Guanidine Research Articles

DOCKING STUDIES ON IMIDAZOLIDINE ANALOGUES FOR MANAGEMENT OF DIABETES

Glycogen synthase kinase-3I² (GSK-3I²) has recently emerged, in the field of medicinal chemistry, as one of the most attractive therapeutic targets for type II diabetes. Phenylmethylene hydantoins (PMHs) forms strong interactions with the hinge region of GSK-3I²; carbonyl oxygen at position 2 form a H-bonding with backbone nitrogen of Val135 and the NH at position 3 to the carbonyl oxygen of Asp133. The hydantoin ring was sandwiched between Ala83, on top, and Leu188, on the bottom. The aromatic ring is rotated out of plane from the hydantoin plane, allowing extensive interactions with the nucleotide-binding loop. Furthermore, the substituted benzylidene ring system builds an H-bonding interaction with the guanidine moiety of Arg141. Targeting Arg141 is important to improve the activity in the process of designing new derivatives because it is considered the selectivity residue for GSK-3I².

Properties and mechanisms of different guanidine flame retardant wood pulp paper

In the present paper, two different guanidine salt flame retardants including guanidine phosphate (GP) and guanidine sulfamate (GS) were employed to flame-retard wood pulp paper (WPP), respectively. Both vertical flame test and microscale combustion calorimetric (MCC) analysis showed that GP-WPP exhibited much higher flame retardant efficiency as compared to GS-WPP. Their different mechanisms were investigated through thermogravimetric analysis (TGA), scanning electron microscope (SEM), energy dispersive spectrometer (EDS), and pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS). It was concluded that the volatilization of the acid anhydride of GS in high temperature range weakened the catalytic charring effect. In contrast, involatile phosphides decomposed by GP could sustainably increase the acidity of the system, and meanwhile react with some N-containing intermediate decomposition products from the guanidine to produce stable N-P compounds. Hence, it can more effectively promote the formation of the char layer as well as the flame retardant efficiency.

Synthesis and Characterization of 2,2'-Dinitramino-5,5'-bi(1-oxa-3,4-diazole) and Derivatives as Economic and Highly Dense Energetic Materials.

2,2'-Dinitramino-5,5'-bi(1-oxa-3,4-diazole) (2) is a new highly energetic material with superior calculated detonation performance in comparison to cyclo-1,3,5-trimethylene-2,4,6-trinitramine (RDX) and penta-erythritoltetranitrate (PETN) and can be prepared by an economical and practical two-step synthesis. The starting material 2,2'-diamino-5,5'-bi(1-oxa-3,4-diazole) (1) is synthesized by the reaction of oxalyl dihydrazide with cyanogen bromide. Nitration of 1 yields the title compound in perfect yield and purity. The combination of its high density of 1.986 g cm-3 , the positive heat of formation (+190 kJ mol-1 ), and a slightly positive oxygen balance (+6.2 %) results in ideal calculated detonation parameters (e.g. detonation velocity 9296 m s-1 ). The sensitivities toward impact and friction can be adjusted by deprotonation and formation of corresponding nitrogen-rich salts, for example, ammonium (3), hydroxylammonium (4), and guanidinium (5) salts.

Abstract 747: An improved fixative for histomorphology, recovery of nuclic acids and proteins

Abstract Neutral Buffered Formalin (NBF) has been the primary diagnostic fixative for histopathology for nearly a century. The limitations of NBF are well known, especially with reference to the analysis of RNA and proteins. Alternative fixatives have been proposed, but not been widely adopted. Recently, the US Environmental Protection Agency (EPA) classified formaldehyde as a carcinogen, further tilting the balance away from the continued use of NBF. We recently described a fixative based on 70% ethanol and phosphate buffered saline, called BE70. Using BE70 as the base fixative, we have developed a modular fixative in which different chemicals can be supplemented for “fit for purpose” applications. The addition of guanidinium salts to BE70 , termed BE70G results in a fixative in which both proteins and nucleic acids are improved in quantity and quality after extraction from the paraffin block. The guanidinium replaces non-freezable water, and prevents hydrolysis and oxidation of the biomolecules. Histomorphology is not disrupted at lower concentrations, with only alterations of hematoxylin intensity at higher concentrations. Studies are underway to evaluate the stability of RNA and protein in the tissue block as well as on cut sections. This fixative, BE70G has the potential to address a number of challenges facing the development of precision biomarkers, while preserving histomorphology, and improving the safety of pathology staff. Other formulations are currently being evaluated that may support applications for cytology and electron microscopy. The goal is a well characterized fixative, in which modifications to the chemistry are defined and can be applied to obtain the optimal pathology specimen for both histomorphologic and molecular analysis. Citation Format: Stephen M. Hewitt, Joon-Yong Chung, Candice Perry, Kris Ylaya, William M-A Smith, Robert A. Star. An improved fixative for histomorphology, recovery of nuclic acids and proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 747. doi:10.1158/1538-7445.AM2017-747

Synthesis, characterization, thermal properties and theoretical investigation on Bis(guanidinium) 4,4′- Azo-1H-1,2,4-triazol-5-one

Bis(guanidinium) 4,4′-Azo-1H-1,2,4-triazol-5-one [G2(ZTO)] was synthesized and characterized by X-ray single crystal diffraction, elemental analyzer and Fourier Transform Infrared (FT-IR) spectrometer. The result from X-ray single crystal diffraction indicates that G2(ZTO) crystallizes in the monoclinic space group P2(1)/c with parameters of a = 4.779(2) Å, b = 9.081(4) Å, c = 14.676(6) Å, α = 90.00°, β = 92.43(7)°, γ = 90.00°, V = 636.4(5) Å3, Z = 2, μ(Mo Kα) = 0.131, F(000) = 328, S = 1.071, Dc = 1.640 g·cm−3, R1 = 0.0510 and wR2 = 0.1389. Interestingly enough, its structure does not contain crystallization water, which is a unique characteristic in this material. Besides, the molecular geometry of the compound was optimized by using Density Functional Theory (DFT) method at B3LYP/6-31G (d, p) level in the ground state, revealing that the obtained geometric parameters are in accordance with the X-ray result of the structure. The experimental vibrational spectrum was compared with the calculated spectrum. Besides, molecular electrostatic potential (MEP) of G2(ZTO) was computed with the same method in gas phase, theoretically. The thermal properties of this compound were investigated by DSC, TG/DTG and micro-DSC methods. The results manifest that its thermal behavior can be divided into two main decomposition stages, the first intense decomposition peak temperature is 248.11 °C at the heating rate of 10 °C·min−1, which is higher than that of RDX (219 °C) but slightly lower than that of G(ZTO)·H2O (252.08 °C). The constant-volume combustion heat (ΔcU) of G2(ZTO), G(ZTO)·H2O and ZTO were determined and then the enthalpy of formation were calculated. The results show that G2(ZTO) possesses the highest standard molar enthalpy of formation, which may be explained by the fact that G2(ZTO) contains no water and possesses the highest nitrogen content in all guanidine salts. Moreover, the apparent activation energy (E), thermal stability and safety parameters (TSADT, TTIT, Tb) were also calculated. Besides, the calculated thermodynamic functions (ΔS≠, ΔH≠ and ΔG≠) for the main exothermic decomposition process of the title compound are 47.25 J·mol−1·K−1, 169.20 kJ·mol−1 and 144.24 kJ·mol−1, respectively.

(E)‐1,2‐Bis(3,5‐dinitro‐1H‐pyrazol‐4‐yl)diazene – Its 3D Potassium Metal–Organic Framework and Organic Salts with Super‐Heat‐Resistant Properties

(E)‐1,2‐Bis(3,5‐dinitro‐1H‐pyrazol‐4‐yl)diazene (H2NPA, 1) and its energetic salts, which are a series of new, energetic, highly heat‐resistant, dense explosives, were synthesized. The explosives contain four nitro groups and an azo‐bridged framework and were characterized by 1H and 13C NMR (in some cases 15N NMR) spectroscopy, IR spectroscopy, and elemental analysis. The crystal structures of K2NPA (a three‐dimensional metal–organic framework, 3D MOF) and the guanidinium salt 4 were determined by single‐crystal X‐ray diffraction, and their properties (density, thermal stability, and sensitivity towards impact and friction) were investigated. The detonation properties were evaluated from the measured density and calculated heat of formation by the EXPLO5 v6.01 program. All of the salts exhibit thermal stabilities with decomposition temperatures ranging from 156 to 315 °C, high densities (1.70–2.15 g cm–3), high detonation velocities (8224–9083 m s–1), and high positive heats of formation (45.7–1040.1 kJ mol–1). The obtained 3D metal–organic framework explosive K2NPA combines exceptional thermal stability (Td = 315 °C) with a high density (d = 2.15 g cm–3) and possesses ideal calculated detonation velocity (vD = 8275 m s–1) and pressure (PCJ = 31.1 GPa) values. Moreover, its suitable impact sensitivity (IS) of 1.5 J and friction sensitivity (FS) of 60 N make K2NPA an outstanding, highly heat‐resistant, green primary explosive. The guanidinium salt 4 also exhibits a high thermal stability (Td = 304 °C) that is superior to that of HMX, insensitivity to impact (IS > 40 J) and friction (FS > 360 N) comparable to those of 1,3,5‐triamino‐2,4,6‐trinitrobenzene (TATB), and a high detonation performance (vD = 8391 m s–1).

Development of PET agent for cardiac sympathetic nervous system

Many cardiac sympathetic changes occur before clinical symptoms being found in heart disease. PET/CT imaging can sensitively detect abnormal cardiac sympathetic nerve function. The recent development of several 11C and 18F labeled cardiac sympathetic imaging agents is reviewed in this paper. 11C-meta-hydroxyephedrine (11C-HED) and 6-18F-fluorodopamine (18F-FDA) have been comprehensively studied already. N-11C-CH3-dopamine (11C-MDA) and N-(3-bromo-4-(3-18F-fluoropropoxy)-benzyl)-guanidine (18F-LMI1195) are novel imaging agents with potential for clinical application. Key words: Radioactive tracers; Positron-emission tomography; Sympathetic nervous system; Heart; Trends

(Invited) Growth of Endohedral Metallofullerenes: The Transformation of Sc3n@D 3-C68 into Sc3n@C80

Carbon cages that entrap metals were first observed just days after the landmark discovery of C60. The synthesis of Sc3N@C80, which is comprised of a planar Sc3N cluster encapsulated within an icosahedral C80 cage, transformed significantly the field of endohedral metallofullerenes (EMFs). Recently, efficient routes toward arc discharge plasma synthesis of EMFs by vaporization of graphite, metal oxide, and solid nitrogen sources, such as guanidine thocyanate and guanidinium salts, have been developed. However, the origin of EMFs produced by plasma synthesis techniques and any associated formation processes that take place remains still unclear. Here, we report some recent results on the gas-phase synthesis of Sc3N@C2n and particularly on the transformation of the pentalene-containing Sc3N@D 3-C68 compound, which transform through a bottom-up mechanism into Sc3N@C80. We will discuss on potential pathways for the growth of Sc3N@D 3-C68 when it is exposed to an atmosphere of carbon plasma produced from graphite, and on the potential role that heptagonal rings may play.

The A Priori Design and Selection of Ionic Liquids as Solvents for Active Pharmaceutical Ingredients.

In this paper we derive a straightforward computational approach to predict the optimal ionic liquid (IL) solvent for a given compound, based on COSMO-RS calculations. These calculations were performed on 18 different active pharmaceutical ingredients (APIs) using a matrix of 210 hypothetical ILs. These results indicated that the 18 APIs could be classified into three distinct categories based on their relative hydrogen bond donating or accepting ability, with similar optimal IL solvent predictions within each class. Informed by these results, a family of strongly hydrogen bond donating ILs based on the N-alkylguanidinium cation were prepared and characterized. The solubility of the APIs in each of these classes was found to be qualitatively consistent with the predictions of the COSMO-RS model. The suitability of these novel guanidinium salts as crystallization solvents was demonstrated by the use of N-butylguanidinium bis(trifluoromethanesulfonyl)imide for the purification of crude fenofibrate using dimethylsulfoxide as an antisolvent, which resulted in good yields and excellent purities. Finally, a simple descriptor based model is proposed to suggest the best IL solvent for arbitrary APIs.

Derivatives of the triaminoguanidinium ion, 5. Acylation of triaminoguanidines leading to symmetrical tris(acylamino)guanidines and mesoionic 1,2,4-triazolium-3-aminides.

Depending on the reaction conditions, N,N’,N’’-tris(benzylamino)guanidinium salts can react with carboxylic acid chlorides to form either symmetrical N,N’,N’’-tris(N-acyl-N-benzylamido)guanidines 6 or mesoionic 4-amino-1,2,4-triazolium-3-hydrazinides 7. The latter were converted into 1,2,4-triazolium salts by protonation or methylation at the hydrazinide nitrogen atom. Neutral 1,2,4-triazoles 10 were obtained by catalytic hydrogenation of an N-benzyl derivative. Crystal structure analyses of a 4-benzylamino-1,2,4-triazolium-3-hydrazinide and of two derived 1,2,4-triazolium salts are presented.

Electrogenic transport by lipophilic guanidinium salts as anion carriers in bilayer membranes

Anion transport by four isomers of tetradecylguanidinium in vesicle bilayer membranes was investigated by ion-selective electrode and pH-sensitive fluorescence methods. On a macroscopic scale, these carriers mediate hydroxide-anion antiport. In the absence of an externally imposed ionic gradient, the carriers produce a pH gradient due to rapid partition-deprotonation of the carrier and diffusion of the guanidine conjugate base. The formally coupled anion transport is slow relative to this process, and the system exhibits a corresponding membrane polarisation detected with potential-sensitive fluorescent dyes. Selective anion transport in competition with the efficient hydroxide transport is detected only with relatively easily extracted anions and N,N′-disubstituted isomers. Membrane polarisation changes can be deduced from simple equivalent circuits derived from the Goldman–Hodgkin–Katz voltage equation.

Pentacyclic Guanidine Alkaloids from Far Eastern Sponge Monanchora Ulchra – Inhibitors of O-Glycosyl Hydrolases of Marine Macro- and Micro-organisms

Pentacyclic Guanidine Alkaloids from Far Eastern Sponge Monanchora Ulchra – Inhibitors of O-Glycosyl Hydrolases of Marine Macro- and Micro-organisms

Guanidinium can both Cause and Prevent the Hydrophobic Collapse of Biomacromolecules

A combination of Fourier transform infrared and phase transition measurements as well as molecular computer simulations, and thermodynamic modeling were performed to probe the mechanisms by which guanidinium (Gnd+) salts influence the stability of the collapsed versus uncollapsed state of an elastin-like polypeptide (ELP), an uncharged thermoresponsive polymer. We found that the cation’s action was highly dependent upon the counteranion with which it was paired. Specifically, Gnd+ was depleted from the ELP/water interface and was found to stabilize the collapsed state of the macromolecule when paired with well-hydrated anions such as SO42–. Stabilization in this case occurred via an excluded volume (or depletion) effect, whereby SO42– was strongly partitioned away from the ELP/water interface. Intriguingly, at low salt concentrations, Gnd+ was also found to stabilize the collapsed state of the ELP when paired with SCN–, which is a strong binder for the ELP. In this case, the anion and cation were both found to be enriched in the collapsed state of the polymer. The collapsed state was favored because the Gnd+ cross-linked the polymer chains together. Moreover, the anion helped partition Gnd+ to the polymer surface. At higher salt concentrations (>1.5 M), GndSCN switched to stabilizing the uncollapsed state because a sufficient amount of Gnd+ and SCN– partitioned to the polymer surface to prevent cross-linking from occurring. Finally, in a third case, it was found that salts which interacted in an intermediate fashion with the polymer (e.g., GndCl) favored the uncollapsed conformation at all salt concentrations. These results provide a detailed, molecular-level, mechanistic picture of how Gnd+ influences the stability of polypeptides in three distinct physical regimes by varying the anion. It also helps explain the circumstances under which guanidinium salts can act as powerful and versatile protein denaturants.

A new procedure to obtain ε-caprolactam catalyzed by a guanidinium salt

A new procedure to prepare ε-caprolactam by the Beckmann rearrangement of cyclohexanone oxime is described.

Adsorption-photometric determination of iron using silica with nitroso-R salt and nitroso-N salt functional groups

Adsorbents based on silica sequentially modified by polyhexamethylene guanidine and nitroso-R salt or nitroso-N salt are proposed for the preconcentration and adsorption-photometric determination of iron. It is shown that these adsorbents quantitatively recovered Fe(III) at pH 3.5–4.0 and Fe(II) at pH 4.5–7.0. In the adsorption of Fe(III) and Fe(II), intensely colored green complexes formed on the adsorbent surface. Based on the absence of signals in EPR spectra, it was concluded that iron in the oxidation state +2 was included into surface complexes with nitroso-R salt or nitroso-N salt. When Fe(III) interacted with nitroso-R salt or nitroso-N salt immobilized on the adsorbent surface, it was reduced to Fe(II). Diffuse reflection spectra of the surface complexes of iron(II) were broad bands with maxima at 720 and 710 nm. Procedures of the adsorption-photometric determination of iron in natural waters and snow samples were developed with the limit of detection of 0.05 μg of iron per 0.2 g of the adsorbent.

Electrochemical Oxygen Reduction Activity of Metal Embedded Nitrogen Doped Carbon Nanostructures Derived from Pyrolysis of Nitrogen-Rich Guanidinium Salt

Nitrogen and transition metal containing carbon composites are considered as promising non-platinum oxygen reduction catalysts with potential to replace Pt in fuel cell cathodes and metal-air batteries. Nitrogen-rich precursor guanidinium chloride, transition metal salts (Fe/Co) and high surface area carbon spheres are pyrolyzed to yield non-platinum composite electrocatalysts with new and interesting morphological features. Based on rotating ring-disk electrode (RRDE) experiments, both cobalt, and iron containing composite catalysts exhibited significant oxygen reduction activity in alkaline solutions with E1/2 values (∼60 mV lower) of best catalyst comparable to Pt/C. The kinetic parameter analysis, using Koutecky-Levich relation, for the best catalyst made of cobalt, nitrogen and carbon (Co-N-C) show specific exchange current densities of 0.1 mA mg−1, Tafel slopes of 75–80 mV dec−1 and %H2O2 of 10–13% of the total current in alkaline solution. XRD, BET, XPS and Raman spectral study serve as a complementary tool to evaluate the structure of the composite electrocatalysts.

Anionic and cationic Hofmeister effects are non-additive for guanidinium salts.

To understand specific ion effects on a molecular level we explore the effect of salts on the rotational mobility of a model amide using dielectric spectroscopy. Based on our previous studies on the effect of strong denaturing anions or cations, here we study the additivity of the anionic and cationic effect. Using salts consisting of denaturing spherical anions and spherical cations we find such salts to affect the amide according to what one expects based on the additive activity of the individual ions. The guanidinium (Gdm+) cation appears to be a notable exception, as our results suggest that GdmI (and accordingly GdmSCN) is less efficient in hindering the rotation of the amide than KI or GdmCl.

Synthesis of Bicyclic and Tricyclic Chiral Guanidinium Salts by an Intramolecular Alkylation Approach

Synthetic studies leading to three new types of chiral guanidinium scaffolds are described. Structures of interest include bicyclic guanidine derivatives with various substitution patterns around the guanidine core, as well as a highly rigid tricyclic scaffold. The challenging targets were accessed by application of mercury(II)‐promoted guanylation of N‐Boc‐substituted thioureas and Ishikawa's desulfurative cyclization. In addition to our synthetic logics, a scalable synthesis of the tricyclic guanidinium salt is presented.

Simple generalized reaction conditions for the conversion of primary aliphatic amines to surfactant-like guanidine salts with 1H-pyrazole carboxamidine hydrochloride

ABSTRACTImproved reaction conditions for the electrophilic reaction between a free aliphatic amine and 1H-pyrazole carboxamidine have been discovered. The surfactant-like guanidine salts, which are often hard to work with, were obtained in decent yields with short reaction times, minimal workup, and high level of purity.

Three new compounds based on 4,4′-azo-1,2,4-triazol-5-one: Synthesis, crystal structure and thermal properties

A series of guanidine salts of 4,4′-azo-1,2,4-triazol-5-one with guanidine(1), aminoguanidine(2), diaminoguanidine(3) and triaminoguanidine(4) was prepared. Compounds 2―4 were characterized by infrared(IR) spectroscopy, elemental analysis and single-crystal X-ray diffraction. Thermal decomposition processes of compounds 1―4 were investigated by differential scanning calorimetry(DSC), and all the compounds showed good thermal stability up to 190 °C. Moreover, these four guanidine salts are more unstable with the increasing number of amino groups. Thermal stability parameters(Te, 0 and Tb) and thermodynamic functions(ΔS≠, ΔH≠ and ΔG≠) for compounds 1―4 were calculated. The constant-volume combustion heats(ΔcU) for compounds 2―4 were determined and tended to increase with the increase of the number of amino groups. The calculated standard molar enthalpy of formation(ΔfHm0) of compounds 2―4 are–541.04,–178.67 and–83.08 kJ/mol, respectively. The impact sensitivities results indicate these four energetic salts are less sensitive than 1,3,5-trinitrotriazacyccohexane(RDX) and 1,3,5,7-tetranitrotetraqza-cyclo-octane(HMX).