Propyl Moiety Research Articles

Ether modifications to 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine (SA4503): Effects on binding affinity and selectivity for sigma receptors and monoamine transporters

Two series of novel ether analogs of the sigma (σ) receptor ligand 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine (SA4503) have been prepared. In one series, the alkyl portion of the 4-methoxy group was replaced with allyl, propyl, bromoethyl, benzyl, phenethyl, and phenylpropyl moieties. In the second series, the 3,4-dimethoxy was replaced with cyclic methylenedioxy, ethylenedioxy and propylenedioxy groups. These ligands, along with 4-O-des-methyl SA4503, were evaluated for σ1 and σ2 receptor affinity, and compared to SA4503 and several known ether analogs. SA4503 and a subset of ether analogs were also evaluated for dopamine transporter (DAT) and serotonin transporter (SERT) affinity. The highest σ1 receptor affinities, Ki values of 1.75–4.63nM, were observed for 4-O-des-methyl SA4503, SA4503 and the methylenedioxy analog. As steric bulk increased, σ1 receptor affinity decreased, but only to a point. Allyl, propyl and bromoethyl substitutions gave σ1 receptor Ki values in the 20–30nM range, while bulkier analogs having phenylalkyl, and Z- and E-iodoallyl, ether substitutions showed higher σ1 affinities, with Ki values in the 13–21nM range. Most ligands studied exhibited comparable σ1 and σ2 affinities, resulting in little to no subtype selectivity. SA4503, the fluoroethyl analog and the methylenedioxy congener showed modest six- to fourteen-fold selectivity for σ1 sites. DAT and SERT interactions proved much more sensitive than σ receptor interactions to these structural modifications. For example, the benzyl congener (σ1Ki=20.8nM; σ2Ki=16.4nM) showed over 100-fold higher DAT affinity (Ki=121nM) and 6-fold higher SERT affinity (Ki=128nM) than the parent SA4503 (DAT Ki=12650nM; SERT Ki=760nM). Thus, ether modifications to the SA4503 scaffold can provide polyfunctional ligands having a broader spectrum of possible pharmacological actions.

Thermodynamic phase transition triggered by distinct distortion and ordering of dipropylammonium picrate.

Dipropylammonium picrate (compound 1) undergoes a first-order phase transition at 185.0 K. Differential scanning calorimetry (DSC) measurements show reversible anomaly peaks with a thermal hysteresis of 10.2 K. Dielectric responses with distinct anisotropy and striking anomaly further confirm the phase transition. Detailed structural analyses demonstrate that the phase transition in 1 is dominated by order-disorder transformations of the dipropylammonium (DPA) cations and the picrate anions. Moreover, the unique distortions of the terminal propyl moieties in the flexible chain-like DPA cation also play an important role in this structural phase transition. All these results indicate that 1 is a potential phase-transition material.

Manipulating efficiencies through modification of N-heterocyclic phenyltriazole ligands for blue iridium(III) complexes

Novel kinds of blue-emitting heteroleptic iridium(III) complexes (fpdmtz)2Ir(mpypz) (1), (fpmptz)2Ir(mpypz) (2) and (fpmptz)2Ir(pypz) (3) with N-heterocyclic phenyltriazole ligands were designed and synthesized under the guidance of theoretical calculations. Especially, the effect of substituent groups on their emission properties was systematically studied through introducing methyl and propyl moieties into the cyclometalated and ancillary ligands. The experimental results showed that 2 and 3 modified by propyl groups exhibited higher photoluminescence and electroluminescence efficiencies than 1 modified by methyl moiety in its cyclometalated ligands. Such greatly improved emission efficiencies were tentatively attributed to the suppressed intermolecular interactions in solid state caused by the introduction of propyl group, indicating that the photoluminescence and electroluminescence properties of iridium(III) complexes can be manipulated just by modifying simple small molecule groups into the cyclometalated ligands.

Syntheses, crystal structures and copper-binding capabilities of amidate-hanging platinum mononuclear complexes containing alkylamine moieties

As analogs of cis-[Pt(piam)2(NH3)2]·2H2O (1, piam=pivalamidate), two kinds of platinum mononuclear complexes, cis-[Pt(piam)2(NH2C3H7)2]·H2O (2) and cis-[Pt(piam)2(NH2C4H9)2] (3), have been synthesized and characterized by single-crystal X-ray analyses. The square-planar complexes 2 and 3 contain propyl and butyl moieties, respectively, enhancing the hydrophobicity. Both compounds have non-coordinated oxygen atoms in the piam ligands that can bind to a second metal, such as the Cu2+ ion, to afford trinuclear Pt–Cu–Pt complexes. UV–Vis and electron paramagnetic resonance spectra of the reaction of 2 and 3 with the Cu2+ ion show that both compounds form dinuclear Pt–Cu complexes as intermediates.

Increment of Antimycobaterial Activity on Lichexanthone Derivatives

A new dihydropyranexanthone derived from the natural xanthone lichexanthone (1) was synthesised and, together with other 18 derivatives including ω-bromo and ω-aminoalkoxylxanthones (containing methyl, ethyl, propyl, tertbutylamino and piperidinyl moieties), were tested against Mycobacterium tuberculosis. Nine ω-aminoalkoxylxanthones showed good antimycobacterial activity, and their in vitro cytotoxicity was determined using VERO cells in order to calculate the selectivity index (SI). One of these nitrogenated xanthone derivatives showed very promising results, with MIC of 2.6 μM and SI of 48. This MIC is comparable to values found in "first and second line" drugs commonly used to treat TB. In order to understand better about this compound, it was evaluated together with two other ones that showed good SI, against resistant clinical strains of M. tuberculosis to verify the existence of cross-resistance. A chemometrical approach was useful to establish a pattern of antitubercular activity among the group of ω-aminoalkoxylxanthones, according to some structural and chemical features.

Ethylene polymerization using metallocene catalyst supported on hybrid indenyl silica produced by sol–gel process

In this work, hybrid silica that contained an indenylpropyl organic moiety was synthesized using the sol–gel method from indenylpropylsilane and tetraethylorthosilicate (TEOS). These functionalized silica samples were used in the synthesis of supported metallocene catalysts that were active in the production of linear polyethylene. The reaction conditions, such as the catalyst type and reaction time, for the preparation of indenyl-functionalized silane influenced the incorporation of the organic precursor and the xerogel morphology. Hybrid materials that contained the indenidepropyl ligand were obtained at reaction times between 2 and 6h with the use of HF or NH3 as catalysts, which resulted in materials with different porosities, surface areas and morphologies. The indenyl-functionalized silica samples with organic contents greater than 10wt% were thermally stable up to 350°C. 13C CP-MAS-NMR showed the presence of propyl and indenyl moieties in the hybrid materials. These organic precursors were reacted with ZrCl4·2THF, which led to the formation of supported metallocene catalysts that, when tested in ethylene polymerization reactions, exhibited a dependence on the reaction temperature and the Al/Zr ratio.

Phenyl Linker-Induced Dense PEG Conformation Improves the Efficacy of C-Terminally MonoPEGylated Staphylokinase

PEGylation can improve the protein efficacy by prolonging serum half-life and reducing proteolytic sensitivity and immunogenicity. However, PEGylation may decrease the bioactivity of a protein by interfering with binding of its substrate or receptors. Here, staphylokinase (SAK), a thrombolysis agent for therapy of myocardial infarction, was mono-PEGylated at the C-terminus of SAK far from its bioactive domain. Phenyl, propyl, and amyl moieties were used as linkers between SAK and polyethylene glycol (PEG), respectively. Flexible propyl and amyl linkers lead to loose conformation. In contrast, rigid and hydrophobic phenyl linker induces dense PEG conformation that can extensively shield most domains adjacent to C-terminus (e.g., the antigen epitopes and proteolytic sites) of SAK and inefficiently shield its bioactive domain. As compared with loose PEG conformation, dense PEG conformation is more efficient to maintain the bioactivity, increase the plasma half-life, and decrease the proteolytic sensitivity and immunogenicity of the PEGylated SAK.

Encapsulation of adefovir bis(l-leucine propyl)ester pro-virucide in cucurbit[7]uril and its activity against tobacco mosaic virus

The interaction of cucurbit[7]uril (Q[7]) with a pro-virucide, adefovir bis(l-leucine propyl)ester (PMEA-Leu) in aqueous solutions and in solid state was studied by 1H NMR, UV absorption spectroscopy, fluorescence and IR spectroscopy. The 1H NMR revealed that the leucine propyl moiety of the compound could be entrapped in the cavity of the host Q[7], and the other moiety except for leucine propyl moieties, including aminopurine, was probably located at the portal area of Q[7]. Absorption and fluorescence spectroscopy proved that the interaction of Q[7] with PMEA-Leu led to the formation of host–guest inclusion complexes (2:1) that were controlled by the concentration of the host Q[7]. Formation of the inclusion complex between Q[7] and PMEA-Leu was confirmed by IR spectroscopy in solid state. In addition, deliquescent stability studies indicated that the moisture stability of the host–guest complex was significantly enhanced. The phenomenon was explained by the fact that the formation of solid inclusion complexes can prevent the compounds from absorbing water. Finally, bioactivity of PMEA-Leu and its inclusion complex against tobacco mosaic virus (TMV) was tested. The compound PMEA-Leu and its inclusion complexes showed some inhibitory activity against TMV at 500 μg/ml in vivo.

Polymerization of ethylene with (nBuCp)2ZrCl2 supported over mesoporous SBA-15 functionalized with sulfonic acid groups

The polymerization of ethylene in n-heptane with (nBuCp)2ZrCl2 supported over mesoporous SBA-15 catalysts functionalized with propyl or aryl sulfonic acid groups and impregnated with either MAO or TMA was investigated and compared with reference samples. All the supports showed mesoscopic ordering with pore sizes of 7.8–6.6nm, BET surface areas around 700m2g−1, sulfonic acid loadings between 10 and 20 wt% and an acidity of roughly 1–1.7mmol H+g−1. None of the catalysts were capable of polymerizing ethylene in the absence of MAO in spite of using TMA or TIBA as scavengers. The addition of MAO (Al/Zr=800 or 5000) led towards ethylene polymerization, being the activity dependent on Al/Zr molar ratio (higher for Al/Zr=5000). The catalysts treated with TMA during the impregnation exhibited considerable leaching, unlike those treated with MAO wherein the leaching was low (<9 wt%). The presence of the sulfonic acid moiety enhanced the activity of the catalysts. In addition, the activity was also augmented with the increase of the sulfonic acid content from 10 to 20 wt%. Interestingly, the molecular weight of the polyethylene synthesized with the SBA-15 functionalized with sulfonic acid groups were 1.5–2.5 times higher, especially with the propyl moiety which leads towards Mw∼350,000gmol−1 at 1.2barg. The results were explained through an interaction between the sulfonic acid moiety and the chlorinated MAO species, which activates the metallocene.

Chemical modifications of a natural xanthone and antimicrobial activity against multidrug resistant Staphylococcus aureus and cytotoxicity against human tumor cell lines

A series of 15 ω-aminoalkoxylxanthones containing methyl, ethyl, propyl, tert-butylamino and piperidinyl moieties were synthesized from a natural xanthone isolated from a lichen species. These compounds were tested for their in vitro antibacterial properties against Gram-positive and Gram-negative bacteria and cytotoxicity against a number of human tumor cell lines was too evaluated. The newly synthesized derivatives revealed selective activity against Staphylococcus aureus (Gram-positive), and the most promising results are for a multidrug resistant strain, for which six of these compounds showed good activity (MICs 4 µg/mL). Many derivatives inhibited tumor cells growth and most compounds were active on multiple lines.

ChemInform Abstract: Synthesis and Antiviral Activity of Nucleotide Analogues Bearing the ( S)-(3-Hydroxy-2-phosphonylmethoxy)propyl Moiety Attached to Adenine, Guanine, and Cytosine

ChemInform Abstract: Synthesis and Antiviral Activity of Nucleotide Analogues Bearing the ( S)-(3-Hydroxy-2-phosphonylmethoxy)propyl Moiety Attached to Adenine, Guanine, and Cytosine

Electrical and Electrochemical Properties of Alkyl-Monolayer Modified Si ( 111 ) in the Presence of Water

Fundamental electronic properties of methyl-modified n-Si(111) interfaces created by the displacement of on surface by the methyl group from Grignard reagents (; or , R = methyl) were measured in the presence and absence of water. The presence of water played a significant role in determining the behavior of the devices. The structure of /methyl monolayer/ was not rectifying but only consisted of series resistances. On the other hand, a diode-like rectifying property was observed with the water/methyl layers/ heterojunction structure. Functionalization of surfaces with various alkyl moieties such as methyl, ethyl, propyl, butyl, and mixed methyl/propyl, was studied by electrochemical measurements performed in a mixture of and by surface characterization with synchrotron radiation X-ray photoelectron spectroscopy. The transistor characteristics of field effect transistor-like devices with water/alkyl/ gate structures were investigated. The device properties clearly depended on the alkyl moiety: transistor-like behavior was observed only for devices with methyl moiety, and for those with a mixed methyl-propyl monolayer prepared by using Grignard reagents with mixed methyl and propyl moieties, whereas no transistor-like behavior was observed for devices with butyl or ethyl moiety.

Biotransformation of β-hydroxyphenyl selenides, diphenyldiselenide and benzeneseleninic acid by whole cells of Aspergillus terreus

Aspergillus terreus CCT 3320 and A. terreus URM 3571 catalysed the biotransformations of organic β-hydroxyphenyl selenides through oxidation and methylation reactions. The kinetic resolution of ( RS)-1-(phenylseleno)-2-propanol ( 1) via enantioselective oxidation produced (+)-( S)- 1 in high enantiomeric excess (>99%) and in a yield of 50% as determined by product isolation. Oxidation of the R-enantiomer of 1, followed by elimination of the propyl moiety and subsequent methylation of the presumed intermediate, led to the formation of methylphenyl-selenide, which was isolated in a yield of 40%. Whole cells of A. terreus also biocatalysed transformations of diphenyldiselenide, benzeneseleninic acid, ( RS)-1-(phenylseleno)-2-pentanol and ( RS)-1-(phenylseleno)-3-methyl-2-butanol, but not of ( RS)-1-(phenylseleno)-2-phenyl-methanol. This is the first report of the biomethylation of organoselenium compounds by whole cells of A. terreus.

Nucleotide analogues with immunobiological properties: 9-[2-Hydroxy-3-(phosphonomethoxy)propyl]-adenine (HPMPA), -2,6-diaminopurine (HPMPDAP), and their N6-substituted derivatives

Newly developed acyclic nucleoside phosphonates, derivatives of adenine and 2,6-diaminopurine bearing the 2-hydroxy-3-(phosphonomethoxy)propyl (HPMP) moiety at the N 9-side chain (i.e., HPMPA and HPMPDAP, respectively) were screened for in vitro immunobiological activity, using mouse resident peritoneal macrophages and splenocytes. Both HPMPA and HPMPDAP augmented the interferon-γ-triggered production of NO as well as expression of inducible nitric oxide synthase (iNOS) mRNA in macrophages. HPMPDAP activated secretion of tumor necrosis factor-α (TNF-α), chemokines “regulated-upon-activation, normal T cell expressed and secreted” (RANTES) and macrophage inflammatory protein-1α (MIP-1α), and marginally also secretion of interleukin-10 (IL-10) in both macrophages and splenocytes. The HPMPA, less prominently than HPMPDAP, elevated only secretion of RANTES and TNF-α. The compounds also activated secretion of TNF-α (HPMPDAP > HPMPA) in human peripheral blood mononuclear cells (PBMC). Distinct N 6-substituted derivatives, i.e., N 6-dimethyl-, N 6-cyclopropyl-, N 6-piperidin-1-yl-, N 6-(2-methoxyethyl)-, N 6-(2-hydroxyethyl)-, N 6-allyl- and N 6-2-(dimethylamino)ethyl-HPMPA/HPMPDAP as well as 6-thio and 6-hydroxy derivatives usually showed loss of the activity compared to the parent compounds. The immunomodulatory effects were found to be at least in part dependent on P 1 purinoreceptors, and mediated by transcriptional factor nuclear factor-κB.

Antimycobacterial activity of piperidinylpropyl esters of alkoxy-substituted phenylcarbamic acids.

A series of 17 hydrochlorides of piperidinylpropyl esters of alkoxy-substituted phenylcarbamic acids with the alkoxy group in position 2, 3 or 4 on the phenyl ring, and basic substituents attached to the moiety in position 3, were evaluated for in vitro antimycobacterial activity against the strains of Mycobacterium tuberculosis, M. kansasii and M. avium. To describe the structure-antimycobacterial activity relationships (QSAR), an approach based on the Free-Wilson method was employed to express the differences between individual moieties (including propyl and ethyl). The change of ethyl to propyl moiety increases the activity to M. tuberculosis but decreases the antimycobacterial activity to all potentially pathogenic strains under study.

High-precision position-specific isotope analysis of 13C/12C in leucine and methionine analogues.

We report an automated method for high-precision position-specific isotope analysis (PSIA) of carbon in amino acid analogues. Carbon isotope ratios are measured for gas-phase pyrolysis fragments from multiple sources of 3-methylthiopropylamine (3MTP) and isoamylamine (IAA), the decarboxylated analogues of methionine and leucine, using a home-built gas chromatography (GC)-pyrolysis-GC preparation system coupled to a combustion-isotope ratio mass spectrometry system. Over a temperature range of 620-900 degrees C, the characteristic pyrolysis products for 3MTP were CH4, C2H6, HCN, and CH3CN and for IAA products were propylene, isobutylene, HCN, and CH3CN. Fragment origin was confirmed by 13C-labeling, and fragments used for isotope analysis were generated from unique moieties with > 95% structural fidelity. Isotope ratios for the fragments were determined with an average precision of SD(delta13C) < 0.3% per thousand, and relative isotope ratios of fragments from different sources were determined with an average precision of SD(delta(delta)13C) < 0.5% per thousand. Delta(delta)13C values of fragments were invariant over a range of pyrolysis temperatures. The delta(delta)13C of complementary fragments in IAA was within 0.8% per thousand of the delta(delta)13C of the parent compounds, indicating that pyrolysis-induced isotopic fractionation is effectively taken into account with this calibration procedure. Using delta(delta)13C values of fragments, delta(delta)13C values were determined for all four carbon positions of 3MTP and for C1, C2, and the propyl moiety of IAA, either directly or indirectly by mass balance. Large variations in position-specific isotope ratios were observed in samples from different commercial sources. Most dramatically, two 3MTP sources differed by 16.30% per thousand at C1, 48.33% per thousand at C2, 0.37% per thousand at C3, and 5.36% per thousand at C(methyl). These PSIA techniques are suitable for studying subtle changes in intramolecular isotope ratios due to natural processes.

Adamantyl Modified Silica via Olefin Hydrosilation on a Hydride Intermediate

Adamantyl‐containing reversed phase (RP) bonded materials were prepared by applying catalytic olefin hydrosilylation as the main surface modification reaction. Reversed phases containing adamantyl groups attached to the silica surface through ethyl and propyl moieties were prepared in this work. The corresponding olefins, namely 1‐vinyladamantane (adamantyl‐ethene) and 1‐allyladamantane (3‐adamantyl‐propene) are not commercially available, and therefore, they were synthesized prior to the hydrosilation reaction. Infrared and nuclear magnetic resonance (NMR) characterizations of the olefins, and more importantly, those of the resulting bonded phases confirmed success of the reactions. Finally, the chromatographic characterization of the bonded phases, with special emphasis on the separation of basic solutes, was performed. A comparison of the separation performance of the new bonded materials with that obtained from conventional organosilanization is also an important part of the present work. The comparison has been extended to a C18 bonded phase to further emphasize the relationship between solute retention and the chemical nature of the modified silica surfaces.

Synthesis, antiarrhythmic, and antihypertensive effects of novel 1-substituted pyrrolidin-2-one and pyrrolidine derivatives with adrenolytic activity

A series of 1-substituted pyrrolidin-2-one and pyrrolidine derivatives were synthesised and tested for electrocardiographic, antiarrhythmic, and antihypertensive activity as well as for α 1- and α 2-adrenoceptors binding affinities . Among the newly synthesised derivatives several compounds with 3-(4-arylpiperazin-1-yl)propyl moiety displayed strong antiarrhythmic ( 7a– 12a) and antihypertensive ( 7a– 11a) activities. Compound 11a, 1-[2-acetoxy-3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one, was the most potent in this series. The pharmacological results and binding studies suggest that their antiarrhythmic and hypotensive effects may be related to their α-adrenolytic properties, and that those properties depend on the presence of the 1-phenylpiperazine moiety with a methoxy- or chloro- substituent in the ortho position in the phenyl ring.

Effects of Mobile-Phase Composition and Temperature on the Selectivity of Poly(N-isopropylacrylamide)-Bonded Silica Gel in Reversed-Phase Liquid Chromatography

We developed a simple preparation method for poly(N-isopropylacrylamide) (poly(NIPAM))-bonded silica using a water-organic two-phase system to directly copolymerize N-isopropylacrylamide with 3-(methacryloxy)propyl moieties on the silica surfaces. The stationary phase showed a phase transition with the change in temperature or in methanol content, resulting in notable changes in selectivity which cannot be expected with alkyl-type stationary phases. The packing material showed an increase in retention and column efficiency with the increase in temperature between 30 and 40 °C or in methanol content between 10 and 20%. The temperature-responsive properties were reduced with the increase in methanol content of the mobile phase and lost at 40% or higher. Significant changes in retention selectivity by the addition of methanol were observed for benzene derivatives below the transition temperature of poly(NIPAM). The preferential retention of hydrogen bond acceptors was observed at low temperatures in the mobile phase of low methanol content, while dominant contribution of the hydrophobic interaction to the retention of solutes was observed at the higher temperature in aqueous mobile phase or at the higher methanol concentration. The temperature increase brought about similar changes in retention behavior of the poly(NIPAM)-bonded silica packing materials to the addition of methanol to the mobile phase.

Synthesis of 14C-labelled CGS 16949A (Fadrozole HCl), a potent aromatase inhibitor

CGS 16949A (Fadrozole HCl) is an aromatase inhibitor currently used in Japan for the treatment of estrogen-dependent cancer. A 14C-labelled form of this compound was synthesized for metabolism and pharmacokinetic studies. The synthesis pathway includes six steps, which are shown in synthetic Scheme 2. Initially, 4-bromotoluene was reacted with [14C]CuCN to yield 4-tolunitrile-[14C]-cyano. The nitrile was brominated on the α carbon to give an intermediate that was used to N-alkylate a known imidazole analogue. The product was treated with thionyl chloride to convert a 3-hydroxy propyl moiety to its chloro analogue. Treatment with potassium butoxide gave [14C] fadrozole as the free base via ring closure. Hydrogen chloride gas was used to give the desired salt [14C]CGS 16949A. Using this procedure, [14C]CGS 16949A was prepared with 97% radiochemical purity. The overall radiochemical yield for the synthesis was 1% from [14C]KCN. © 1997 John Wiley & Sons, Ltd.