Pyrrolidine Ring Research Articles

Dispirooxindoles Based on 2-Selenoxo-Imidazolidin-4-Ones: Synthesis, Cytotoxicity and ROS Generation Ability.

A regio- and diastereoselective synthesis of two types of dispiro derivatives of 2-selenoxoimidazolidin-4-ones, differing in the position of the nitrogen atom in the central pyrrolidine ring of the spiro-fused system—namely, 2-selenoxodispiro[imidazolidine-4,3′-pyrrolidine-2′,3″-indoline]-2″,5-diones (5a-h) and 2-senenoxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-diones (6a-m)—were developed based on a 1,3-dipolar cycloaddition of azomethine ylides generated from isatin and sarcosine or formaldehyde and sarcosine to 5-arylidene or 5-indolidene-2-selenoxo-tetrahydro-4H-imidazole-4-ones. Selenium-containing dispiro indolinones generally exhibit cytotoxic activity near to the activity of the corresponding oxygen and sulfur-containing derivatives. Compounds 5b, 5c, and 5e demonstrated considerable in vitro cytotoxicity in the 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) test (concentration of compounds that caused 50% death of cells (CC50) 7.6–8.7 μM) against the A549 cancer cell line with the VA13/A549 selectivity index 5.2–6.9; some compounds (5 and 6) increased the level of intracellular reactive oxygen species (ROS) in the experiment on A549 and PC3 cells using platinized carbon nanoelectrode. The tests for p53 activation for compounds 5 and 6 on the transcriptional reporter suggest that the investigated compounds can only have an indirect p53-dependent mechanism of action. For the compounds 5b, 6b, and 6l, the ROS generation may be one of the significant mechanisms of their cytotoxic action.

Synthesis and application of alternate cyclopolymers of β-diallylaminoethyliminodiacetic acid with maleic acid and sulfur dioxide

Bis-cationic monomer β-diallylaminoethyliminodiacetic acid dihydrochloride (I) underwent alternate cyclocopolymerizations with SO2 and maleic acid to give poly(bis-zwitterion) (PBZ) (± ±) II, and III, respectively. The PBZs contained the chelating motifs of [NH+(CH2)2NH+(CH2CO2−)2] embedded in the pyrrolidine ring of each repeating unit. Both the PBZs were water-insoluble, however they became water-soluble with assistance from salts like NaCl. PBZs II and III, having the point of zero charge at pH 2.4, became water soluble outside the pH-windows of 0.81–4.46 and 1.49–3.35, respectively, whereby the electroneutral pH-responsive polymers become charge-imbalanced. The ‘apparent’ pKas of the protonated amine centers in II were found to be 5.18 and 9.92. As an antiscalant, PBZ III (2.5 ppm) demonstrated inhibition of CaSO4 scale formation with 99% efficacy for over 180 min, while at 1.5 ppm inhibition efficiency was found to be 98% for 50 min. PBZ II at concentrations of 20 and 10 ppm demonstrated CaCO3 scale inhibition of 98% for over 240 min and 95% for over 90 min, respectively. A synergistic mixture of III (20 ppm) and KI (400 ppm) arrested corrosion of mild steel in 1 M HCl with a remarkable efficacy of 98% for 24 h at 60 οC.

Crystal structure and Hirshfeld surface analysis of (RS)-3-hy-droxy-2-{[(3aRS,6RS,7aRS)-2-(4-methyl-phenyl-sulfon-yl)-2,3,3a,6,7,7a-hexa-hydro-3a,6-ep-oxy-1H-isoindol-6-yl]meth-yl}isoindolin-1-one.

The title compound, C24H24N2O5S, crystallizes with two independent mol-ecules (A and B) in the asymmetric unit. In the central ring systems of both mol-ecules, the tetra-hydro-furan rings adopt envelope conformations, the pyrrolidine rings adopt a twisted-envelope conformation and the six-membered ring is in a boat conformation. In mol-ecules A and B, the nine-membered groups attached to the central ring system are essentially planar (r.m.s. deviations of 0.002 and 0.003 Å, respectively). They form dihedral angles of 64.97 (9) and 56.06 (10)°, respectively, with the phenyl rings. In the crystal, strong inter-molecular O-H⋯O hydrogen bonds and weak inter-molecular C-H⋯O contacts link the mol-ecules, forming a three-dimensional network. In addition weak π-π stacking inter-actions [centroid-to centroid distance = 3.7124 (13) Å] between the pyrrolidine rings of the nine-membered groups of A mol-ecules are observed. Hirshfeld surface analysis and two-dimensional fingerprint plots were used to qu-antify the inter-molecular inter-actions present in the crystal, indicating that the environments of the two mol-ecules are very similar. The most important contributions for the crystal packing are from H⋯H (55.8% for mol-ecule A and 53.5% for mol-ecule B), O⋯H/H⋯O (24.5% for mol-ecule A and 26.3% for mol-ecule B) and C⋯H/H⋯C (12.6% for mol-ecule A and 15.7% for mol-ecule B) inter-actions.

Crystal structure and Hirshfeld surface analysis of 2-benzyl-4,5-di-bromo-2,3,3a,4,5,6,7,7a-octa-hydro-3a,6-ep-oxy-1H-isoindol-1-one.

The title compound, C15H15Br2NO2, crystallizes with two mol-ecules in the asymmetric unit of the unit cell. In both mol-ecules, the tetra-hydro-furan rings adopt an envelope conformation with the O atom as the flap and the pyrrolidine rings adopt an envelope conformation. In the crystal, mol-ecules are linked by weak C-H⋯O hydrogen bonds, forming sheets lying parallel to the (002) plane. These sheets are connected only by weak van der Waals inter-actions. The most important contributions to the surface contacts are from H⋯H (44.6%), Br⋯H/H⋯Br (24.1%), O⋯H/H⋯O (13.5%) and C⋯H/H⋯C (11.2%) inter-actions, as concluded from a Hirshfeld surface analysis.

Crystal structure and Hirshfeld surface analysis of 4,5-di-bromo-6-methyl-2-phenyl-2,3,3a,4,5,6,7,7a-octa-hydro-3a,6-ep-oxy-1H-isoindol-1-one.

In the title compound, C15H15Br2NO2, two bridged tetra-hydro-furan rings adopt envelope conformations with the O atom as the flap. The pyrrolidine ring also adopts an envelope conformation with the spiro C atom as the flap. In the crystal, the mol-ecules are linked into dimers by pairs of C-H⋯O hydrogen bonds, thus generating R 2 2(18) rings. The crystal packing is dominated by H⋯H, Br⋯H, H⋯π and Br⋯π inter-actions. One of the Br atoms is disordered over two sites with occupation ratio of 0.833 (8):0.167 (8).

Electrostatics Favor PNA : DNA Stability over Stereochemistry in Pyrrolidine‐Based Cationic Dual‐Backbone PNA Analogues

AbstractModifications to the peptide nucleic acid (PNA) backbone has been well known to alter the thermodynamical parameters of PNA : DNA complexes to broaden their utility for different applications. Electrostatic interactions between a modified PNA having a positively charged backbone and the negatively charged DNA has been shown to enhance thermal stabilities of PNA : DNA complexes at various instances. On the other hand, chiral introduction in PNA backbone leads to stereochemical preference that affects binding properties. However, the interplay between electrostatics and stereochemistry has not been systematically studied so far. Herein, we report the synthesis and biophysical characterization of cationic PNA named dapPNA, first of its kind, having a dual PNA backbone constituting of a pyrrolidine ring having a β‐substitution. One of the aims of this study was to investigate the role of electrostatics over stereochemical preferences. The results show that electrostatic attraction between cationic dapPNA and negatively charged DNA overcomes the unfavorable stereochemical effects and enhances stability of PNA : DNA complexes. Moreover, two different PNA backbones derived from a single PNA monomer expands the repertoire of pyrrolidine based PNA analogues.

Isolation, characterization and semi-synthesis of natural products dimeric amide alkaloids

Isolation, characterization and semi-synthesis of natural products dimeric amide alkaloids

Study and optimization of Diels-Alder reaction of piperine in aqueous ionic solutions using Gn.HCl as a catalyst

Study and optimization of Diels-Alder reaction of piperine in aqueous ionic solutions using Gn.HCl as a catalyst

Crystal structure and Hirshfeld surface analysis of ethyl (4R,4aS)-2-methyl-5,8-dioxo-6-phenyl-4a,5,6,7,7a,8-hexa-hydro-4H-furo[2,3-f]iso-indole-4-carboxyl-ate.

In the title compound, C20H19NO5, the central six-membered ring has a slightly distorted half-chair conformation, with puckering parameters of Q T = 0.3387 (11) Å, θ = 49.11 (19)° and φ = 167.3 (2)°. The conformation of the fused pyrrolidine ring is that of an envelope. Mol-ecules are connected by inter-molecular C-H⋯O hydrogen bonds, C-H⋯π inter-actions and π-π stacking inter-actions [centroid-to-centroid distance = 3.9536 (11) Å, with a slippage of 2.047 Å], forming a three-dimensional network. The most important contributions to the surface contacts are from H⋯H (46.3%), O⋯H/H⋯O (31.5%) and C⋯H/H⋯C (17.3%) inter-actions, as concluded from a Hirshfeld surface analysis.

The effects of 4,7-di(pyrrolidin-1-yl) substituents on the reduction and oxidation mechanisms of 1,10-phenanthrolines: New perspectives in tailoring of phenantroline derivatives

The oxidation and reduction mechanisms of substituted 4,7-di(pyrrolidin-1-yl)-1,10-phenanthrolines were investigated in non-aqueous environment by means of cyclic voltammetry. Reduction of these derivatives leads to the formation of radical anion and subsequent reductive cleavage of pyrrolidine-1-yl moiety in overall ECE reduction processes. The regenerating formation of 1,10-phenanthroline was observed. IR spectroelectrochemistry and HPLC-MS/MS analysis were applied to support this result. The presence of pyrrolidine-1-yl moiety significantly thermodynamically facilitates the reduction of the 1,10-phenanthroline structure. Concerning oxidation, the primarily formed cation radical on nitrogen of the pyrrolidine moiety is further oxidized and undergoes a coupled nucleophilic addition of water and hydroxylated compound is formed as the oxidation product. Additionally, further opening of pyrrolidine ring and oxidative cleavage of alkyl are other proposed reactions. The results presented in this work pave the way for novel chelating agents with electrochemically controlled polarity. Furthermore, reductive regeneration of individual components of the molecular assemblies described in this work opens new directions in electrochemical technologies for the environmental protection.

Diastereoselective synthesis of conformationally restricted KOR agonists.

In order to analyze the bioactive conformation of flexible KOR agonists the ethylenediamine KOR pharmacophore was conformationally constrained by incorporation into a bicyclic system. For this purpose, 2-azabicyclo[3.2.1.]octan-7-amines were designed, synthesized and pharmacologically evaluated. The primary amine 14 as first key intermediate was prepared in a six-step synthesis starting with methyl cyclopent-3-enecarboxylate 9. Whereas phenylacetamides failed to provide bicyclic compounds, the intramolecular nucleophilic substitution of the sulfonamide 25 was initiated by deprotonation with NaH affording the bicyclic compound 26 in 72% yield. The three-step introduction of the pharmacophoric pyrrolidine ring started with nucleophilic substitution of exo-configured tosylate 26 with NaN3, which unexpectedly occurred under retention of configuration leading to exo-configured azide 31. The final KOR agonists 35 and 36 with exo-configured amino moieties were obtained by removal of the N-tosyl moiety of 33 and introduction of the second pharmacophoric element by acylation with dihalophenylacetyl chlorides. The KOR affinity of the pyrrolidine 35a is in the high nanomolar range (Ki = 862 nM). The low KOR affinity is explained by a non-appropriate dihedral angle of 137°/141° of the N(pyrrolidine)-C-C-N(acyl) system. As observed for stereoisomers of potent KOR agonists, phenylacetamide 35a and more importantly sulfonamides 33a and 33b show moderate affinity at σ1 receptors (Ki = 109-208 nM).

Covalent organic functionalization of graphene nanosheets and reduced graphene oxide via 1,3-dipolar cycloaddition of azomethine ylide.

Organic functionalization of graphene is successfully performed via 1,3-dipolar cycloaddition of azomethine ylide in the liquid phase. The comparison between 1-methyl-2-pyrrolidinone and N,N-dimethylformamide as dispersant solvents, and between sonication and homogenization as dispersion techniques, proves N,N-dimethylformamide and homogenization as the most effective choice. The functionalization of graphene nanosheets and reduced graphene oxide is confirmed using different techniques. Among them, energy-dispersive X-ray spectroscopy allows to map the pyrrolidine ring of the azomethine ylide on the surface of functionalized graphene, while micro-Raman spectroscopy detects new features arising from the functionalization, which are described in agreement with the power spectrum obtained from ab initio molecular dynamics simulation. Moreover, X-ray photoemission spectroscopy of functionalized graphene allows the quantitative elemental analysis and the estimation of the surface coverage, showing a higher degree of functionalization for reduced graphene oxide. This more reactive behavior originates from the localization of partial charges on its surface due to the presence of oxygen defects, as shown by the simulation of the electrostatic features. Functionalization of graphene using 1,3-dipolar cycloaddition is shown to be a significant step towards the controlled synthesis of graphene-based complex structures and devices at the nanoscale.

Proline Rich Antimicrobial Peptides-----A tool to Counter Antimicrobial Resistance

Bacterial resistant to antibiotics is a global health problem that necessitates the production of new effective therapeutics. Antimicrobial peptides (AMPs) are commonly accepted as viable alternatives to currently used antibiotics. Some AMPs have the ability to work against not only planktonic bacteria but microbial biofilms as well. Proline rich antimicrobial peptides (PR-AMPs) are a distinctive group of AMPs, isolated in various animal sources, exhibiting an exceptionally high proline content. PR-AMPs function through non-lytic mechanisms and are generally regarded as non-toxic to mammalian cells. These peptides block bacterial protein translation by binding on and inactivating the ribosome. Proline, the only cyclic proteinogenic amino acid has the ability to undergo cis-trans isomerisation. When two different pyrrolidine ring conformations (exo and endo pucker) are adopted, these rotational isomers along the peptidyl-proline bond have different stabilities. Protein structure has ability to regulate itself either by preferring unique conformations and by improving hydrophobic interactions. Pseudoprolines (ΨPro) are mimetics of proline and function as molecular hinges. These ΨPro can be used for tailoring cis / trans isomerization around the Xaa- ΨPro amide bond (Xaa can be any amino acid) and hydrophobicity modulation.

Synthesis of Three-Dimensionally Fascinating Diterpenoid Alkaloids and Related Diterpenes.

Three-dimensional cage-like natural products represent astounding and long-term challenges in the research endeavors of total synthesis. A central issue that synthetic chemists need to address lies in how to efficiently construct the polycyclic frameworks as well as to install the requisite substituent groups. The diterpenoid alkaloids that biogenetically originate from amination of diterpenes and diversify through late-stage skeletal reorganization belong to such a natural product category. As the characteristic components of the Aconitum and Delphinium species, these molecules display a rich array of biological activities, some of which are used as clinical drugs. More strikingly, their intricate and beautiful architectures have rendered the diterpenoid alkaloids elusive targets in the synthetic community. The successful preparation of these intriguing compounds relies on the development of innovative synthetic strategies.Our laboratory has explored the total synthesis of a variety of diterpenoid alkaloids and their biogenetically related diterpenes over the past decade. In doing so, we have accessed 6 different types of skeletons (atisine-, denudatine-, arcutane-, arcutine-, napelline-, and hetidine-type) and achieved the total synthesis of 6 natural products (isoazitine, dihydroajaconine, gymnandine, atropurpuran, arcutinine, and liangshanone). Strategically, an oxidative dearomatization/Diels-Alder (OD/DA) cycloaddition sequence was widely employed in our synthesis to form the ubiquitous [2.2.2]-bicyclic ring unit and its related ring-distorted derivatives in these complex target molecules. This protocol, in combination with additional bond-forming key steps, allowed us to prepare the corresponding polycyclic alkaloids and a biogenetically associated diterpene. For example, bioinspired C-H activation, aza-pinacol, and aza-Prins cyclizations were used toward a unified approach to the atisine-, denudatine-, and hetidine-type alkaloids via ajaconine intermediates in our first work. To pursue the synthesis of atropurpuran and related arcutine alkaloids, we harnessed a ketyl-olefin radical cyclization to assemble the carbocycle and an aza-Wacker cyclization to construct the unusual pyrrolidine ring. Furthermore, a one-pot alkene cleavage/Mannich cyclization tactic, sequential Robinson annulation, and intramolecular aldol addition were developed, which facilitated the formation of the napelline alkaloid scaffold and the first total synthesis of liangshanone. Finally, the utility of the Mannich cyclization and enyne cycloisomerization reactions allowed for access to the highly functionalized A/E and C/D ring fragments of aconitine (regarded as the "Holy Grail" of diterpenoid alkaloids). This Account provides insight into our synthetic designs and approaches used toward the synthesis of diterpenoid alkaloids and relevant diterpenes. These endeavors lay a foundation for uncovering the biological profiles of associated molecules and also serve as a reference for preparing other three-dimensionally fascinating natural products.

Structural analysis of prolines and hydroxyprolines binding to the l-glutamate-γ-semialdehyde dehydrogenase active site of bifunctional proline utilization A

Proline utilization A (PutA) proteins are bifunctional proline catabolic enzymes that catalyze the 4-electron oxidation of l-proline to l-glutamate using spatially-separated proline dehydrogenase and l-glutamate-γ-semialdehyde dehydrogenase (GSALDH, a.k.a. ALDH4A1) active sites. The observation that l-proline inhibits both the GSALDH activity of PutA and monofunctional GSALDHs motivated us to study the inhibition of PutA by proline stereoisomers and analogs. Here we report five high-resolution crystal structures of PutA with the following ligands bound in the GSALDH active site: d-proline, trans-4-hydroxy-d-proline, cis-4-hydroxy-d-proline, l-proline, and trans-4-hydroxy-l-proline. Three of the structures are of ternary complexes of the enzyme with an inhibitor and either NAD+ or NADH. To our knowledge, the NADH complex is the first for any GSALDH. The structures reveal a conserved mode of recognition of the inhibitor carboxylate, which results in the pyrrolidine rings of the d- and l-isomers having different orientations and different hydrogen bonding environments. Activity assays show that the compounds are weak inhibitors with millimolar inhibition constants. Curiously, although the inhibitors occupy the aldehyde binding site, kinetic measurements show the inhibition is uncompetitive. Uncompetitive inhibition may involve proline binding to a remote site or to the enzyme-NADH complex. Together, the structural and kinetic data expand our understanding of how proline-like molecules interact with GSALDH, reveal insight into the relationship between stereochemistry and inhibitor affinity, and demonstrate the pitfalls of inferring the mechanism of inhibition from crystal structures alone.

Induced expression of rolC for study of its effect on the expression of genes associated with nicotine synthesis in tobacco

Background. Agrobacterium rhizogenes rol genes cause not only hairy root syndrome in plants, but also affect their secondary metabolism. There are cases of increasing of nicotine content in transgenic tobacco roots expressing rolC alone or in combination with other rol genes. In this work, we evaluated the change in the expression of nicotine synthesis genes and their regulators in response to the induction of expression of rolC.
 Materials and methods. Plant material was represented by three Nicotiana tabacum genotypes: cv. Samsun and two transgenic lines, derived from this cultivar and containing rolC under dexamethasone inducible promoter: A. rhizogenes rolC (Pdex-A4rolC) and N. tabacum rolC (Pdex-trolC) correspondingly. Fluidigm Biomark RT-PCR was used for evaluation of expression of QPT1, QPT2, A622, ODC, ADC, PMT1, PMT2, PMT3, PMT4, MPO1, MPO2, BBL, MATE1, MATE2, ARF6, ERF168, ERF189, A4rolC, NtrolC, and reference gene gapdh. HPLC-MS / MS analysis was used to determine content of nicotine and its derivatives in plant tissues.
 Results. Expression of PMT genes for the synthesis of the pyrrolidine ring, as well as the genes, controlling enzyme for final stages of nicotine synthesis, was higher in transgenic lines without induction of rolC expression. Regulatory genes were activated by dexamethasone in both transgenic and control lines, indicating the inapplicability of rolC dexamethasone induction for their study. The level of expression of PMT and MPO genes increased over time in transgenic dexamethasone-induced lines. Nicotine content decreased in transgenic dexamethasone-induced plants.
 Conclusions. The rolC gene does not play a primary role in the regulation of nicotine synthesis genes. The mechanism of regulation of different nicotine biosynthesis genes and TFs varies.

Five‐Membered Nitrogen Heterocycles Synthesis through 1,3‐Dipolar Cycloaddition of Non‐Stabilized Azomethine Ylides with 2‐Pyridone Heteroaromatic Systems as Dipolarophiles

AbstractWe report an efficient 1,3‐dipolar cycloaddition involving non‐stabilized electron‐rich azomethine ylides and diversely substituted 2‐pyridones bearing two potential C=C dipolarophilic sites. The 1,3‐dipoles were prepared in situ under TFA catalysis and cycloadditions were studied according to the nature of the pyridones and position of the various substituents. These reactions occur under mild conditions, and lead to the expected cycloadducts in good yields and full control of the regioselectivity. Furthermore, mono‐ or biscycloadditions were performed, leading to the formation of polycyclic scaffolds bearing biologically relevant pyrrolidine rings, prevalent in natural products. The diastereoselectivity of the second cycloaddition was fully controlled by the first addition, leading to heterocycles with a trans relative stereochemistry of the two generated rings in the final tricyclo‐adduct.

Catalytic asymmetric total syntheses of (R)-bgugaine and (R)-irnidine

An enantioselective total synthesis of ( R )-bgugaine and the first enantioselective total synthesis of ( R )-irnidine are reported. The key steps are the asymmetric ‘clip-cycle’ formation of the pyrrolidine ring in 94:6 e.r., which is common to both natural products, followed by Liebeskind–Srogl coupling and Wolf-Kishner reduction. The route yields ( R )-bgugaine and ( R )-irnidine in 6 steps and in overall yields of 33% and 18% respectively.

SYNTHESIS OF α-SPIROCYCLIC PYRROLIDINES

Different approaches and recent advances in methodologies for the synthesis of α-spirocyclic pyrrolidines are presented. The microreview covers the latest selected examples (2009–2019) on the synthesis of such compounds based on pyrrolidine ring construction. The advantages and features of the methods are discussed.

Fullerene derivatives as dual inhibitors of HIV-1 reverse transcriptase and protease

In the present study, we newly synthesized three types of novel fullerene derivatives: pyridinium-type derivatives trans-3a and 4a-5b, piperidinium-type derivative 9, and proline-type derivatives 10a-12. Among the assessed compounds, 5a, 10e, 10f, 10i, 11a-d, and 12 were found to inhibit both HIV reverse transcriptase and HIV protease (HIV-PR), with IC50 values in the low micromolar range being observed. Regarding HIV-PR inhibition activity, proline-type derivatives 11a-11d and 12, bearing an alkyl chain between the hydroxylmethylcarbonyl (HMC) moiety and pyrrolidine ring, were more potent than other derivatives. This result might indicate that connecting HMC moieties with proline-type fullerene derivatives through properly sized alkyl chain leads to improved HIV-PR inhibitory activity.