Propionate Arms Research Articles

Efficacy of topical progesterone versus topical clobetasol propionate in patients with vulvar Lichen sclerosus – A double-blind randomized phase II pilot study

BackgroundLichen sclerosus (LS) is a chronic inflammatory skin disease that mostly affects the anogenital region of women and lowers patients’ quality of life. Current standard treatment of LS is topical steroids. ObjectiveTo evaluate the efficacy of topical progesterone 8% ointment and compare to standard therapy with topical clobetasol propionate 0.05% in premenopausal women presenting with previously untreated early onset LS. Study designRandomized, double-blind, 2-arm, single center superiority trial in premenopausal women with histologically confirmed vulvar LS who were randomized in a 1:1 ratio to receive clobetasol propionate 0.05% ointment or progesterone 8% ointment. The primary outcome was the clinical severity LS score after 12 weeks, which consists of six clinical features assessed by the physician. Secondary outcomes were the symptom severity LS score, which consists of three symptoms rated by the patient, the Short Form SF-12 physical and mental health scores, and adverse events. Response to medication was assessed by biopsy at the end of the treatment to evaluate inflammatory parameters. ResultsOverall, 105 women were screened, 102 underwent vulvar biopsy and 37 received a histologically confirmed diagnosis of LS and were randomized: 17 to progesterone and 20 to clobetasol propionate. At 12 weeks, the mean clinical LS scores improved from 4.6 (SD 2.0) to 4.5 (SD 1.7) in the progesterone arm, and from 4.6 (SD 2.8) to 2.9 (SD 2.2) in the clobetasol propionate arm (difference in favor of clobetasol 1.61; 95% CI 0.44 to 2.77, p = 0.009), and the mean symptom severity LS scores improved from 4.5 (SD 3.8) to 3.1 (SD 3.0) in the progesterone arm, and from 4.7 (SD 2.8) to 1.9 (SD 1.8) in the clobetasol propionate arm (difference in favor of clobetasol 1.32; 95% CI −0.25 to 2.89, p = 0.095). LS was in complete remission in 6 out of 10 patients (60%) with available biopsy in the progesterone arm, and in 13 out of 16 patients (81.3%) in the clobetasol propionate arm (odds ratio in favor of clobetasol 0.35; 95% CI 0.06 to 2.06, p = 0.234). No drug-related serious adverse event occurred during the trial. ConclusionsTopical progesterone 8% ointment is inferior to standard therapy with topical clobetasol propionate 0.05% in previously untreated premenopausal women with vulvar LS after 12 weeks treatment.

Synthetic, structural, spectral and DNA binding aspects of copper(II), nickel(II) and zinc(II) dimers of new carboxylate-based tripodal ligand

The synthesis, structural investigation, spectral properties and DNA binding aspects of three dimetallic complexes, [Cu2(L2)2(H2O)2]∙H2O (1), [Ni2(L2)2(H2O)2] (2) and [Zn2(L2)2(H2O)2] (3), based on carboxylate containing new asymmetric tripodal ligand, 3-(carboxymethyl-pyridin-2-ylmethyl-amino)-propionic acid (H2L2) are reported. All the complexes have been characterized by elemental analysis, solution molar electrical conductivity, FTIR, UV–Vis, mass spectrometry, including single crystal X-ray crystallography. The crystal structure of 1 reveals that the two copper(II) centers assume a six-coordinate distorted octahedral geometry with Cu---Cu separation of 3.283(2) Å. The single crystals of 2 and 3 could not be isolated; however, the DFT optimized structures of 2 and 3 disclose that two nickel(II) and zinc(II) centers are in a distorted octahedral geometry with Ni---Ni and Zn---Zn separations of 2.815 and 2.847 Å, respectively. In each of these complexes, the metal ions are bridged by the oxygen atoms of the propionate arms of two ligands in a μ2:η2 monodentate fashion, forming a M2O2 central core. DNA binding abilities of all complexes have been studied by UV–Vis and fluorescence spectroscopy, and viscosity measurements.

Triamcinolone Acetonide versus Fluticasone Propionate in the Treatment of Perennial Allergic Rhinitis: A Randomized, Parallel-Group Trial

Background: Intranasal sprays are recommended as targeted therapy for allergic rhinitis (AR). Triamcinolone acetonide is a nasal corticosteroid preparation indicated for the treatment of seasonal and perennial AR (PAR) in different countries worldwide. Objectives: In order to determine the efficacy of triamcinolone acetonide in the treatment of PAR, the non-inferiority of triamcinolone acetonide to fluticasone propionate was assessed in Russian adults. Methods: In this randomized, double-blind, parallel-group, multicenter, prospective, non-inferiority, phase III clinical trial, a total of 260 patients with persistent PAR were randomized to receive either triamcinolone acetonide or fluticasone propionate nasal sprays for 4 weeks. The efficacy in symptom control was evaluated using the reflective total nasal symptom score (rTNSS) from baseline (day 0) to day 28. Safety was assessed through the reporting of adverse events. Results: The rTNSS mean values decreased from baseline to the end of study treatment (day 28) in both groups: –8.2 ± 3.0 in the triamcinolone acetonide arm versus –8.0 ± 2.8 in the fluticasone propionate arm. The mean difference between the groups (triamcinolone acetonide – fluticasone propionate) for rTNSS change from baseline was –0.2 (95% confidence interval –0.89 to 0.54), with an upper confidence limit of 0.54, which is lower than the non-inferiority margin of 0.8. Triamcinolone acetonide was well tolerated, with no difference in adverse event occurrence compared with fluticasone propionate. Conclusions: Triamcinolone acetonide proved to be non-inferior to fluticasone propionate in adult patients with PAR; both treatments decreased rTNSS values and showed a good safety profile.

A novel dinuclear manganese(II) compound incorporating two bis(imidazolyl) based ligands with single μ2-η1:η1-carboxylato bridges. Molecular and crystal structure and magnetic properties of [Mn2Cl(BIP)(HBIMAM)(H2O)5]Cl3·4H2O (BIP = 3,3-di(2-1H-2-imidazolyl)propanoate; BIMAM = N-methyldi(1H-2-imidazolyl)methanamine)

This paper reports the synthesis, X-ray structure and magnetic characterization of [Mn2Cl(BIP) (HBIMAM)(H2O)5]Cl3·4H2O a novel dinuclear manganese(II) incorporating two related bis(imidazolyl)-based ligands, BIP (3,3-di(2-1H-2-imidazolyl)propanoate) and BIMAM (N-methyldi(1H-2-imidazolyl)methanamine). The metal atoms in the dinuclear entity are bridged by a μ2-η1:η1 carboxylate group (from the propionate arm of the BIP ligand) acting in an anti–anti coordination bridging mode, with an intramolecular Mn⋯Mn distance of 6.47Å. The coordination around the Mn(II) ions shows a distorted octahedral geometry for both MnClN2O3 and MnN2O4 chromophores. Between the imidazole rings of neighbouring dinuclear units there significant aromatic–aromatic interactions. The propagation of these interactions generates chains of π-stacked dinuclear units, roughly running along the [100] direction. Magnetic susceptibility measurements in the range 2–300K show weak antiferromagnetic exchange interactions which were analysed by means of the isotropic S1=S2=5/2 spin-coupled dimer model Hˆ=-2J(Sˆ1·Sˆ2). Finally, the observed magnetic behavior (2J=−0.38(1)cm−1) is compared with that observed in related manganese(II) compounds with single [Mn(μ2-η1:η1-carboxylato)Mn] core.

Molecular modeling for Cu(II)-aminopolycarboxylate complexes: Structures, conformational energies, and ligand binding affinities

A ligand field molecular mechanics (LFMM) force field (FF) has been developed for d(9) copper(II) complexes of aminopolycarboxylate ligands. Training data were derived from density functional theory (DFT) geometry optimizations of 14 complexes comprising potentially hexadentate N2O4, tetrasubstituted ethylenediamine (ed), and propylenediamine cores with various combinations of acetate and propionate side arms. The FF was validated against 13 experimental structures from X-ray crystallography including hexadentate N2O4 donors where the nitrogens donors are forced to be cis and bis-tridentate ONO ligands which generate complexes with trans nitrogen donors. Stochastic conformational searches for [Cu{ed(acetate)n(propionate)(4-n)}](2-), n = 0-4, were carried out and the lowest conformers for each system reoptimized with DFT. In each case, both DFT and LFMM predict the same lowest-energy conformer and the structures and energies of the higher-energy conformers are also in satisfactory agreement. The relative interaction energies for n = 0, 2, and 4 computed by molecular mechanics correlate with the experimental log β binding affinities. Adding in the predicted log β values for n = 1 and 3 suggest for this set of complexes a monotonic decrease in log β as the number of propionate arms increases.

Tris(phosphonomethyl)cyclen Derivatives: Thermodynamic Stability, Kinetics, Solution Structure, and Relaxivity of Ln3+ Complexes

AbstractThe lanthanide (Ln3+) complexes of three cyclen‐based ligands containing three methylphosphonate pendant arms were studied, the ligands being 1,4,7,10‐tetraazacyclododecane‐1,4,7‐triyltris(methylphosphonic acid) (H6do3p), 3‐[4,7,10‐tris(phosphonomethyl)‐1,4,7,10‐tetraazacyclododec‐1‐yl]propanoic acid (H7do3p1pr), and 10‐(3‐hydroxypropyl)‐1,4,7,10‐tetraazacyclododecane‐1,4,7‐triyltris(methylphosphonic acid) (H6do3p1ol). The three macrocyclic ligands form complexes of very high thermodynamic stability with all studied Ln3+ ions. Kinetic studies showed that the acid‐assisted dissociation of Ce3+ complexes of these ligands is much faster than for the complex of the related ligand H8dotp [1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetrayltetrakis(methylphosphonic acid)]. The number of water molecules coordinated to the Eu3+ and Gd3+ complexes was estimated to be < 1 for the do3p1ol ligand but ca. 1 for the other two ligands, as obtained by time‐resolved luminescence spectroscopy and by 1H and 17O relaxometric measurements. The NMR spectroscopic data indicate the existence of a considerable contribution from second‐sphere water molecules to the relaxivity of all the Gd3+ complexes studied. The 1H and 31P NMR spectra of the Eu3+, Yb3+ and Lu3+ complexes showed that the propionate arm in the [Ln(do3p1pr)]4– complexes and the propanol arm in the [Ln(do3p1ol)]3– complexes are not bound to the Ln3+ ion. The [Ln(do3p)]3– and [Ln(do3p1pr)]4– complexes have a clear preference for the TSAP (twisted square antiprismatic) isomer, while both SAP (square antiprismatic) and TSAP isomers are present in solutions of the [Ln(do3p1ol)]3– complexes.

Structural diversity of transition-metal complexes derived from N-propionic acid functionalized 1,4,7-triazacyclononane: From enchanting cluster motifs to unprecedented homometallic polymeric networks

Self-assembly between perchlorate salts of Cu(II), Zn(II) and Cd(II) with tri-substituted N-propionic acid functionalized 1,4,7-triazacyclononane (H33L11) or the mono-substituted one (HL22) results in the formation of four novel complexes [Cu5(H2O)6(L11)2](ClO4)4 (1), [Zn9(L11)4(H2O)18](ClO4)6·9H2O (2), [Cd2(H22L11)2](ClO4)2 (3) and [Cd(L22)]ClO4·CH3OH (4) with different aggregation modes. All these complexes were structurally characterized by solid state X-ray diffraction measurement. Complex 1 belongs to a homometallic 2D polymer, where each [Cu(L11)]− complex entity acts as a three-connected node joined to three Cu(II) ions through μ2 bridged propionate arms to afford a puckered honeycomb framework. In complex 2, two face-to-face arranged [Zn(L11)]− moieties clip three Zn(II) ions by virtue of pendant propionate arms generating a macrotricyclic metallacryptate. Two such metallacryptates are fused via co-sharing one lateral Zn(II) ion into an unprecedented nonazinc cluster with a double-cage architecture. Complex 3 exhibits a discrete centrosymmetric dinuclear unit [Cd2(H22L11)2]2+ consisting of two pendant propionate groups linked to a [Cd2O2] core. Complex 4 reveals Cd(II) centers are associated through the unique propionate bridge of the L22− ligand leading to an infinite 1D zig–zag polymeric chain of [Cd(L22)]+ cations. Deduced from the structural investigations, the linkage patterns of the selected macrocyclic ligands towards metal centers may be exquisitely tuned according to the type of metals and the number of the coordinating pendant arms present in the macrocyclic ligands, and then the architectural variation of these metal–organic coordination species is achieved. In addition, magnetic studies for complex 1 show a weak Cu⋯Cu antiferromagnetic coupling in the 2D honeycomb layer with a Weiss temperature of −4.31 K.

Construction of a Series of 1D and 2D Inorganic–Organic Hybrid Coordination Polymers Based on 1,1′‐Bis(propionic acid)‐2,2′‐biimidazole

The substitution reactions of cadmium or zinc nitrate and the new multifunctional ligand Pra 2 biim 2- [Pra 2 biim = 1,1'-bis(propionic acid)-2,2'-biimidazole] produce a series of coordination polymers with d 10 metal centers, namely, 1D [Cd(HPra 2 biim)(H 2 O)Cl] n ·nH 2 O (1), 1D [Cd 2 (Pra 2 biim)(H 2 O) 4 -(NO 3 ) 2 ] n (2), and 2D [Zn(HPra 2 biim)Cl]n (3) in acidic aqueous solutions. The presence of a strong inorganic acid, such as HCl, lead to the protonation of Pra 2 biim 2- as observed in polymers 1 and 3. Compounds 1 and 3 contain the doubly N,N'-biim-bridged [M 2 (μ 2 -N,N'-biim) 2 ] and compound 2 the singly bridged [M 2 (μ 2 -N,N'-biim)] as secondary building blocks that are interconnected by the propionate arms into 1D chains in 1 and 2, and into a 2D layer in 3. These d 10 metal polymers exhibit luminescent emissions that are sensitive to the coordination geometry of the metal centers.

Crystal and molecular structure of four copper(II) ethylenediaminedisuccinates, [Cu2(RR,SS-Edds)] · 6H2O, Ba2[Cu(RR,SS-Edds)](ClO4)2 · 8H2O, Ba[Cu(SS-HEdds)]ClO4 · 2H2O, and Ba3[Cu2(RR,SS-Edds)2](ClO4)2 · 6H2O

Four Cu(II) complexes with the RR,SS-Edds4− and SS-HEdds3− anions are synthesized, and their crystal structures are studied. In the compounds [Cu2(RR,SS-Edds)] · 6H2O (I) and Ba2[Cu(RR,SS-Edds)](ClO4)2 · 8H2O (II), the ligand forms hexacoordinate chelate [Cu(Edds)]2− complexes with the N atoms and O atoms of the propionate groups in the equatorial positions and the O atoms of the acetate groups in the axial vertices. In the compounds Ba[Cu(SS-HEdds)]ClO4 · 2H2O (III) and Ba3[Cu2(RR,SS-Edds)2](ClO4)2 · 6H2O (IV), one of the propionate arms, the protonated arm in III and the deprotonated arm in IV, does not enter into the coordination sphere of the Cu atom. An acetate arm moves to its position in the equatorial plane, and the free axial vertex is occupied by an O atom of the perchlorate ion. In I–IV, the lengths of the equatorial Cu-N and Cu-O bonds fall in the ranges 1.970–2.014 and 1.921–1.970 A, respectively. The axial Cu-O bonds with the acetate groups and ClO4− anions are elongated to 2.293–2.500 and 2.727–2.992 A, respectively. In structure I, the second Cu atom acts as a counterion forming bonds with the O atoms of two water molecules and three O atoms of the Edds ligands. In II–IV, the Ba2+ cations are hydrated and bound to the O atoms of the anionic complexes and (except for one of the cations in IV) ClO4− anions. The coordination number of the Ba cations is nine. The structural units in I–IV are connected into layers. In I, an extended system of hydrogen bonds links the layers into a framework. In II and III, the layers are linked only by weak hydrogen bonds, one bond per structural unit. In IV, ClO4− anions are bound to the Ba and Cu atoms of neighboring layers, thus serving as bridges between the layers.

Fine-tuning water exchange on GdIII poly(amino carboxylates) by modulation of steric crowding

In the objective of optimizing water exchange rate on stable, nine-coordinate, monohydrated Gd(III) poly(amino carboxylate) complexes, we have prepared monopropionate derivatives of DOTA4- (DO3A-Nprop4-) and DTPA5- (DTTA-Nprop5-). A novel ligand, EPTPA-BAA(3-), the bisamylamide derivative of ethylenepropylenetriamine-pentaacetate (EPTPA5-) was also synthesized. A variable temperature 17O NMR study has been performed on their Gd(III) complexes, which, for [Gd(DTTA-Nprop)(H2O)]2- and [Gd(EPTPA-BAA)(H2O)] has been combined with multiple field EPR and NMRD measurements. The water exchange rates, k(ex)(298), are 8.0 x 10(7) s(-1), 6.1 x 10(7) s(-1) and 5.7 x 10(7) s(-1) for [Gd(DTTA-Nprop)(H2O)]2-, [Gd(DO3A-Nprop)(H2O)]- and [Gd(EPTPA-BAA)(H2O)], respectively, all in the narrow optimal range to attain maximum proton relaxivities, provided the other parameters (electronic relaxation and rotation) are also optimized. The substitution of an acetate with a propionate arm in DTPA5- or DOTA4- induces increased steric compression around the water binding site and thus leads to an accelerated water exchange on the Gd(III) complex. The k(ex) values on the propionate complexes are, however, lower than those obtained for [Gd(EPTPA)(H2O)]2- and [Gd(TRITA)(H2O)]- which contain one additional CH(2) unit in the amine backbone as compared to the parent [Gd(DTPA)(H2O)]2- and [Gd(DOTA)(H2O)]-. In addition to their optimal water exchange rate, [Gd(DTTA-Nprop)(H2O)]2- has, and [Gd(DO3A-Nprop)(H2O)]- is expected to have sufficient thermodynamic stability. These properties together make them prime candidates for the development of high relaxivity, macromolecular MRI contrast agents.

Ferromagnetic interactions mediated by syn–anti carboxylate bridging in tetranuclear copper(II) compounds

The tridentate ligand N-(2-hydroxypropyl)aminopropionic acid (H2hap) and the tripod ligand nitrilodi(propionic acid) acetic acid (H3ndpa) have been synthesised and found to interact with Cu(II) to produce tetranuclear compounds. In the cyclic complex [Cu(Hhap)(NO3)]4 (1), the four Cu(II) centres form a slightly buckled square linked via syn–anti carboxylate bridges. In [Cu4(ndpa)2(H2O)8(NO3)2]·2H2O (2), and [Cu4(ndpa)2(H2O)10]SO4·6H2O (3), two Cu(II) centres are each chelated by a ndpa3− ligand which in turn are linked by coordination of the outer carboxylate oxygens on the longer propionate arms of the ligands to two further {Cu(H2O)3}2+ units resulting in a rhomboid array of Cu(II) centres. In the closely related complexes [Cu4(ndpa)2(H2O)6Cl2]·4H2O (4), and [Cu4(ndpa)2(H2O)6Br2]·4H2O (5), replacement of one aqua ligand by an outer carboxylate oxygen from the shorter acetate arm of an adjacent complex results in the formation of infinite sheets of linked tetranuclear units. Magnetic studies performed between 1.8 and 300 K on these complexes indicate that ferromagnetic or antiferromagnetic coupling between Cu(II) ions can be observed depending on the geometry of the carboxylate bridging mode. Compound 1 shows a paramagnetic behaviour with a ferromagnetic interaction (J/kB=+3.9 K, S=2 ground state) between adjacent Cu(II) ions through equatorial–equatorial syn–anti carboxylate bridges. In compound 2, within the rhombus motif ferromagnetic (J1/kB=+12.1 K) and antiferromagnetic (J2/kB=−0.4 K) interactions through syn–anti bridges but in equatorial–equatorial and equatorial–axial modes, respectively, are present. Finally, in the 2-D 4 and 5 the linkage of the rhombus motif, which is isolated in 2, by equatorial–axialanti–anti carboxylate bridges, leads to dominating ferromagnetic interactions (J′=+0.2 K) between the ferromagnetically interacting Cu(II) dimers (J1=+8.8 K).

Confirmation by an X-ray crystallography study of a molecular modeling prediction about the coordination scheme of a new (1,4,8,11-(tetra-2-carboxyethyl)-1,4,8,11-tetraazacyclotetradecane)cerium(III) complex

The synthesis and characterization of a new cerium(III) complex with the ligand 1,4,8,11-(tetra-2-carboxyethyl)-1,4,8,11-tetraazacyclotetradecane (TETP), Ce(C22N4O8H38)(NO3)(H2O)3 · 3 H2O, is described. The cerium ion is eight-coordinated, linked to four carboxyl oxygen atoms belonging to four different TETP macrocycles as well as to three solvate water molecules, and to one oxygen atom of a disordered NO3 - anion. Each asymmetric unit consists of two different half TETP ligands. Each centrosymmetric TETP macrocycle possesses a [3434] conformation, two propionate arms being extended and the others folded towards two protonated nitrogen atoms. The four functionalized chains of the ligand whatever their conformation (extended or folded) are involved in the coordination polyhedron of cerium ion. This coordination mode was predicted from Molecular Electrostatic Potential calculations which showed the more negative potential sites of the ligand where the lanthanide cation would approach and coordinate.

Disodium Hexadecahydrate Diprotonated Form of 1,4,8,11-Tetra(2-carboxy)ethyl-1,4,8,11-tetraazacyclotetradecane (H2TETP)2−at 110 K

The diprotonated (H2TETP)2− macrocycle in the title compound, 2Na+.(C22H38N4O8)2−.16H2O [2Na+·(H2TETP)2−.16H2O], possesses a [3434] conformation, the propionate arms all being deprotonated. Two are extended and the other two are folded towards two protonated N atoms. The crystal structure is stabilized by a complex hydrogen-bonding scheme since the unit cell contains 16 water molecules.

Coordination chemistry of hexadentate EDTA-type ligands with M(III) ions

In recent years, many edta-type ligands have been prepared and used to form hexadentate complexes with Co(III), Cr(III), and Rh(III). Absolute configurations have been determined by X-ray crystallography for representative complexes, substantiating assignments based on circular dichroism (CD) spectra. Within the first absorption band, the CD patterns for Co(III) complexes differ in energies of CD peaks relative to the absorption maximum, depending on the combinations of acetate and propionate arms. The overall pattern suggests that different combinations of three transitions usually appear. Some enlargement of chelate rings intended to relieve strain has been found to introduce other strain. Unexpected C-N bond cleavage for Cr(III) complexes of edta-type ligands with propionate arms led to the identification of conformational isomers.