene 3 showed a spectral pattern pointing out a clear involvement of the ester moieties in the NO+ entrapping, beside the formation of significant charge-transfer interactions. 1H NMR spectroscopy and molecular modeling clearly supported these findings.

Bioactive phenolic compounds from aerial parts of Plinia glomerata.

The present work describes the antinociceptive properties and chemical composition of the aerial parts of Plinia glomerata (Myrtaceae). Both of the extracts evaluated, acetonic and methanolic, showed potent antinociceptive action, when analyzed against acetic acid-induced abdominal constrictions in mice, with calculated ID50 (mg/kg, i. p.) values of 24.8 and 3.3, respectively. Through usual chromatographic techniques with an acetonic extract, the following compounds were obtained: 3,4,3'-trimethoxy flavellagic acid (1), 3,4,3'-trimethoxy flavellagic acid 4'-O-glucoside (3) and quercitrin (4), which were identified based on spectroscopic data. Compounds 1 (ID50 = 3.9 mg/kg, i. p., or 10.8 micromol/kg) and 3 (ID50 = 1.3 mg/kg or 2.5 micromol/kg) were notably more active than some well-known analgesic drugs used here for comparison.

Gas-phase enantioselectivity of chiral amido[4]resorcinarene receptors.

Diastereomeric proton-bound [1(L)HA]+ complexes between selected amino acids (A=phenylglycine (Phg), tryptophan (Trp), tyrosine methyl ester (TyrOMe), threonine (Thr), and allothreonine (AThr)) and a chiral amido[4]resorcinarene receptor (1(L)) display a significant enantioselectivity when undergoing loss of the amino acid guest A by way of the enantiomers of 2-aminobutanes (B) in the gas phase. The enantioselectivity of the B-to-A displacement is ascribed to a combination of thermodynamic and kinetic factors related to the structure and the stability of the diastereomeric [1(L)HA]+ complexes and of the reaction transition states. The results of the present and previous studies allow classification of the [1(L)HA]+ complexes in three main categories wherein: i) guest A does not present any additional functionalities besides the amino acid one (alanine (Ala), Phg, and phenylalanine (Phe)); ii) guest A presents an additional alcohol function (serine (Ser), Thr, and AThr); and iii) guest A contains several additional functionalities on its aromatic ring (tyrosine (Tyr), TyrOMe, Trp, and 3,4-dihydroxyphenylalanine (DOPA)). Each category exhibits a specific enantioselectivity depending upon the predominant [1(L)HA]+ structures and the orientation of the 2-aminobutane reactant in the relevant adducts observed. The results may contribute to the understanding of the exceptional selectivity and catalytic properties of enzyme mimics towards unsolvated biomolecules.

Derivatization does not influence antimicrobial and antifungal activities of applanoxidic acids and sterols from Ganoderma spp.

Applanoxidic acids and sterols, isolated from Ganoderma spp., were acetylated and/or methylated. The antibacterial activity against Escherichia coli and Staphylococcus aureus and the antifungal activity against Candida albicans and Trichophyton mentagrophytes of the derivatives were investigated by a microdilution method, and compared with those of the natural products. Both natural and modified compounds exhibited comparable antibacterial and antifungal activities in a range of 1.0 to > 2.0 mg/ml minimal inhibitory concentration.

Novel prenyltransferase enzymes as a tool for flavonoid prenylation.

The recent identification of genes encoding a novel family of soluble aromatic prenyltransferases from Streptomyces species and the structural characterization of one of these proteins are challenging discoveries in the biochemistry of natural compounds. In addition to their notable physiological role in the biosynthesis of aminocoumarin antibiotics, these enzymes represent an advanced tool for exploring novel isoprenoid substitutions in aromatic compounds and are expected to foster the emerging pharmacological applications of prenylated flavonoids.

Prenylated flavonoids: pharmacology and biotechnology.

Within the flavonoid class of natural products the prenylated sub-class is quite rich in structural variety and pharmacological activity. In the last twenty years a huge number of new structures has been reported, mostly from Leguminosae and Moraceae, with few coming from other genera. The presence, in different forms, of the isoprenoid chain can lead to impressive changes in biological activity, mostly attributed to an increased affinity for biological membranes and to an improved interaction with proteins. Molecules, such as xanthohumol and sophoraflavanone G, while being very structurally simple, show numerous pharmacological applications and are ideal candidates for SAR aimed to the discovery of new drugs. Only recently the biogenesis of these compounds has been more extensively studied and much attention has been focused on the enzymes involved in the modification and transfer of the prenyl unit.

Chiral recognition by resorcin[4]arene receptors: intrinsic kinetics and dynamics.

Molecular recognition of representative amino acids (A) by a chiral amido[4]resorcinarene receptor (1(L)) was investigated in the gas phase by ESI-FT-ICR mass spectrometry. The ligand displacement reaction between noncovalent diastereomeric [1(L).H.A](+) complexes and the 2-aminobutane enantiomers (B) exhibits a distinct enantioselectivity with regard to both the leaving amino acid A and the amine reactant B. The emerging selectivity picture, discussed in the light of molecular mechanics and molecular dynamics calculations, points to chiral recognition by 1(L), as determined by the effects of the host asymmetric frame on the structure, stability, and rearrangement dynamics of the diastereomeric [1(L).H.A](+) complexes and the orientation of the amine reactant B in encounters with [1(L).H.A](+). The results contribute to the development of a dynamic model of chiral recognition of biomolecules by enzyme mimics in the unsolvated state.

Chalcone dimethylallyltransferase from Morus nigra cell cultures. Substrate specificity studies.

A new prenyltransferase (PT) enzyme derived from the microsomal fractions of cell cultures of Morus nigra was shown to be able to prenylate exclusively chalcones with a 2',4'-dihydroxy substitution and the isoflavone genistein. Computational studies were performed to shed some light on the relationship between the structure of the substrate and the enzymatic activity. PT requires divalent cations, particularly Mg(2+), to be effective. The apparent K(m) values for gamma,gamma-dimethylallyldiphosphate and 2',4'-dihydroxychalcone were 63 and 142 microM, respectively. The maximum activity of the enzyme was expressed during the first 10 days of cell growth.

Two new O-geranyl coumarins from the resinous exudate of Haplopappus multifolius.

From the resinous exudate of leaves of Haplopappus multifolius two new coumarins were isolated and assigned the structures 6-hydroxy-7-(5'-hydroxy-3',7'-dimethylocta-2',6'-dien)-oxycoumarin (1) and 6-hydroxy-7-(7'-hydroxy-3',7'-dimethylocta-2',5'-dien)-oxy coumarin (2).

Synthesis and molecular modelling studies of resorcin[4]arene-capped porphyrins.

Three new resorcin[4]arene-capped porphyrins (3, 5 and 7) different in the porphyrin skeleton, in the linking arms and in the cavity dimensions, have been synthesised. Molecular modelling calculations explored the conformations and the cavity size of the three compounds and showed that their hydrophobic pockets can accommodate one molecule of water or methane (3 and 5), or benzene (7) without any distortion. Notably, the capped porphyrin 5 was able to inhibit the oxidation of Co(II) to Co(III), whereas compound 7 did it only partially.

Novel hypotensive agents from Verbesina caracasana: structure, synthesis and pharmacology.

The number and the pharmacological activities of drugs featuring a guanidine group is actually amazing. Many synthetic guanidine derivatives have attracted pharmacologists in search of new antihypertensive drugs for their ability to block adrenergic nerve activity through central and/or peripheral mechanisms. As a result, compounds such as guanethidine, guanabenz, guanfacine, and pinacidil have been introduced in antihypertensive drug therapy. A crude methanol extract of the Venezuelan plant Verbesina caracasana Fries (Compositae), intravenously administered to mice, was found to induce biological effects such as erection of hair, initial stimulation and subsequent blockade of breathing. Biologically controlled purification yielded a series of active guanidine derivatives, namely G1-G7, which were extensively studied with the focus on the following items: (1) The structure determination of the active compounds by spectral data and a set of reactions; (2) The confirmation of the structures by a biogenetically oriented synthesis; (3) The study of the pharmacological profiles of the isolated drugs; (4) The synthesis of analogous and homologous products in the effort to shed some light on the structure-activity relationship. The metabolites of V. caracasana were characterized, in anesthetized rats, as hypotensive drugs of high (G2), mild (G1, G7) and low (G3,G5,G6) potency, devoid of consistent actions in heart rate, and provided with moderate stimulatory effects on cardiac inotropism and breathing (at selected non-toxic intravenous doses). Autonomic neurogenic components and/or peripheral adrenergic and cholinergic receptor-related pathways were involved in the cardiovascular effects. Synthetic analogs and homologs of G1 and G5 were all shown to be hypotensive drugs of low-mild potency, not affecting appreciably cardiac inotropism and/or breathing. The pharmacodynamic differences among the studied compounds were likely to depend on their ability to cross the blood-brain barrier, lipophilicity and pharmacokinetics. Since most of the compounds did not induce reflex tachycardia and depression of myocardial contractility as the majority of the antihypertensive drugs, they might be useful in the treatment of arterial hypertension of various genesis.

Biotransformation of a dibenzylbutanolide to podophyllotoxin analogues by shoot cultures of Haplophyllum patavinum.

A peroxidase from spent medium of shoot cultures from Haplophyllum patavinum (L.) G. Don catalyzes the biotransformation of a synthetic dibenzybutanolide into a podophyllotoxin analogue and a novel compound, derived by the opening of the lactone ring.

Labdane diterpenes from Haplopappus illinitus.

A chemical study of aerial parts of Haplopappus illinitus afforded five labdane diterpenoids whose structures were elucidated by high field NMR spectroscopy and 2D techniques. Four of them are dicarboxylic acids previously reported as the corresponding dimethyl ester derivatives and the fifth is a new compound.

Enantioselective guest exchange in a chiral resorcin[4]arene cavity.

Gas-phase proton-bound complexes between a chiral resorcin[4]arene and some representative amino acids, that is, L- and D-alanine or L- and D-serine, were generated in the source of a Fourier transform ion cyclotron resonance mass spectrometer. Gas-phase exchange of the amino acid from the diastereomeric complexes with the enantiomers of 2-butylamine exhibits a significant enantioselectivity, which depends not only upon the configuration of the leaving guest but also on that of the incoming amine. These findings, coupled with molecular dynamic calculations, point to the observed gas-phase enantioselectivity as determined by the effects of the resorcin[4]arene chiral cavity upon the diastereomeric exchange transition structures.