Lipophilic Groups Research Articles

Fabrication of Vanadium Oxide-encapsulated Hybrid Carbon Nanospheres for Enhanced Tribological Performance.

A new sulfur-containing carbon nanospheres encapsulated with vanadium oxide (V@SCN) is synthesized through a one-pot oxidation polymerization and then carbonization method. The prepared V@SCNs exhibit good dispersibility as a lubricant additive, which is owing to the inherited lipophilic organic functional groups in the sulfur-containing carbon shell derived from the carbonization of polythiophene. The agglomeration and precipitation of metals in the base oil are also avoided through the encapsulation of lipophilic carbon shells. The stress and thermal simulation results show that the vanadium oxide core bestows upon the carbon nanospheres enhanced load resistance and superior thermal conductivity, which contributes to their excellent tribological properties. Introducing 0.04M-V@SCN to the base oil leads to favorable tribological characteristics, such as a fourfold rise in extreme pressure capacity from 250 to 1050N, a reduction in friction coefficient from 0.2 to ≈0.1, and a substantial decrease in wear by 90.2%. The lubrication mechanism of V@SCNs as lubricant additive involves the formation of a robust protective film on the friction pair, which is formed via complex physical and chemical reactions with the friction pair during friction.

Highly Cytotoxic Cryptophycin Derivatives with Modification in Unit D for Conjugation.

Cytotoxic payloads for drug conjugates suitable for directed tumor therapy need to be highly potent and require a functional group for conjugation with the homing device (antibody, peptide, or small molecule). Cryptophycins are cyclodepsipeptides that stand out from the realm of natural products due to their extraordinarily high cytotoxicity. However, the installation of a suitable conjugation handle without compromising the toxicity is highly challenging. The unit D, natively 2-hydroxyisocaproic acid (leucic acid), was envisaged as a promising attachment site based on structural information from X-ray analysis. A versatile, scalable and efficient synthetic route towards conjugable cryptophycins with modification in unit D was developed and an array of new cryptophycin analogues was synthesized. Several derivatives, especially those containing lipophilic groups with low steric demand such as alkylated amino groups, exhibit low picomolar cytotoxicity often combined with efficacy against multidrug-resistant tumor cells. The newly established cryptophycin analogues comprise a broad range of relevant functional groups used as conjugation handles, among them amino, hydroxy, carboxy, as well as sulfur-containing derivatives. X-ray crystallographic analysis of a tubulin-bound cryptophycin together with quantitative structure activity relationship manifested rationales for the synthesis of most potent cryptophycin derivatives and further confirmed the suitability of modifications in unit D.

Optimization screening, performance and mechanism analysis of green and low-carbon surfactants for oil-based drilling cuttings treatment

Oil-Based Drilling Cuttings (OBDC) have attracted extensive attention from scholars due to their high annual generation and high toxicity. At present, the thermal cleaning technology of surfactant is one of the research hotspots for treating OBDC, but it still faces the problems of high toxicity of surfactant, high carbon emission and unknown treatment mechanism. Therefore, we sequentially optimized screening the surfactants through the perspectives of greenness, treatment performance and costs, and low-carbon. A single-variable experiment was used to optimize the process parameters for treating OBDC, and the oil removal mechanism was explored by oil droplet size, TSI, Zeta potential and SARA fractions. The SLM was the most green and low carbon surfactant in this study, and had a better treatment performance for OBDC (51.56% oil removal rate). The optimal treatment parameters for SLM treatment of OBDC were 70 °C, 45 min, 300 r/min, 1:4 (solid/liquid) and pH 8.2. The lipophilic groups of SLM "striped" the asphaltenes and saturates in oil phase from the solid phase surface and "integrated" them into the water phase by its hydrophilic group. The mean value of the oil droplet sizes (Dmean) and Turbiscan stability index (TSI) value of the OBDC-water mixtures increased and the |Zeta potential| decreased after treatment, and the mixture system became more unstable, which promotes the subsequent separation of the oil phase from the solid phase.

Long-chain alkyl emulsifiers induced asphalt particle dispersion: Lipophilicity-enhancement effect

The structure of the lipophilic groups within the emulsifiers plays a pivotal role in uniformly dispersing the asphalt particles in the water regarding the storage and thermal stability of emulsified asphalt. This study combines laboratory experiments with molecular dynamics simulations, investigating the influence of alkyl chain length on emulsified asphalt dispersion and behavior at the oil/water interface. The results reveal that long-chain alkyl emulsifiers (C16TAC and C18TAC) present a lipophilicity-enhancement effect. This phenomenon increases the free volume fraction of emulsified asphalt, reducing viscosity and improving the compatibility of emulsion. This results in smaller asphalt particle sizes (D50 = 1.982μm) and more uniform dispersion. Vigorously lipophilic long-chain alkyl promotes emulsifier molecular migration towards the asphalt phase, thickening the oil/water interfacial layer and reducing interfacial tension and energy by more than 90 %. Notely, long-chain alkyl emulsifiers establish strong hydrogen bonds with water molecules, leading to water molecule aggregation into a hydration layer. Laboratory experimental results demonstrate that this lipophilicity-enhancement effect significantly improves the storage and thermal stability of emulsified asphalt. This research recommends long-chain alkyl emulsifiers in developing and designing energy-efficient pavement engineering regarding high-performance emulsified asphalt.

The Influencing Factors and Mechanism of Anionic and Zwitterionic Surfactant on Viscosity Reduction in Heavy O/W Emulsions.

The high viscosity of heavy crude oil has been an obstacle to its safe production and economic transportation. In this work, a screened emulsified viscosity reducer system is conducted. Experimental results demonstrate that the most effective viscosity reducing agent comprises sodium oleate (NaOl) and cocamidopropyl betaine (CAB-35) in a ratio of 1:2, achieving a viscosity reduction rate of 94.65%. Additionally, the interfacial tension between oil and water decreases from 27 to 4 mN/m with 0.1 mass % TEOA and NaOH in a 1:1 ratio. The oil droplet size is uniformly distributed with D mean is 14 μm and D 50 is 11 μm. Droplets flocculate as the salinity increases to 0.2 mol/L, which corresponds to the apparent increase of viscosity. The adsorption of long alkyl chain lipophilic groups on surfactant molecules at the oil-water interface and the water film alters the wettability of pipe steel to water-wet, further enhancing the application of emulsification and viscosity reduction effects. The primary mechanism behind the viscosity reduction in emulsification is attributed to strong electrostatic interactions stemming from molecular electrostatic potential distributions.

Mechanism of two styryl BODIPYs as fluorescent probes and protective agents in lipid bilayers against aqueous ClO.

Two styryl BODIPY derivatives, BOH and BOE, with different hydrophilic properties, were investigated for their reaction mechanisms in lipid bilayers against aqueous ClO-, by both experimental and theoretical methods. Density functional theory (DFT) calculations confirmed their identical conformations in solution. Fluorescence spectra and high-resolution mass spectra corroborated the central vinyl group as a common antioxidation moiety against ClO- oxidation. In giant unilamellar vesicles (GUVs), distinct reaction kinetics with ClO- suggested that BOE provided superior protective effects compared to BOH on lipids. Molecular dynamics simulations indicated that the lipophilic octyloxy group in BOE led to its deeper localization within the lipid phase, bringing it closer to the corresponding lipid target group. This study establishes the two styryl BODIPYs as promising fluorescent probes for detecting aqueous ClO- in lipid-water polyphasic systems.

High‐Performance n‐Type Organic Thermoelectrics with Exceptional Conductivity by Polymer‐Dopant Matching

AbstractAchieving high electrical conductivity (σ) and power factor (PF) simultaneously remains a significant challenge for n‐type organic themoelectrics (OTEs). Herein, we demonstrate the state‐of‐the‐art OTEs performance through blending a fused bithiophene imide dimer‐based polymer f‐BTI2g‐SVSCN and its selenophene‐substituted analogue f‐BSeI2g‐SVSCN with a julolidine‐functionalized benzimidazoline n‐dopant JLBI, vis‐à‐vis when blended with commercially available n‐dopants TAM and N‐DMBI. The advantages of introducing a more lipophilic julolidine group into the dopant structure of JLBI are evidenced by the enhanced OTEs performance that JLBI‐doped films show when compared to those doped with N‐DMBI or TAM. In fact, thanks to the enhanced intermolecular interactions and the lower‐lying LUMO level enabled by the increase of selenophene content in polymer backbone, JLBI‐doped films of f‐BSeI2g‐SVSCN exhibit a unprecedent σ of 206 S cm−1 and a PF of 114 μW m−1 K−2. Interestingly, σ can be further enhanced up to 326 S cm−1 by using TAM dopant as a consequence of its favorable diffusion behavior into densely packed crystalline domains. These values are the highest to date for solution‐processed molecularly n‐doped polymers, demonstrating the effectiveness of the polymer‐dopant matching approach carried out in this work.

High-Performance n-Type Organic Thermoelectrics with Exceptional Conductivity by Polymer-Dopant Matching.

Achieving high electrical conductivity (σ) and power factor (PF) simultaneously remains a significant challenge for n-type organic themoelectrics (OTEs). Herein, we demonstrate the state-of-the-art OTEs performance through blending a fused bithiophene imide dimer-based polymer f-BTI2g-SVSCN and its selenophene-substituted analogue f-BSeI2g-SVSCN with a julolidine-functionalized benzimidazoline n-dopant JLBI, vis-à-vis when blended with commercially available n-dopants TAM and N-DMBI. The advantages of introducing a more lipophilic julolidine group into the dopant structure of JLBI are evidenced by the enhanced OTEs performance that JLBI-doped films show when compared to those doped with N-DMBI or TAM. In fact, thanks to the enhanced intermolecular interactions and the lower-lying LUMO level enabled by the increase of selenophene content in polymer backbone, JLBI-doped films of f-BSeI2g-SVSCN exhibit a unprecedent σ of 206 S cm-1 and a PF of 114 μW m-1 K-2. Interestingly, σ can be further enhanced up to 326 S cm-1 by using TAM dopant as a consequence of its favorable diffusion behavior into densely packed crystalline domains. These values are the highest to date for solution-processed molecularly n-doped polymers, demonstrating the effectiveness of the polymer-dopant matching approach carried out in this work.

Rational Design of Mono-Substituted Gd-DOTA as Highly Stable and Efficient MRI Contrast Agents for Hepatobiliary and Inflammation Imaging.

Hepatobiliary-specific magnetic resonance imaging contrast agents (MRI CAs) play a crucial role in the early diagnosis of hepatocellular carcinoma (HCC). However, only two acyclic CAs, Gd-BOPTA and Gd-EOB-DTPA, exhibit unfavorable kinetic inertness. Our study focused on the development of superior stable innovative macrocyclic CAs. By introducing a lipophilic benzyloxy group (OBn) into the H4DOTA ring (Gd-L1), we achieved significant enhancement in kinetic inertness. In vivo experiments in mice demonstrated that 40% of the dosage was distributed to the liver at 5 min, providing sustained hepatic enhancement for over 35 min. We also developed an MPO-responsive MRI CA (Gd-L3), which can participate in the "peroxidase cycle" as the substrate, generating oligomers with a 3.8-fold increase in relaxivity, and selectively enhance the lesion in an acute gout mouse model. Overall, our work represents a significant advancement in the field of hepatic and inflammatory MRI, offering promising avenues for early diagnosis and improved imaging outcomes.

Peptidic Boronic Acid Plasmodium falciparum SUB1 Inhibitors with Improved Selectivity over Human Proteasome.

Plasmodium falciparum subtilisin-like serine protease 1 (PfSUB1) is essential for egress of invasive merozoite forms of the parasite, rendering PfSUB1 an attractive antimalarial target. Here, we report studies aimed to improve drug-like properties of peptidic boronic acid PfSUB1 inhibitors including increased lipophilicity and selectivity over human proteasome (H20S). Structure-activity relationship investigations revealed that lipophilic P3 amino acid side chains as well as N-capping groups were well tolerated in retaining PfSUB1 inhibitory potency. At the P1 position, replacing the methyl group with a carboxyethyl substituent led to boralactone PfSUB1 inhibitors with remarkably improved selectivity over H20S. Combining lipophilic end-capping groups with the boralactone reduced the selectivity over H20S. However, compound 4c still showed >60-fold selectivity versus H20S and low nanomolar PfSUB1 inhibitory potency. Importantly, this compound inhibited the growth of a genetically modified P. falciparum line expressing reduced levels of PfSUB1 13-fold more efficiently compared to a wild-type parasite line.

Amphiphilic Heparinoids as Potent Antiviral Agents against SARS-CoV-2.

Herein, we report the synthesis and biological evaluation of a novel series of heparinoid amphiphiles as inhibitors of heparanase and SARS-CoV-2. By employing a tailor-made synthetic strategy, a library of highly sulfated homo-oligosaccharides bearing d-glucose or a C5-epimer (i.e., l-idose or l-iduronic acid) conjugated with various lipophilic groups was synthesized and investigated for antiviral activity. Sulfated higher oligosaccharides of d-glucose or l-idose with lipophilic aglycones displayed potent anti-SARS-CoV-2 and antiheparanse activity, similar to or better than pixatimod (PG545), and were more potent than their isosteric l-iduronic acid congeners. Lipophilic groups such as cholestanol and C18-aliphatic substitution are more advantageous than functional group appended lipophilic moieties. These findings confirm that fine-tuning of higher oligosaccharides, degree of sulfation, and lipophilic groups can yield compounds with potent anti-SARS-CoV-2 activity.

Structure optimizing of flavonoids against both MRSA and VRE

Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) cause more than 100,000 deaths each year, which need efficient and non-resistant antibacterial agents. SAR analysis of 162 flavonoids from the plant in this paper suggested that lipophilic group at C-3 was crucial, and then 63 novel flavonoid derivatives were designed and total synthesized. Among them, the most promising K15 displayed potent bactericidal activity against clinically isolated MRSA and VRE (MICs = 0.25–1.00 μg/mL) with low toxicity and high membrane selectivity. Moreover, mechanism insights revealed that K15 avoided resistance by disrupting biofilm and targeting the membrane, while vancomycin caused 256 times resistance against MRSA, and ampicillin caused 16 times resistance against VRE by the same 20 generations inducing. K15 eliminated residual bacteria in mice skin MRSA-infected model (>99 %) and abdominal VRE-infected model (>92 %), which was superior to vancomycin and ampicillin.

Discovery of Salifungin as a Repurposed Antibiotic against Methicillin-Resistant Staphylococcus aureus with Limited Resistance Development.

Exploring novel antimicrobial drugs and strategies has become essential to the fight MRSA-associated infections. Herein, we found that membrane-disrupted repurposed antibiotic salifungin had excellent bactericidal activity against MRSA, with limited development of drug resistance. Furthermore, adding salifungin effectively decreased the minimum inhibitory concentrations of clinical antibiotics against Staphylococcus aureus. Evaluations of the mechanism demonstrated that salifungin disrupted the level of H+ and K+ ions using hydrophilic and lipophilic groups to interact with bacterial membranes, causing the disruption of bacterial proton motive force followed by impacting on bacterial the function of the respiratory chain and adenosine 5'-triphosphate, thereby inhibiting phosphatidic acid biosynthesis. Moreover, salifungin also significantly inhibited the formation of bacterial biofilms and eliminated established bacterial biofilms by interfering with bacterial membrane potential and inhibiting biofilm-associated gene expression, which was even better than clinical antibiotics. Finally, salifungin exhibited efficacy comparable to or even better than that of vancomycin in the MRSA-infected animal models. In conclusion, these results indicate that salifungin can be a potential drug for treating MRSA-associated infections.

Structure-activity studies of di-cationic imidazolyl porphyrins for PDI of E. coli

SignificanceSeveral studies have underlined the potential use of cationic imidazolyl porphyrins as photosensitizers for PDI, specially for gram-negative bacteria, being the structure/activity effects one of the most important areas of study. ApproachThis work incorporates the synthesis of di-cationic imidazolyl porphyrin-based photosensitizers, whose amphiphilicity was modulated in attempt to develop molecules with optimized structures and properties for the inactivation of E. coli. ResultsThe developed family of cationic porphyrins was obtained with good yields and the photophysical and photochemical characterization of the synthesized compounds was performed, as well as biological studies in planktonic E. coli. The most promising results were observed for the photosensitizer bearing a bigger alkyl chain and OH groups at the end of the chain. ConclusionsThese findings suggest that hydrophilic groups at the end of an alkyl chain promotes a higher inactivation of E. coli when compared to lipophilic groups and smaller alkyl chains.

Synthesis and preliminary anticancer evaluation of photo-responsive prodrugs of hydroxymethylene bisphosphonate alendronate

The antitumoral activity of hydroxymethylene bisphosphonates (HMBP) such as alendronate or zoledronate is hampered by their exceptional bone-binding properties and their short plasmatic half-life which preclude their accumulation in non-skeletal tumors. In this context, the use of lipophilic prodrugs represents a simple and straightforward strategy to enhance the biodistribution of bisphosphonates in these tissues. We describe in this article the synthesis of light-responsive prodrugs of HMBP alendronate. These prodrugs include lipophilic photo-removable nitroveratryl groups which partially mask the highly polar alendronate HMBP scaffold. Photo-responsive prodrugs of alendronate are stable in physiological conditions and display reduced toxicity compared to alendronate against MDA-MB-231 cancer cells. However, the antiproliferative effect of these prodrugs is efficiently restored after cleavage of their nitroveratryl groups upon exposure to UV light. In addition, substitution of alendronate with such photo-responsive substituents drastically reduces its bone-binding properties, thereby potentially improving its biodistribution in soft tissues after i.v. administration. The development of such lipophilic photo-responsive prodrugs is a promising approach to fully exploit the anticancer effect of HMBPs on non-skeletal tumors.

Conjugating uncoupler compounds with hydrophobic hydrocarbon chains to achieve adipose tissue selective drug accumulation

One potential approach for treating obesity is to increase energy expenditure in brown and white adipose tissue. Here we aimed to achieve this outcome by targeting mitochondrial uncoupler compounds selectively to adipose tissue, thus avoiding side effects from uncoupling in other tissues. Selective drug accumulation in adipose tissue has been observed with many lipophilic compounds and dyes. Hence, we explored the feasibility of conjugating uncoupler compounds with a lipophilic C8-hydrocarbon chain via an ether bond. We found that substituting the trifluoromethoxy group in the uncoupler FCCP with a C8-hydrocarbon chain resulted in potent uncoupling activity. Nonetheless, the compound did not elicit therapeutic effects in mice, likely as a consequence of metabolic instability resulting from rapid ether bond cleavage. A lipophilic analog of the uncoupler compound 2,6-dinitrophenol, in which a C8-hydrocarbon chain was conjugated via an ether bond in the para-position (2,6-dinitro-4-(octyloxy)phenol), exhibited increased uncoupling activity compared to the parent compound. However, in vivo pharmacokinetics studies suggested that 2,6-dinitro-4-(octyloxy)phenol was also metabolically unstable. In conclusion, conjugation of a hydrophobic hydrocarbon chain to uncoupler compounds resulted in sustained or improved uncoupling activity. However, an ether bond linkage led to metabolic instability, indicating the need to conjugate lipophilic groups via other chemical bonds.

Ligand Lipophilicity Determines Molecular Mechanisms of Nanoparticle Adsorption to Lipid Bilayers.

The interactions of ligand-functionalized nanoparticles with the cell membrane affect cellular uptake, cytotoxicity, and related behaviors, but relating these interactions to ligand properties remains challenging. In this work, we perform coarse-grained molecular dynamics simulations to study how the adsorption of ligand-functionalized cationic gold nanoparticles (NPs) to a single-component lipid bilayer (as a model cell membrane) is influenced by ligand end group lipophilicity. A set of 2 nm diameter NPs, each coated with a monolayer of organic ligands that differ only in their end groups, was simulated to mimic NPs recently studied experimentally. Metadynamics calculations were performed to determine key features of the free energy landscape for adsorption as a function of the distance of the NP from the bilayer and the number of NP-lipid contacts. These simulations revealed that NP adsorption is thermodynamically favorable for all NPs due to the extraction of lipids from the bilayer and into the NP monolayer. To resolve ligand-dependent differences in adsorption behavior, string method calculations were performed to compute minimum free energy pathways for adsorption. These calculations revealed a surprising nonmonotonic dependence of the free energy barrier for adsorption on ligand end group lipophilicity. Large free energy barriers are predicted for the least lipophilic end groups because favorable NP-lipid contacts are initiated only through the unfavorable protrusion of lipid tail groups out of the bilayer. The smallest free energy barriers are predicted for end groups of intermediate lipophilicity which promote NP-lipid contacts by intercalating within the bilayer. Unexpectedly, large free energy barriers are also predicted for the most lipophilic end groups which remain sequestered within the ligand monolayer rather than intercalating within the bilayer. These trends are broadly in agreement with past experimental measurements and reveal how subtle variations in ligand lipophilicity dictate adsorption mechanisms and associated kinetics by influencing the interplay of lipid-ligand interactions.

Trifluoromethylthiolation of Arenes Using Lewis Acid and Lewis Base Dual Catalysis.

Incorporation of the highly lipophilic trifluoromethanesulfenyl group into bioactive molecules facilitates transport through lipid membranes, and thus, CF3S-containing compounds are important for drug discovery. Although reagents and procedures have been reported for arene trifluoromethylthiolation, methods are still required that are applicable to a diverse substrate scope and can be performed under mild conditions. Here, we describe a rapid and efficient approach for the trifluoromethylthiolation of arenes by catalytic activation of N-trifluoromethylthiosaccharin using a combination of iron(III) chloride and diphenyl selenide. This dual catalytic process allowed regioselective functionalization of a wide range of arenes and N-heterocycles under mild conditions and was used for the trifluoromethylthiolation of bioactive compounds such as tyrosine and estradiol.

Structural optimization of a lysine demethylase 5 inhibitor for improvement of its cellular activity

Lysine demethylase 5 (KDM5) subfamily proteins are important in epigenetic gene regulation. They are involved in the growth and drug resistance of cancer cells. Therefore, KDM5s are potential cancer therapeutic targets, and their inhibitors hold promise as anti-cancer drugs. Several KDM5 inhibitors, including KDM5-C49 (2a), have exhibited potent KDM5-inhibitory activities in in vitro enzyme assays. However, they do not show enough cellular activity despite being converted to their prodrugs. We hypothesized that their poor lipophilicity should prevent them from sufficiently penetrating the cell membrane, and introducing more lipophilic groups should improve cellular activities. In this study, we investigated 2a and KDM5-C70 (3a), a prodrug of 2a, and attempted to improve its cellular activity by replacing the N,N-dimethyl amino group of 3a with more lipophilic groups. N-Butyl, N-methyl amino compound 2e exhibited potent and selective KDM5-inhibitory activity equal to that of 2a. Furthermore, the cell membrane permeability of 3e, an ethyl ester prodrug of 2e, was six times higher than that of 3a in a parallel artificial membrane permeation assay. In addition, western blot analysis indicated that treating human lung cancer A549 cells with 3e increased histone methylation levels more strongly than that with 3a. Thus, we identified compound 3e as a more cell-active KDM5 inhibitor that has sufficient cell membrane permeability.

Elongation of N6-benzyladenosine scaffold via Pd-catalyzed C–C bond formation leads to derivatives with antiflaviviral activity

Decoration of nucleoside analogues with lipophilic groups often leads to compounds with improved antiviral activity. For example, N6-benzyladenosine derivatives containing elongated lipophilic substituents in the benzyl core efficiently inhibit reproduction of tick-borne encephalitis virus (TBEV), while N6-benzyladenosine itself potently inhibits reproduction of human enterovirus A71 (EV-A71). We have extended a series of N6-benzyladenosine analogues using effective synthetic methods of CC bond formation based on Pd-catalyzed cross-coupling reactions (Sonogashira and Suzuki) in order to study the influence of bulky lipophilic substituents in the N6 position of adenosine on the antiviral activity against flaviviruses, such as TBEV, yellow fever virus (YFV) and West Nile virus (WNV), as well as a panel of enteroviruses including EV-A71, Echovirus 30 (E30), and poliovirus type 2 (PV2). Reproduction of tested flaviviruses appeared to be inhibited by the micromolar concentrations of the compounds, while cytotoxicity in most cases was beyond the detection limit. Time-of-addition studies demonstrated that the hit compounds inhibited the stage of viral RNA synthesis, but not the stages of the viral entry or protein translation. As a result, several new promising antiflaviviral leads have been identified. On the other hand, none of the synthesized compounds inhibited enterovirus reproduction, indicating a possibility of involvement of flavivirus-specific pathways in their mechanism of action.