Pyrrole Moiety Research Articles

1-/2-/3-Fluoroalkyl-substituted indoles, promising medicinally and biologically beneficial compounds: Synthetic routes, significance and potential applications

Abstract Synthesis, significance and potential applications of such medicinally and biologically beneficial compounds as fluoroalkylated at the pyrrole moiety indoles (1-/2-/3-fluoroalkyl-substituted indoles) are described. Having various bioactive properties, R F -indoles are promising medicinally and biologically beneficial compounds. At present, known synthetic routes for the preparation of R F -indoles affect a fairly wide variety of advanced methods. These important substances can be synthesized either via direct fluoroalkylation or via procedures involving transformations of fluoroalkylated building-blocks. In direct fluoroalkylation (trifluoromethylation), indole and its derivatives were used in the reactions with such fluoroalkylating agents as fluoroalkyl halides, CF 3 CO 2 Na (in the presence of CuI), Ruppert–Prakash reagent (a Pd-catalyzed trifluoromethylation), CuI/FO 2 SCF 2 CO 2 Me. 2-CF 3 -4-pyrones can be used as trifluoromethylated building blocks for regioselective syntheses of CF 3 -indoles. Cyclizations of some R F -bearing ortho -disubstituted benzene derivatives allow preparation of various R F -indoles. Reactivity of the trifluoromethyl group and indole moiety of CF 3 -indoles is considered.

2-(Naphthalen-1-yl)thiophene as a New Motif for Porphyrinoids: Meso-Fused Carbaporphyrin.

The first synthesis of meso-fused carbaporphyrin via a premodification method was accomplished by substituting two pyrrole moieties and one meso-carbon with 2-(naphthalen-1-yl)thiophene. The obtained global π-conjugation pathway of the macrocycle noticeably disturbs the 10π local aromaticity of naphthalene, and its aromatic nature was supported by NMR spectroscopy together with nucleus-independent chemical shift, anisotropy of the induced current density, and harmonic oscillator stabilization energy calculations. In addition, the meso-fused carbaporphyrin also allowed the formation of a square planar Pd(II) complex.

Out of the Blue! Azuliporphyrins and Related Carbaporphyrinoid Systems.

First reported in 1997, azuliporphyrins have proven to be a truly remarkable family of porphyrin analogues. In this system, although the porphyrin framework is retained, one of the pyrrolic moieties has been replaced by an azulene unit. Azulene favors electrophilic substitution at the 1,3-positions, which are structurally analogous to the α-positions in pyrrole, and this property facilitates the construction of azulene-containing porphyrinoid systems. Azuliporphyrins were first prepared from tripyrranes and 1,3-azulenedicarbaldehyde using a "3 + 1" variant on the MacDonald reaction. Subsequently, azulenes were shown to react with acetoxymethylpyrroles under acidic conditions to generate azulitripyrranes that could be utilized in a back-to-front "3 + 1" methodology to form azuliporphyrins and related heteroporphyrinoids. In addition, the favorability of azulenes toward 1,3-substitution was applied to one-pot syntheses of tetraarylazuliporphyrins and calix[4]azulenes. Azuliporphyrins have significant diatropic character that is greatly enhanced upon protonation. They have been shown to form organometallic complexes with Ni(II), Pd(II), Pt(II), Ir(III), Rh(III), and Ru(II) and undergo selective oxidations at the internal carbon with copper(II) or silver(I) salts to afford 21-oxyazuliporphyrins. In addition, oxidative ring contractions readily occur under basic conditions in the presence of peroxides to give benzocarbaporphyrins, and this reactivity provides access to tetraarylbenzocarbaporphyrins and their organometallic derivatives. A diazulenylmethane dialdehyde has been shown to react with dipyrrylmethanes in the presence of HCl or HBr to give diazuliporphyrins that were isolated in a monoprotonated form, and metalation with palladium(II) acetate afforded a stable zwitterionic palladium(II) complex. Equally intriguing dicarbaporphyrinoids incorporating indene and azulene rings have been reported, and these systems exhibit significant aromatic character. Recent studies have demonstrated that calixazulenes form supramolecular complexes with quaternary ammonium salts and afford a 1:1 complex with C60. In addition, conjugated structures have been prepared from calixazulenes that are structurally related to quatyrin, the theoretically important hydrocarbon analogue of the porphyrins. Examples of expanded azuliporphyrinoids have also been described. These azulene-containing porphyrinoids exhibit unique and complex reactivity that compares favorably with better studied porphyrin analogue systems such as the N-confused porphyrins, and azuliporphyrin derivatives show promise in the development of new catalytic systems.

Dyes based on the azo‐1H‐pyrrole moiety – synthesis, spectroscopic and electrochemical properties, and adsorption on TiO2

A series of novel azo dyes based on the azo‐1H‐pyrrole moiety were synthesised. The dyes were characterised in terms of their spectroscopic, electrochemical, and physicochemical properties. In these dyes, the electron‐rich 1H‐pyrrole moiety was assembled as π‐bridges in donor–acceptor π‐conjugated dye, and aminophenylimine fragments and the carboxyl group were used as donor and anchoring acceptor groups respectively. The dyes had adequate HOMO and LUMO levels that matched the conduction band of TiO2 and the redox potential of the electrolyte. The adsorption of these azo compounds with carboxyl group(s) on TiO2 was investigated. Experimental data showed that the introduction of two carboxyl groups could greatly enhance the adsorption efficiency of the studied dyes on TiO2. The sorption kinetics was measured for selected dyes derived from 5‐aminoisophthalic acid. Results indicate that a pseudo‐second‐order equation can better describe the adsorption kinetics of these dyes on TiO2.

Macrocyclic Transformations from Norrole to Isonorrole and an N‐Confused Corrole with a Fused Hexacyclic Ring System Triggered by a Pyrrole Substituent

AbstractThree kinds of fused porphyrinoids, L2–L4, possessing different types of corrole‐based frameworks were synthesized from a pyrrole‐substituted corrole isomer (norrole L1). Oxidation of L1 afforded a unique N‐Cmeso‐fused pyrrolyl isonorrole L2, involving the fusion of an auxiliary pyrrolic NH moiety with a meso‐sp3‐hybridized carbon atom. Subsequently, L2 underwent macrocycle transformations to give singly and doubly N‐CAr‐fused N‐confused corroles, L3 and L4, respectively. L3 and L4 contain fused [5.7.6.5]‐tetra‐ and [5.6.7.7.6.5]‐hexacyclic structures, respectively, prepared through lateral annulation. These skeletal transformation reactions from norrole to its isomer isonorrole and finally to N‐confused corrole indicate that multiply fused porphyrinoids could be readily synthesized from pyrrole‐appended confused porphyrinoids.

Macrocyclic Transformations from Norrole to Isonorrole and an N-Confused Corrole with a Fused Hexacyclic Ring System Triggered by a Pyrrole Substituent.

Three kinds of fused porphyrinoids, L2-L4, possessing different types of corrole-based frameworks were synthesized from a pyrrole-substituted corrole isomer (norrole L1). Oxidation of L1 afforded a unique N-Cmeso -fused pyrrolyl isonorrole L2, involving the fusion of an auxiliary pyrrolic NH moiety with a meso-sp(3) -hybridized carbon atom. Subsequently, L2 underwent macrocycle transformations to give singly and doubly N-CAr -fused N-confused corroles, L3 and L4, respectively. L3 and L4 contain fused [5.7.6.5]-tetra- and [5.6.7.7.6.5]-hexacyclic structures, respectively, prepared through lateral annulation. These skeletal transformation reactions from norrole to its isomer isonorrole and finally to N-confused corrole indicate that multiply fused porphyrinoids could be readily synthesized from pyrrole-appended confused porphyrinoids.

Design and synthesis of a new selective fluorescent chemical sensor for Cu2+ based on a Pyrrole moiety and a Fluorescein conjugate

A new fluorescein derivative, namely, (E)-2-(((1H-pyrrol-2-yl) methylene)amino)-3′,6′-dihydroxyspiro[isoindoline-1,9′-xanthen]-3-one (FLPY), was designed, synthesized, and structurally characterized to develop a chemosensor. The interactions of FLPY with different metal ions have been studied over UV–vis absorption spectra and fluorescent spectra. The results show that FLPY exhibits high sensitivity and selectivity toward Cu2+ among many other metal cations in a DMSO/HEPES (3:1, v/v, 1mM, pH 7.2) solution. The binding association constant (Ka) of FLPY for Cu2+ based on a 1:1 stoichiometry was estimated to be 1.29×104M−1 in the solution. The detection limit of Cu2+ by FLPY was further determined to be 0.296μM.

Schiff bases containing triphenylamine and pyrrole units: synthesis and electrochromic, acidochromic properties

Five Schiff bases (SBs) containing pyrrole and different triphenylamine (TPA) moieties were synthesized and the structures were confirmed by infrared spectroscopy (IR) and the nuclear magnetic resonance (NMR) technique. SB1 exhibited intense fluorescence emission in contrast to SB2–SB5. The electrochemical behaviors of the SBs were investigated by the cyclic voltammetry (CV) technique. SB2–SB5 exhibited redox stability with one well-defined and reversible redox couple upon electrochemical oxidation. On the contrary, SB1 revealed two oxidation peaks and one reduction peak in the first CV curve, followed by four well-defined redox couples in the steady-state CV curves. Electrochromic behaviors of the SBs have been observed, accompanied with a new absorption peak appearing with obvious color change from pale yellow neutral form to red oxidation form. SB1–SB5 also displayed sensitive acidochromic behaviors, and a linear dependence of maximum absorption wavelength as a function of pH values has been observed which proved the SBs could be used as alternative pH sensors in the given range.

Modulation of the fluorescence properties of diketopyrrolopyrroles via various electron-rich substituents

Electron-donating functionalities allow modulation of the emission properties of diketopyrrolopyrroles.

Chemical Conversion of Ryanodol to Ryanodine.

Ryanodine (1) is a plant-derived natural product with powerful pharmacological and insecticidal action, and is a potent modulator of intracellular calcium release channels. Compound 1 possesses a 1H-pyrrole-2-carboxylate ester at the C3-position of heptahydroxylated terpenoid ryanodol (2). Whereas 2 was readily obtained from 1 by basic hydrolysis, 1 has never been synthesized from 2, due to the extreme difficulty in selectively introducing the bulky pyrrole moiety at the severely hindered C3-hydroxyl group of heptaol 2. Here we report chemical conversion of 2 to 1 for the first time. The derivatization was realized through the use of a new protective group strategy and the application of on-site construction of the pyrrole-2-carboxylate ester from the glycine ester and 1,3-bis(dimethylamino)allylium tetrafluoroborate.

Synthesis and Analgesic Activity of New Analogues of Tyr-MIF Including Pyrrole Moiety

Pain is one of many medical problems of modern society. Together with a number of other diseases such as heart attacks, strokes, tumors, etc. it ranks among the first in manifestation. There are a huge number of medical drugs more or less effective against pain in a practice. Globally, the searching of new molecules with analgesic activity and better selectivity or greater effect at lower doses continues. In addition, some groups trying to improve the properties of known molecules in medical practice as various heterocyclic compounds by modifying one or another of their part. Other groups work on the creation of new mimetics of natural molecules with well established physiological activity. In this global context, here we report the synthesis of two new compounds which are hybrid molecules between the specifically substituted pyrrole (Pyr) and analogues of Tyr-MIF-1 peptide. All investigations on the analgesic activity show better activity at the same dose than natural Tyr-MIF-1 peptide for the analogue Pyr-Tyr-Phe-Leu-Ala-OH. Compound Pyr-Ala-Leu-Phe-Tyr-OH has no better effect comparable to that of the parent peptide. The obtained results clearly show that it is essential that Tyr residue occupies N-terminal position of MIF-1 analogue. The lack of better activity of the analogue Pyr-Ala-Leu-Phe-Tyr-OH reveals that Pyr residue does not influence on the analgesic activity. In addition we found that C-terminal amide function generally presented in natural MIF-1 is not absolutely necessary for activity.

Exploiting Transient Protein States for the Design of Small-Molecule Stabilizers of Mutant p53

SummaryThe destabilizing p53 cancer mutation Y220C creates an extended crevice on the surface of the protein that can be targeted by small-molecule stabilizers. Here, we identify different classes of small molecules that bind to this crevice and determine their binding modes by X-ray crystallography. These structures reveal two major conformational states of the pocket and a cryptic, transiently open hydrophobic subpocket that is modulated by Cys220. In one instance, specifically targeting this transient protein state by a pyrrole moiety resulted in a 40-fold increase in binding affinity. Molecular dynamics simulations showed that both open and closed states of this subsite were populated at comparable frequencies along the trajectories. Our data extend the framework for the design of high-affinity Y220C mutant binders for use in personalized anticancer therapy and, more generally, highlight the importance of implementing protein dynamics and hydration patterns in the drug-discovery process.

Asymmetric Total Synthesis of (+)-Ryanodol and (+)-Ryanodine.

(+)-Ryanodine (1) is the ester derivative of 1H-pyrrole-2-carboxylic acid and the complex terpenoid (+)-ryanodol (2), which possesses eleven contiguous stereogenic centers on the ABCDE-ring system. Compound 1 is known to be a potent modulator of intracellular calcium release channels, whereas the activity of 2 is significantly weaker. To chemically construct 1, the multiple oxygen functional groups must be installed on the fused pentacycle in stereoselective fashions and the extremely hindered C3-hydroxy group must be acylated in a site-selective manner. First, the total synthesis of 2 was accomplished by introducing the five stereocenters from the previously prepared enantiopure ABDE-ring 7. Stereoselective construction of the C3-secondary, C2- and C6-tertiary alcohols was achieved by three nucleophilic reactions. The C9- and C10-trisubstituted carbon centers were regio- and stereoselectively introduced by hydroboration/oxidation of the six-membered C-ring, which was formed by the ring-closing metathesis reaction. Direct esterification of the C3-alcohol with pyrrole-2-carboxylic acid proved unsuccessful; therefore, we developed a new, two-step protocol for attachment of the pyrrole moiety. The C3-hydroxy group was first converted into the less sterically cumbersome glycine ester, which was then transformed into the pyrrole ring through condensation with 1,3-bis(dimethylamino)allylium tetrafluoroborate. This procedure resulted in the first total synthesis of 1.

Incorporation of a Non‐Natural Arginine Analogue into a Cyclic Peptide Leads to Formation of Positively Charged Nanofibers Capable of Gene Transfection

AbstractFunctionalization of the tetracationic cyclic peptide (Ka)4 with a single guanidiniocarbonyl pyrrole (GCP) moiety, a weakly basic but highly efficient arginine analogue, completely alters the self‐assembly properties of the peptide. In contrast to the nonfunctionalized peptide 2, which does not self‐assemble, GCP‐containing peptide 1 forms cationic nanofibers of micrometer length. These aggregates are efficient gene transfection vectors. DNA binds to their cationic surface and is efficiently delivered into cells.

Incorporation of a Non-Natural Arginine Analogue into a Cyclic Peptide Leads to Formation of Positively Charged Nanofibers Capable of Gene Transfection.

Functionalization of the tetracationic cyclic peptide (Ka)4 with a single guanidiniocarbonyl pyrrole (GCP) moiety, a weakly basic but highly efficient arginine analogue, completely alters the self-assembly properties of the peptide. In contrast to the nonfunctionalized peptide 2, which does not self-assemble, GCP-containing peptide 1 forms cationic nanofibers of micrometer length. These aggregates are efficient gene transfection vectors. DNA binds to their cationic surface and is efficiently delivered into cells.

Microwave‐activated Synthesis of Pyrroles: A Short Review

In the current scenario for continuous requirement of better drugs, medicinal chemists must visage the challenging task of preparing novel patentable compounds, combining high activity and selectivity, good drug‐likeness, and pharmacokinetic properties. There is an acute need of new molecules in both lead identification and lead optimization. Chemists thoroughly scrutinize ways to simplify synthetic protocols using green chemistry approaches, for example, microwaves. Reduction in the reaction time by the use of microwaves has emerged as a promising method for bringing out new leads in organic synthesis. Among the azaheterocyclic systems, synthesis of pyrrole moiety has been a highly attractive and an inspiring proposition. It has been found to be an inbuilt pharmacophore of various momentous pharmacologically active compounds in medicinal chemistry. This article outlines the basic principles of microwave technology and its use in the synthesis of pyrrole derivatives wherein this technology has made a tremendous impact.

A theoretical investigation on the π-conjugation effect on the structures and spectral properties of tetra pyrrole zinc complexes

The structures and properties of a family of different π-conjugation tetra pyrrole Zn complexes are reported. The tetra pyrrole moiety can be divided as porphyrin, one tripyrrin and one pyrrole, two dipyrrines, one dipyrrin and two pyrroles, and four pyrroles. The Zn complexes possess different geometries and tunable spectral bands depending on the mode of the different metal-coordination. For Zn porphyrin, the frontier molecular orbitals (FMOs) are the major contribution to the intense B-like band and weak Q-like band absorptions, and this is in agreement with the Gouterman’s four-orbital model. But because of the breakdown of the π-conjugation from complex 1 to 5, the FMOs are no longer separated from the other MOs in energy, the orbital with metal distribution is approaching to lowest unoccupied molecular orbital (LUMO), the absorption band is no longer intense at B-like bond and weak at Q-like bond as Gouterman's four-orbital model mentioned. The calculated fluorescence spectra in toluene solution show that fluorescence can be observed in the visible region of complexes 1–4 because of the bright higher electronic excited states.

Crystal structure of halogenase PltA from the pyoluteorin biosynthetic pathway.

Pyoluteorin is an antifungal agent composed of a 4,5-dichlorinated pyrrole group linked to a resorcinol moiety. The pyoluteorin biosynthetic gene cluster in Pseudomonas fluorescens Pf-5 encodes the halogenase PltA, which has been previously demonstrated to perform both chlorinations in vitro. PltA selectively accepts as a substrate a pyrrole moiety covalently tethered to a nonribosomal peptide thiolation domain PltL (pyrrolyl-S-PltL) for FAD-dependent di-chlorination, yielding 4,5-dichloropyrrolyl-S-PltL. We report a 2.75 Å-resolution crystal structure of PltA in complex with FAD and chloride. PltA is a dimeric enzyme, containing a flavin-binding fold conserved in flavin-dependent halogenases and monooxygenases, and an additional unique helical region at the C-terminus. This C-terminal region blocks a putative substrate-binding cleft, suggesting that a conformational change involving repositioning of this region is necessary to allow binding of the pyrrolyl-S-PltL substrate for its dichlorination by PltA.

Cytotoxicity of pyrrolizidine alkaloid in human hepatic parenchymal and sinusoidal endothelial cells: Firm evidence for the reactive metabolites mediated pyrrolizidine alkaloid-induced hepatotoxicity

Pyrrolizidine alkaloids (PAs) widely distribute in plants and can cause hepatic sinusoidal obstruction syndrome (HSOS), which typically presents as a primary sinusoidal endothelial cell damage. It is well-recognized that after ingestion, PAs undergo hepatic cytochromes P450 (CYPs)-mediated metabolic activation to generate dehydropyrrolizidine alkaloids (DHPAs), which are hydrolyzed to dehydroretronecine (DHR). DHPAs and DHR are reactive metabolites having same core pyrrole moiety, and can bind proteins to form pyrrole-protein adducts, which are believed as the primary cause for PA-induced HSOS. However, to date, the direct evidences supporting the toxicity of DHPAs and DHR in the liver, in particular in the sinusoidal endothelial cells, are lacking. Using human hepatic sinusoidal endothelial cells (HSEC) and HepG2 (representing hepatic parenchymal cells), cells that lack CYPs activity, this study determined the direct cytotoxicity of dehydromonocrotaline, a representative DHPA, and DHR, but no cytotoxicity of the intact PA (monocrotaline) in both cell lines, confirming that reactive metabolites mediate PA intoxication. Comparing with HepG2, HSEC had significantly lower basal glutathione (GSH) level, and was significantly more susceptible to the reactive metabolites with severer GSH depletion and pyrrole-protein adducts formation. The toxic potency of two reactive metabolites was also compared. DHPA was more reactive than DHR, leading to severer toxicity. In conclusion, our results unambiguously provided the first direct evidence for the critical role of DHPA and DHR in the reactive metabolites-mediated PA-induced hepatotoxicity, which occurs predominantly in HSEC due to severe GSH depletion and the significant formation of pyrrole-protein adducts in HSEC.

Structure and Substrate Sequestration in the Pyoluteorin Type II Peptidyl Carrier Protein PltL.

Type II nonribosomal peptide synthetases (NRPS) generate exotic amino acid derivatives that, combined with additional pathways, form many bioactive natural products. One family of type II NRPSs produce pyrrole moieties, which commonly arise from proline oxidation while tethered to a conserved, type II peptidyl carrier protein (PCP), as exemplified by PltL in the biosynthesis of pyoluteorin. We sought to understand the structural role of pyrrole PCPs in substrate and protein interactions through the study of pyrrole analogs tethered to PltL. Solution-phase NMR structural analysis revealed key interactions in residues of helix II and III with a bound pyrrole moiety. Conservation of these residues among PCPs in other pyrrole containing pathways suggests a conserved mechanism for formation, modification, and incorporation of pyrrole moieties. Further NOE analysis provided a unique pyrrole binding motif, offering accurate substrate positioning within the cleft between helices II and III. The overall structure resembles other PCPs but contains a unique conformation for helix III. This provides evidence of sequestration by the PCP of aromatic pyrrole substrates, illustrating the importance of substrate protection and regulation in type II NRPS systems.