Guanidine Structure Research Articles

Development of an Intracellular Nitric Oxide-Donating Cell-Penetrating Polypeptide as an Immunogenic Cell Death Inducer.

Recently, nitric oxide (NO) has been shown to induce immunogenic cell death (ICD) in tumor cells through endoplasmic reticulum (ER) stress and mitochondrial outer membrane permeabilization (MOMP). However, NO is unstable, making direct delivery difficult. In this study, we developed a cell-penetrating polypeptide-based NO donor, poly(l-guanidine) (PLG). Given that the guanidine structure can be catalyzed by reactive oxygen species (ROS) to produce NO, helical PLG plays three roles: spontaneous cell penetration, intracellular ROS generation to produce NO, and induction of ICD. The results revealed that helical PLG generates NO inside the cell by self-inducible guanidine oxidation and that NO effectively elicits ICD by ER stress- and MOMP-dependent intertwined mechanisms.

Postpolymerization Modification by Nucleophilic Addition to Styrenic Carbodiimides.

Carbodiimides are electrophilic functional groups that react with select nucleophiles under mild conditions. However, their potential as platforms for postpolymerization modification has been relatively underexplored. We describe the synthesis and radical polymerization of a styrenic carbodiimide which undergoes rapid nucleophilic addition with primary and secondary alkyl amines under ambient conditions, even in the presence of other protic nucleophiles. The monomer is amenable to both free and controlled radical (co)polymerization, and we further demonstrate the utility of this approach by preparing covalent adaptable networks through guanylation of the styrenic carbodiimide with difunctional amines. These materials exhibit a variation in relaxation times according to both the guanidine structure and concentration, providing a facile means for tuning dynamic behavior.

Anion-Controlled Synthesis of Novel Guanidine-Substituted Oxanorbornanes.

The cycloaddition of simple alkyl-substituted guanidine derivatives is an interesting approach toward polycyclic superbases and guanidine-based organocatalysts. Due to the high nucleophilicity of guanidines, an aza-Michael reaction with dienophiles is more common and presents a huge obstacle in achieving the desired synthetic goal. Our preliminary investigations indicated that the proton could act as a suitable protecting group to regulate the directionality of the reaction. To investigate the role of the protonation state and type of anion, the reactivity of furfuryl guanidines with dimethyl acetylenedicarboxylate was explored. Furfuryl guanidines showed a strong reaction dependence on the nucleophilicity of the counterion and the structure of guanidine. While the reaction of DMAD with the guanidinium halides provided products of an aza-Michael addition, Diels-Alder cycloaddition occurred if non-nucleophilic hexafluorophosphate salts were used. Depending on the structure and the reaction conditions, oxanorbornadiene products underwent subsequent intramolecular cyclization. A tendency toward intramolecular cyclization was interpreted in terms of the pKa of different positions of the guanidine functionality in oxanorbornadienes. New polycyclic guanidines had a slightly decreased pKa in acetonitrile and well-defined geometry suitable for the buildup of selective sensors.

Utilizing the synergistic effect between imidazole aromaticity and guanidine structure for the computational design of novel uncharged organic superbases

Proton affinities (PA) and gas phase basicities (GB) of novel structure of non-ionic organic superbases on the basis of guanidine embedded imidazole framework, were computed at B3LYP/6-311+G(d,p) level of theory. The used logic for designing these structures is synergistic effect of guanidine-imidazole twin in order to aromatization and subsequent stabilization of imidazole ring upon protonation which is strengthen with push-pull effect of variety electron-donating groups on the five-membered ring. This strategy caused to the design of organobases with considerable basicity in the range of 985.39–1177.68 kJ mol−1. Majority of the designed structures show the PA values more than 1028 kJ mo1−1, as the threshold of superbasicity. The HOMA/HOMED, and NICS(1)zz analyses were used for each structure and its conjugated acid in order to better understand and discuss the basicity values.

Synthesis of poly(hydroxyurethane) from 5‐membered cyclic carbonate under mild conditions in the presence of bicyclic guanidine and their reaction process

AbstractA series of amines are applied as catalysts in the aminolysis reactions of five‐membered cyclic carbonate (5CC). Kinetic results display that TBD, which has a guanidine structure, exhibits the best catalytic efficacy and the reaction rate constant is about 100 times higher than the blank system without catalyst. The reaction medium, NMP is found to be as both solvent and promoter in the aminolysis of 5CC. Finally, with TBD and NMP as catalyst and solvent, respectively, the polymerization of bis‐functional 5CC (B5CC) and 1, 6‐diaminohexane can proceed almost 100% at room temperature in less than 4 h to obtain poly(hydroxyurethane)s (PHUs) with moderate molecular weight.

Guanidinylation of Chitooligosaccharides Involving Internal Cyclization of the Guanidino Group on the Reducing End and Effect of Guanidinylation on Protein Binding Ability.

In order to synthesize a promising material for developing a novel peptide/protein delivery system, guanidinylation of chitooligosaccharides with 1-amidinopyrazole hydrochloride was investigated herein. The production of guanidinylated chitooligosaccharides was demonstrated by infrared spectroscopy (IR), nuclear magnetic resonance (NMR), and elemental analyses. Interestingly, we found that the reducing end in the guanidinylated chitooligosaccharides was converted to a cyclic guanidine structure (2-[(aminoiminomethyl)amino]-2-deoxy-d-glucose structure). This reaction was carefully proven by the guanidinylation of d-glucosamine. Although this is not the first report on the synthesis of the 2-[(aminoiminomethyl)amino]-2-deoxy-d-glucose, it has provided a rational synthetic route using the high reactivity of the reducing end. Furthermore, we found that the interaction between chitooligosaccharides and bovine serum albumin is weak when in a neutral pH environment; however, it is significantly improved by guanidinylation. The guanidinylated chitooligosaccharides are useful not only for the development of a novel drug delivery system but also as a chitinase/chitosanase inhibitor and an antibacterial agent.

Structure-Activity Relationship of Hetarylpropylguanidines Aiming at the Development of Selective Histamine Receptor Ligands†.

New classes of alkylated hetarylpropylguanidines with different functionality and variation in spacer length were synthesized to determine their behavior at the four histamine receptor (H1R, H2R, H3R, H4R) subtypes. Alkylated guanidines with different terminal functional groups and varied basicity, like amine, guanidine and urea were developed, based on the lead structure SK&F 91486 (2). Furthermore, heteroatomic exchange at the guanidine structure of 2 led to simple analogues of the lead compound. Radioassays at all histamine receptor subtypes were accomplished, as well as organ bath studies at the guinea pig (gp) ileum (gpH1R) and right atrium (gpH2R). Ligands with terminal functionalization led to, partially, highly affine and potent structures (two digit nanomolar), which showed up a bad selectivity profile within the histamine receptor family. While the benzoylurea derivative 144 demonstrated a preference towards the human (h) H3R, S‐methylisothiourea analogue 143 obtained high affinity at the hH4R (pKi=8.14) with moderate selectivity. The molecular basis of the latter finding was supported by computational studies.

Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis.

Rising resistance to current clinical antibacterial agents is an imminent threat to global public health and highlights the demand for new lead compounds for drug discovery. One such potential lead compound, the peptide antibiotic teixobactin, was recently isolated from an uncultured bacterial source, and demonstrates remarkably high potency against a wide range of resistant pathogens without apparent development of resistance. A rare amino acid residue component of teixobactin, enduracididine, is only known to occur in a small number of natural products that also possess promising antibiotic activity. This review highlights the presence of enduracididine in natural products, its biosynthesis together with a review of analogues of enduracididine. Reported synthetic approaches to the cyclic guanidine structure of enduracididine are discussed, illustrating the challenges encountered to date in the development of efficient synthetic routes to facilitate drug discovery efforts inspired by the discovery of teixobactin.

Electronic structure of guanidine and its derivatives from X-ray photoelectron spectroscopy and density functional theory studies

Electronic structure of guanidine, diphenylguanidine, their protonated forms, and guanidinium chloride have been studied by X-ray photoelectron spectroscopy and quantum-chemical modeling. From the derived geometry parameters and electronic structure, the effect of protonation on localization of the electron density has been revealed. The lines in the valence region of the X-ray photoelectron spectra have been assigned.

Synthesis of a Thermostable Polymer-supported Strongly Basic Catalyst and its Catalytic Activity

A novel strongly basic polymer-supported catalyst with guanidine groups has been synthesized and its thermal stability has been investigated. To obtain a thermally stable, cross-linked structure, guanidine groups bound to a polystyrene matrix were allowed to react in a nucleophilic manner with p-xylylene dichloride. Compared with the conventional strongly basic anion-exchange resin 201, it possesses higher thermal stability when placed in deionized water at 95°C for 60 h. This was confirmed by thermogravimetric analysis. The excellent thermal stability can be attributed to the unique structure of guanidine and the cross-linking connection mode between this base and the polymeric matrix. The obtained resin was found to efficiently catalyze Knoevenagel condensation reactions with remarkably high yields. Furthermore, the catalytic efficiency of the resin was found to remain unaffected for seven cycles, whereas that of 201 resin was reduced by 25 % owing to degradation of the strongly basic groups.

Divalent N(I) Character in 2-(Thiazol-2-yl)guanidine: An Electronic Structure Analysis

Several medicinally important compounds carry a 2-(thiazol-2-yl)guanidine unit. These species are generally (erroneously) represented as 1-(thiazol-2-yl)guanidine species. Quantum chemical studies were performed to identify the appropriate tautomeric state of this class of compounds. B3LYP/6-31+G(d) calculations indicate the preferred tautomeric state of these species is associated with the 2-(thiazol-2-yl)guanidine structure rather than the 1-(thiazol-2-yl)guanidine structure. G2MP2 calculations on the model system were carried out to study the electronic structure, electron delocalization, and protonation energy; MESP, ELF, HOMA, AIM, and NBO analyses were also carried out. The results indicate that this class of compounds may be treated as species with hidden ::N(←L)R character. Upon protonation of the thiazole ring nitrogen, these systems show the electronic structure as in ::N(←L)2(⊕) systems with divalent N(I) oxidation state.

Hydrogen-Bonding Networks from First-Principles: Exploring the Guanidine Crystal

Hydrogen bonding is among the most important interactions in molecular crystals, and examples are abundant. As a consequence of such interactions, many molecules crystallize in complex but intriguing structures, in contrast to the relatively simple packing principles of metallic or ionic solids. In this work, we present a computational approach based on plane-wave density-functional theory (DFT) and supercell techniques, aiming to understand and quantify hydrogen-bonded networks in the solid state and in two-, one-, and zero-dimensional fragments derived from the molecular crystal. With such methodology at hand, we investigate guanidine, a fitting example of a molecular crystal and an important compound for inorganic and organic chemistry alike. On the basis of our computations, we discuss the initially proposed layered structure of guanidine and identify both stabilizing and destabilizing cooperative interactions in the three crystalline dimensions.

Effect of structure of the amino acids and amines on the rate and mechanism of their condensations with pyridoxal

Kinetics and mechanism of condensation of amino acids and amines of different structure and their derivatives with pyridoxal were studied. It was established that the amino acid with secondary amino group, proline, adds to pyridoxal with the formation of amino alcohol. α-Amino acids in the course of condensation with pyridoxal form amino alcohols which transform to Schiff bases. The latter compounds by elimination of the α-hydrogen atom or CO2 from the amino acid fragment and the subsequent hydrolysis of the quinoid structure form the final products. β- And ɛ-amino acids react with pyridoxal to form Schiff bases which are stable to chemical transformations. The possibility was shown of their conversion to the quinoid structure. It was established that the guanidine structure of the molecule of L-arginine unlike its α-NH2 group did not take part in the condensation with pyridoxal. The quantitative evaluation of the condensation rates of triptamine, Ltriptofane, and its methyl ester in the stage of dehydration of their amino alcohols was carried out.

Theoretical studies on the activation mechanism of the histamine H2-receptor: The guanidine substitution and its role in the partial agonism of N(alpha)-guanylhistamine

Histamine [2-(4-imidazolyl)ethylamine, HA] is a neurotransmitter that was shown to act on two different receptors, the H1- and H2-receptors. Structure-activity considerations made it possible to identify molecular determinants for the action of drugs on the H2-receptors. A key probe of the resulting hypothesis relating molecular structure to activity on these receptors is its ability to explain the action of partial agonists which are pharmacologic intermediates between agonists and antagonists. We therefore studied the molecular structure and properties of N (alpha)-guanylhistamine [2-(4-imidazolyl)ethylguanidine, NAGHA], which differs from histamine by a substitution of the side chain amine by a guanidine group. To understand how the substitution with the guanidine determines this change in properties, we also studied separately the molecular structure of guanidine and guanidinium in various tautomeric forms, with geometry optimization and several different basis sets. The results suggest the preferred site of protonation and interaction of NAGHA with the negative site of the H2-receptor. For N(3)-H and N(1)-H tautomers of the neutral and cationic species of NAGHA, we did complete geometry optimization at the all electron Hartree-Fock level with the STO-3G basis set. The results support the working hypothesis that, like HA, NAGHA monocation approaches the H2-receptor as the N(3)-H tautomer. Neutralization at the anionic site also shifts the preference in tautomeric equilibrium toward the N(1)-H form, thereby triggering the charge relay sequence that was proposed as an activation mechanism of the H2-receptor. The dependence of these mechanisms of interaction with the receptor on the conformation of the side chain as well as on the position at which the negative receptor site interacts with the guanyl group suggests explanations both for the lower affinity and for the partial agonist properties of NAGHA at the H2-receptor.

Solid‐State Structure of Free Base Guanidine Achieved at Last

"Crystal structure of the free base guanidine determined 148 years after the first synthesis": A prototype structure unveiled--despite its provocative simplicity, the crystal structure of guanidine has not been previously described. 148 years after the first synthesis of guanidine, we now find two Y-shaped symmetry-independent molecules in the unit cell that are interconnected by a hydrogen-bonding network, which results in a fascinating layered structure (see picture).

Total Synthesis of (−)‐ and (+)‐Decarbamoyloxysaxitoxin and (+)‐Saxitoxin

Playing the sax: The enantioselective total syntheses of (-)- and (+)-decarbamoyloxysaxitoxin (doSTX) and (+)-saxitoxin (STX) are reported. A new methodology was developed for the synthesis of STXs, featuring discriminative reduction of the nitro group and N-O bond in nitroisoxazolidine. Enantioselective total syntheses of (-)- and (+)-decarbamoyloxysaxitoxin (doSTX) and (+)-saxitoxin (STX) were achieved. The characteristic spiro-fused cyclic guanidine structure of STX was constructed by oxidation at the C4 position with IBX via an alpha-iminium carbonyl intermediate and acid-promoted cyclization of guanidine at the C5 position. A second-generation methodology was developed for the synthesis of STX, featuring discriminative reduction of the nitro group and N-O bond in nitroisoxazolidine. This approach provides efficient access to the key diamine intermediate for STXs.

Flotation of aluminosilicate minerals using alkylguanidine collectors

The flotation mechanism of aluminosilicate minerals using alkylguanidine collectors was studied through flotation experiments, Zeta potential measurements and FT-IR spectrum analysis. It is shown that kaolinite, illite and pyrophyllite all exhibit good floatability with alkylguanidines as collectors at pH 4–12. The flotation recoveries rise with the increase of the carbon chain length. Isoelectric point(IEP) is determined to be 3.5, 3.0 and 2.3 for kaolinite, illite and pyrophyllite, respectively. However, it is anomalous that the presence of cationic collectors has less influence on the negatively charged mineral surfaces. It is explained by the special structure of guanidine which is one of the strongest bases, having two —NH 2 groups. One of them maybe interacts with minerals by electrostatic forces, and the other maybe forms hydrogen bonding with OH − ions on the aluminosilicate surfaces or in the aqueous solution, increasing the density of negative charge on the aluminosilicate surface and leading unpronounced positive charge to increase on the aluminosilicate. By combining the flotation tests, Zeta potential and FTIR measurements above, the interaction mechanism can be concluded. The simultaneous presence of cationic and neutral amine groups makes it possible for SAG cation to bind on three aluminosilicate minerals by both electrostatic attraction and hydrogen bonding. While in acidic medium, the interaction of the alkylguanidines on the aluminosilicate surfaces is mainly by means of electrostatic force and hydrogen bond; in the alkaline medium, it is by the way of electrostatic effect and hydrogen bond.

Synthetic study of muraymycins using Ugi-four component reaction

The synthetic study of muraymycins (MRYs), which have potent antibacterial activity, is described. The key elements of our approach include the synthesis of L-epicapreomycidine via a C-H amination reaction and a conversient assemblage to construct of the framework of muraymycins using Ugi-four component reaction. First, isonitrile 4 was prepared from uridine in 14 steps. The precursor of carboxylic acid component 15 was synthesised via the C-H amination reaction, formation of cyclic guanidine structure. Muraymycin D2 analogs were synthesized by a model Ugi-four component reaction.

Recent Developments in Guanylating Agents

AbstractFor Abstract see ChemInform Abstract in Full Text.

Recent developments in guanylating agents

Guanidines are important molecules with a wide range of interesting properties. In this overview we summarize recent advances in the development of guanylating reagents which we define as compounds forming a guanidine structure by a chemical transformation. We cover important classes of guanylating agents developed in the last two decades and representative examples are reported.