Isopropyl Moiety Research Articles

Synthesis and biological evaluation of lipid A derived from commensal Bacteroides.

The inflammation-inducing properties of lipopolysaccharides (LPS) of Gram-negative bacteria reside in their lipid A moiety. Bacillus fragilis, which is a commensal Gram-negative bacterium, biosynthesises lipid A that is structurally distinct from that of E. coli and other enteric bacteria. It is composed of a β1,6-linked glucosamine (GlcN) disaccharide that is only phosphorylated at the anomeric center. The major species of B. fragilis has five fatty acids and the amine of the distal GlcN moiety carries the unusual (R)-3-(13-methyltetradecanoyloxy)-1.5-methylhexadecanoic acid. A recent study indicates that the LPS of B. fragilis has anti-viral activity by selective induction of interferon (IFN)-β and is protective in mouse models of vesicular stomatitis virus (VSV) and influenza A. Heterogeneity in the structures of LPS and lipid A and possible contamination with other inflammatory components make it difficult to unambiguously define the immune-modulatory properties of LPS or lipid A. Therefore, we developed a synthetic approach for the preparation of the unusual major lipid A species derived from B. fragilis, which includes a synthetic approach for (R)-3-(13-methyltetradecanoyloxy)-1.5-methylhexadecanoic acid by the Wittig olefination to install the terminal isopropyl moiety. The proinflammatory and antiviral responses of synthetic B. fragilis lipid A were investigated in several cell lines and primary human monocytes by examining the production of interleukin (IL)-6 and IFN-β. It was found that B. fragilis does not induce the production of IL-6 and IFN-β but can partially antagonize the production of pro-inflammatory cytokines induced by E. coli LPS and lipid A.

Optimizing the conjugated structure of aromatic polyurea for high-temperature capacitive energy storage

Polymer dielectrics that can operate under simultaneous electric and thermal extremes are urgently needed in advanced electrical and electronic devices. However, the high thermal stability of polymers is typically endowed by the conjugated aromatic backbones, leading to enhanced conduction loss and poor energy storage density. Herein, we regulate the bridge linkages between adjacent benzene rings to simultaneously improve the thermal stability and optimize the conjugated structure of polyurea (PU), thereby achieving high-temperature energy storage performance. With the introduction of ether, methylene, and isopropyl structural units, the dihedral angles between adjacent benzene planes gradually increase, enabling PU to achieve excellent energy density (Ue) and charge–discharge efficiency (η) with suppressed leakage conduction and improved breakdown strength. The optimal PU with isopropyl moiety achieves an attractive Ue of 5.1 and 2.1 J/cm3 with η above 90% at 30 and 150 °C, respectively. This work provides a facile strategy to improve the energy storage performance of aromatic polymers by optimizing the interaction between adjacent conjugated benzene planes.

Interaction of Atorvastatin-loaded magnetic iron oxide nanoparticles with DNA

The present work aims to tether magnetic iron oxide nanoparticles onto a statin drug, Atorvastatin, in its free- and β-cyclodextrin-encapsulated form. The binding behavior of magnetic iron oxide nanoparticles tethered and β-cyclodextrin-encapsulated Atorvastatin to calf thymus DNA is studied by UV–Visible and fluorescence spectroscopy. The docking poses of Atorvastatin to β-cyclodextrin and DNA prove their binding toward the isopropyl and pyrrole moiety, respectively. The tethering of magnetic iron oxide nanoparticles and the encapsulation of β-cyclodextrin do not affect Atorvastatin’s binding strength toward DNA. The formation of the supramolecular ternary complex from free- and magnetic iron oxide nanoparticles tethered to Atorvastatin can be achieved with β-cyclodextrin and DNA for the drug’s better dissolution, bioavailability, and in-vivo medical applications.

Forensic analysis of the deuterium/hydrogen isotopic ratios of the nerve agent sarin, its reaction by-product diisopropyl methylphosphonate and their precursors by 2H SNIF-NMR

The Deuterium/Hydrogen (D/H) isotope ratios of sarin (5), diisopropyl methylphosphonate (3) and their precursors Isopropanol (1), methylphosphonic acid dichloride (2) and methylphosphonic acid difluoride (4) were measured by the 2H SNIF-NMR technique. The D/H isotope ratios of 1 show a large variation. It is shown, that the formation of 3 by reaction of 1 with 2, the fluorination of 2 to form 4 and the reaction of 4 with 1 to form 5, the D/H isotope ratios of the methyl and isopropyl moieties in 3, 4 and 5 are not significantly changed compared to 1 and 2.

Structural dynamics and in silico design of pyrazolopyran-based inhibitors against Plasmodium serine hydroxymethyltransferases

The clinical efficacy of antimalarial drugs has been reduced due to resistance spreading over many parts of the world. Target-based approaches on attractive drug targets, such as Plasmodium serine hydroxymethyltransferases (SHMTs) exhibiting distinct structure and function as well as kinetic mechanisms from the human enzyme homologue, are highly useful methods to be used for bypassing the present resistance in the field. Herein, 500-ns molecular dynamics (MD) simulations were carried out to investigate the mode of action of pyrazolopyran(+)-85 and pyrazolopyran(+)-86 with the most attractive inhibition efficiency in Plasmodium falciparum and P. vivax SHMTs (in the Schiff base form of PLP-L-serine (PLS) bound enzyme). The binding free energy results indicated the binding affinity of pyrazolopyran(+)-86 to Plasmodium SHMTs that is more favorable than pyrazolopyran(+)-85 by ∼ 2 kcal⋅mol−1, supported by the stronger ligand–protein hydrogen bonding and the lower solvent accessibility within the enzyme active site. According to the per-residue decomposition free energy analysis, residues L124, G128, H129, L130, K139, N356, and T357 are essential for inhibitors binding. By the rational structure-based drug design, the isopropyl moiety on the pyrazolopyran core should be changed to the negatively charged group (e.g., carboxylate group) for interacting with the positively charged residue R371. Alternatively, the phenolic compounds could be substituted with a phenyl or piperidine ring to promote hydrogen bond formation with the surrounding residues. Therefore, our findings presented here provide insights into the mode of inhibition of pyrazolopyran-based inhibitors and rational ideas for designing novel antimalarial drugs targeting Plasmodium SHMTs.

Near-Infrared Absorption Properties of Neutral Bis(1,2-dithiolene) Platinum(II) Complexes Using Density Functional Theory.

Small metal complexes are highly interesting for bioimaging because of their excellent near-infrared (NIR) absorption properties. In this study, neutral complexes of platinum(II) connected to two monoreduced 1,3-diisopropylimidazoline-2,4,5-trithione ligands—namely, [Pt(iPr2timdt)2]—were investigated. Theoretical studies using the density functional theory (DFT) and GW-BSE approximation verified the effects of the geometry of the isopropyl moieties on the NIR absorption spectra. The calculated absorption spectra showed excellent correspondence with the experimental results. The geometry of the isopropyl groups considerably influenced the electronic structures of the metal complexes, which altered the absorption profiles of the respective geometries, as demonstrated in this research.

Biocompatible thermoresponsive N-isopropyl-N-(3-(isopropylamino)-3-oxopropyl)acrylamide-based random copolymer: synthesis and studies of its composition dependent properties and anticancer drug delivery efficiency.

A new acrylamide monomer, N-isopropyl-N-(3-(isopropylamino)-3-oxopropyl)acrylamide (M3i), consisting of both isopropyl and isopropylamidopropyl moieties, has been synthesized from isopropylamine and N-isopropylacrylamide via an aza-Michael addition reaction followed by amidation with acryloyl chloride. The homopolymer of M3i (polyM3i) and a series of random copolymers of M3i and poly(ethylene glycol)methyl ether acrylate (PEGA: CH2CHCO2(CH2CH2O)nMe, Mn = 480, n = 9 on average) with varying compositions have been synthesized via reversible addition-fragmentation chain transfer polymerization using 2-(dodecylthiocarbonothioylthio)-2-methylpropionic acid (DDMAT) as well as 1-phenylethyl phenyl dithioacetate (PEPD) as a RAFT agent. These polymers have been characterized by 1H NMR, FTIR, GPC, UV-Vis, fluorescence, TGDTA, DSC, DLS, and TEM techniques. A lower critical solution temperature (LCST) and glass transition temperature (Tg) for polyM3i prepared using DDMAT were observed at 17 and 133 °C, respectively, while for a polymer formed using PEPD, no LCST was observed until 0 °C and its observed Tg was found at 127.3 °C. The polymers are thermally stable up to 300 °C. Upon an increase in the M3i content in the copolymers, LCST decreases, Tg increases, and the apparent hydrodynamic diameter decreases. Moreover, the effects of concentration and the addition of urea and sodium chloride on the LCST of the copolymer with an LCST close to body temperature were studied. Owing to the incorporation of PEGA, a higher critical micellar concentration and larger TEM particle size of this copolymer were observed with respect to those of polyM3i. The usefulness of the micelles of the copolymers as nano-carriers for the drug doxorubicin was explored. The in vitro tumoricidal activity of the micelles of the doxorubicin-loaded copolymers was also assessed against Dalton's lymphoma cells.

Uranium(III)–Phosphorus(III) Synergistic Activation of White Phosphorus and Arsenic

Uranium(III)–Phosphorus(III) Synergistic Activation of White Phosphorus and Arsenic

A Radical Addition Approach to a Heptafluoroisopropyl Substituted Arene, Combined with a Highly Diastereoselective Annulation Reaction To Synthesize the Tricyclic Core of BMS-986251

We have devised an asymmetric route to the tricyclic core 10 of BMS-986251. The six-step synthesis utilizes readily available starting materials, involves the one-step installation of the perfluoro isopropyl moiety through a radical mechanism, and leverages a novel diastereoselective annulation to build the pyrrolidine ring. Overall, 10 was obtained in 49% yield as a single stereoisomer in 6 steps and 3 isolations using this new route.

Structure-property relationship of poly(2,6-dimethyl-1,4-phenylene oxide) anion exchange membranes with pendant sterically crowded quaternary ammoniums

Steric hindrance engineering is of great significance to the preparation of new stable organic cations and durable polymeric anion exchange membrane materials. In this work, we presented a study of the structure-property relationship in quaternized poly (2,6-dimethyl-1,4-phenylene oxide) containing bulky n-propyl, isopropyl, or cyclohexyl-functionalized quaternary ammonium moieties. To our surprise, PPO-iP membranes possessing isopropyl-based QA cations showed higher water uptake than n-propyl- and cyclohexyl-containing analogues (PPO-nP and PPO-CH), in which obvious microphase-separated morphology was found. Thus, PPO-iP membranes displayed the highest hydroxide conductivity at 20 °C in water (37.3 mS/cm, IEC = 1.90 mmol/g). A standard protocol (1 M or 2 M NaOH at 60 °C) was used to determine the chemical stability of model cations and membranes both having sterically crowded QAs. Minor loss (<2%) in conductivity was observed for PPO-CH membranes after the treatment in 2 M NaOH at 60 °C for 216 h, highlighting the excellent alkaline stability, while significant degradation of PPO-iP and PPO-nP was confirmed by NMR characterization of the aged samples. In addition, the prepared PPO-based AEMs having sterically crowded QA cations were compared in alkaline H2/O2 fuel cells, demonstrating that the highly conductive PPO-iP membrane exhibited a peak power density of 182 mW/cm2 under optimized testing conditions.

Terminal cationization of poly(N-isopropylacrylamide) brush surfaces facilitates efficient thermoresponsive control of cell adhesion and detachment

ABSTRACT A variety of poly(N-isopropylacrylamide) (PIPAAm)-grafted surfaces have been reported for temperature-controlled cell adhesion/detachment. However, the surfaces reported to date need further improvement to achieve good outcomes for both cell adhesion and detachment, which are inherently contradictory behaviors. This study investigated the effects of terminal cationization and length of grafted PIPAAm chains on temperature-dependent cell behavior. PIPAAm brushes with three chain lengths were constructed on glass coverslips via surface-initiated reversible addition-fragmentation chain transfer (RAFT) polymerization. Terminal substitution of the grafted PIPAAm chains with either monocationic trimethylammonium or nonionic isopropyl moieties was performed through the reduction of terminal RAFT-related groups and subsequent thiol-ene reaction with the corresponding acrylamide derivatives. Although the thermoresponsive properties of the PIPAAm brush surfaces were scarcely affected by the terminal functional moiety, the zeta potentials of the cationized PIPAAm surfaces were higher than those of the nonionized ones, both below and above the phase transition temperature of PIPAAm (30°C). When bovine endothelial cells were cultured on each surface at 37°C, the number of adherent cells decreased with longer PIPAAm. Notably, cell adhesion on the cationized PIPAAm surfaces was higher than that on the nonionized surfaces. This terminal effect on cell adhesion gradually weakened with increasing PIPAAm length. In particular, long-chain PIPAAm brushes virtually showed cell repellency even at 37°C, regardless of the termini. Interestingly, moderately long-chain PIPAAm brushes promoted cell detachment at 20°C, with negligible terminal electrostatic interruption. Consequently, both cell adhesion and detachment were successfully improved by choosing an appropriate PIPAAm length with terminal cationization.

Targeting Receptor Tyrosine Kinase VEGFR-2 in Hepatocellular Cancer: Rational Design, Synthesis and Biological Evaluation of 1,2-Disubstituted Benzimidazoles.

In this study, a novel series of 1,2-disubstituted benzo[d]imidazoles was rationally designed as VEGFR-2 inhibitors targeting hepatocellular carcinoma. Our design strategy is two-fold; it aimed first at studying the effect of replacing the 5-methylfuryl moiety of the well-known antiangiogenic 2-furylbenzimidazoles with an isopropyl moiety on the VEGFR-2 inhibitory activity and the cytotoxic activity. Our second objective was to further optimize the structures of the benzimidazole derivatives through elongation of the side chains at their one-position for the design of more potent type II-like VEGFR-2 inhibitors. The designed 1,2-disubstituted benzimidazoles demonstrated potent cytotoxic activity against the HepG2 cell line, reaching IC50 = 1.98 μM in comparison to sorafenib (IC50 = 10.99 μM). In addition, the synthesized compounds revealed promising VEGFR-2 inhibitory activity in the HepG2 cell line, e.g., compounds 17a and 6 showed 82% and 80% inhibition, respectively, in comparison to sorafenib (% inhibition = 92%). Studying the effect of 17a on the HepG2 cell cycle demonstrated that 17a arrested the cell cycle at the G2/M phase and induced a dose-dependent apoptotic effect. Molecular docking studies of the synthesized 1,2-disubstituted benzimidazoles in the VEGFR-2 active site displayed their ability to accomplish the essential hydrogen bonding and hydrophobic interactions for optimum inhibitory activity.

Syntheses of tetrahydroquinoline-based chiral carbene precursors and the related chiral NHC-Au(i) complex.

Four tetrahydroquinoline-based chiral carbene precursors were synthesized using unsymmetrical N,N′-diarylformamidines and chiral 2-allyloxiranes as starting materials. A representative NHC–gold complex has been prepared and fully characterized, the crystal structure of which reveals an intramolecular Au⋯H–C(sp3) interaction between Au(i) and the hydrogen atom of the isopropyl moiety in the N-aryl group.

Profiling and quantification of aminophospholipids based on chemical derivatization coupled with HPLC-MS

In this study, a novel strategy based on acetone stable-isotope derivatization coupled with HPLC-MS for profiling and accurate quantification of aminophospholipids (phosphatidylethanolamine and phosphatidylserine) in biological samples was developed. Acetone derivatization leads to alkylation of the primary amino groups of aminophospholipids with an isopropyl moiety; the use of deuterium-labeled acetone (d6-acetone) introduced a 6 Da mass shift that was ideally suited for profiling and quantification analysis with high selectivity and accuracy. After derivatization, significantly increased column efficiency for chromatographic separation and detection sensitivity for MS analysis of aminophospholipids was observed. Furthermore, an accuracy quantification method was developed. Aminophospholipids in biological samples were derivatized with d0-acetone; while more than two aminophospholipid standards were selected for each class of aminophospholipid and derivatized with d6-acetone, which were then used as the internal standards to typically construct a calibration curve for each class to normalize the nonuniformity response caused by the differential fragmentation kinetics resulting from the distinct chemical constitution of individual aminophospholipid species in the biological samples. The excellent applicability of the developed method was validated by profiling and quantification of aminophospholipids presented in liver samples from rats fed with different diets.

Mechanism of atom economical conversion of alcohols and amines to amides using Fe(ii) pincer catalyst. An outer-sphere metal-ligand pathway or an inner-sphere elimination pathway?

In this present theoretical study, we investigated the reaction mechanism of atom-economical amide formation from alcohols and amines mediated by iron(ii) hydride complex (iPrPNP)Fe(H)(CO) (iPrPNP = N[CH2CH2(PiPr2)]2) using state-of-the-art density functional theory. Two scenarios of mechanistic pathways were considered, the inner-sphere and the outer-sphere pathways. In former case, the reaction of encounter complex of formaldehyde with amine is the rate-determining step with ΔG298 K = 33.75 kcal mol−1 while as in latter case dehydrogenation from trans-hydride is the rate-determining step having ΔG298 K = 21.34 kcal mol−1. Both the mechanistic scenarios operate through stepwise ionic pathways. The assessment of computational results demonstrate that inner-sphere pathway is energetically demanding and thus rendering outer-sphere pathway to be the most plausible mechanism of amide formation. Ligand modifications reveal that electron-withdrawing groups like CF3 near N of PNP ligand reduce the catalytic efficiency of the catalyst. Furthermore, changing the isopropyl moiety of phosphine scaffold with CH3 has a minimal impact on catalytic activity of the catalyst. Overall, our computational results provide new insights for the design and development of new Fe(ii) based pincer catalysts for atom economical amide formation from alcohols and amines.

Oxime K074 – in vitro and in silico reactivation of acetylcholinesterase inhibited by nerve agents and pesticides

Oxime K074 was formerly considered to be a lead structure for design of novel oximes for reactivation of tabun-inhibited acetylcholinesterase (AChE). In this study, we are summarizing its reactivation activity in case of other nerve agents (sarin, cyclosarin, VX and Russian VX) and pesticides (chlorpyrifos, methylchlorpyrifos and DDVP). For this purpose, standard in vitro method using rat brain homogenate was used. As resulted, oxime K074 was able to reactivate brain ChE (cholinesterases) inhibited by all used nerve agents and pesticides excluding cyclosarin-inhibited ChE. Only slight modification in structure of sarin (isopropyl moiety) and cyclosarin (cyclohexyl moiety) caused extraordinary differences in the reactivation of acetylcholinesterase inhibited by these nerve agents. Obtained molecular docking results suggest that the oxime K074 interacts very well with the inhibitors addressed in this work, and the data obtained by the QM/MM approach showed a good correlation with our experimental results of reactivation rate (%) by the oxime K074.

Studying molecular dynamics of the slow, structural, and secondary relaxation processes in series of substituted ibuprofens.

In this paper, the molecular dynamics of a series of ester derivatives of ibuprofen (IBU), in which the hydrogen atom from the hydroxyl group was substituted by the methyl, isopropyl, hexyl, and benzyl moieties, has been investigated using Broadband dielectric (BD), Nuclear magnetic resonance (NMR), and Raman spectroscopies. We found that except for benzyl IBU (Ben-IBU), an additional process (slow mode, SM) appears in dielectric spectra in all examined compounds. It is worth noting that this relaxation process was observed for the first time in non-modified IBU (a Debye relaxation). According to suggestions by Affouard and Correia [J. Phys. Chem. B. 114, 11397 (2010)] as well as further studies by Adrjanowicz et al. [J. Chem. Phys. 139, 111103 (2013)] on Met-IBU, it was attributed to synperiplanar-antiperiplanar conformational changes within the molecule. Herein, we have shown that with an increasing molecular weight of the substituent, the relaxation times of the SM become longer and its activation energy significantly increases. Moreover, this new relaxation mode was found to be broader than a simple Debye relaxation in Iso-IBU and Hex-IBU. Additional complementary NMR studies indicated that either there is a significant slowdown of the rotation around the O=C-O-R moiety or this kind of movement is completely suppressed in the case of Ben-IBU. Therefore, the SM is not observed in the dielectric loss spectra of this compound. Finally, we carried out isothermal experiments on the samples which have a different thermal history. Interestingly, it turned out that the relaxation times of the structural processes are slightly shorter with respect to those obtained from temperature dependent measurements. This effect was the most prominent in the case of Hex-IBU, while for Ben-IBU, it was not observed at all. Additional time-dependent measurements revealed the ongoing equilibration manifested by the continuous shift of the structural process, until it finally reached its equilibrium position. Further Raman investigations showed that this effect may be related to the rotational/conformational equilibration of the long hexyl chains. Our results are the first ones demonstrating that the structural process is sensitive to the conformational equilibration occurring in the specific highly viscous systems.

Transformation of phenolic compounds by peroxymonosulfate in the presence of iodide and formation of iodinated aromatic products

In this work, the transformation of several phenolic compounds by peroxymonosulfate (PMS) in the presence of iodide (I−) was investigated with a focus on the potential formation of iodinated aromatic products of concerns. The addition of I− greatly enhanced the transformation of phenol and bisphenol A (BPA) by PMS, and this enhancement was strongly influenced by several factors (i.e., I− and PMS concentrations and solution pH). This result could be well explained by the competition reactions of hypoiodous acid (HOI) formed in situ with phenols vs PMS under various conditions. Five iodophenols were identified from HOI reaction with phenol, and four iodinated BPA (including mono-, di-, tri- and tetra-iodinated BPA) together with two bond-cleavage iodinated aromatic products were detected in the case of BPA. Reaction pathways mainly involving stepwise substitution of HOI on phenol and BPA were proposed, and β-scission of isopropyl moiety also took place for iodinated BPA. Moreover, evolution of these iodinated aromatic products from phenol and BPA in the PMS/I− system was monitored, and a lower pH or a higher [I−]:[PMS] ratio favored their formation. Comparatively, I− accelerated the transformation of catechol and hydroquinone by PMS but with negligible formation of iodinated aromatic products, where these two phenols underwent oxidation rather than substitution in the presence of HOI formed in situ. This work clearly demonstrates a high potential of forming iodinated aromatic products during treatment of phenolic compounds by PMS in the presence of I−, which depends on the reaction conditions as well as the reactivity and pathway of HOI.

The influence of distal substitution on the base-induced isomerization of long-chain terminal alkynes

When compared to a long-straight chain terminal alkyne, a long chain terminal alkyne with a distal isopropyl unit (isobranched) isomerizes about two times faster when treated with strong base under identical conditions, and appears to follow pseudo first order kinetics. In both cases, equilibration to a 95–97:5–3 mixture of terminal:internal alkyne accompanies isomerization. The difference in rate may be due to an unusual folding of both long-chain alkynes, bringing the distal substituent close to the carbon-carbon-triple bond moiety. The distal isopropyl moiety may provide unanticipated steric hindrance that disrupts such folding, making the propargylic proton more available for reaction with base.

Biosynthesis of the fatty acid isopropyl esters by engineered Escherichia coli.

The fatty acid methyl esters and fatty acid ethyl esters are known as biodiesels which are considered to be renewable, nontoxic and biodegradable biofuels. However, the conventional biodiesels show a high crystallization temperature which is one of the most critical obstacles against the widespread biodiesel usage. The high crystallization temperature of biodiesel can be reduced by replacing the methyl or ethyl ester with an isopropyl moiety. Here we report on a strategy to establish biosynthesis of the fatty acid isopropyl esters(FAIPEs) from the simple substrate glucose in Escherichia coli with heterologous coexpression of atoB encoded acetyl-CoA acetyltransferase and atoAD encode acetoacetyl-CoA transferase from E. coli, ADC encode acetoacetate decarboxylase from Clostridium acetobutylicum, ADH encoded NADP-dependent alcohol dehydrogenase from Clostridium beijerinckii, 'TesA encoded a truncated fatty acyl-ACP thioesterase and FadD encoded fatty acyl-CoA synthetase from E. coli, and the WS/DGAT encoded acyltransferase from Acinetobacter baylyi strain ADP1. It was found that the yield of FAIPEs was up to 203.4mg/L and accounted for around 6.4% (wt/wt) of the dry cell weight. Our results indicates that it is a feasible strategy to improve the yield of FAIPEs by increasing fatty acyl-CoA availability in biosynthetic pathway and exhibit a promising method for production of biodiesels with good low-temperature flow properties.