Dimeric Derivatives Research Articles

Development of a novel antioxidant based on a dimeric dihydroisocoumarin derivative

A biaryl dimer based on eurotiumide A, a dihydroisocoumarin-type natural product possessing a 1,4-hydroquinone skeleton, was synthesized herein. The radical scavenging activity and cytotoxicity were evaluated. The prepared biaryl dimer and eurotiumide A displayed comparable potent antioxidant activities to those of α-tocopherol and edaravone. However, the biaryl dimer did not show any cytotoxicity against murine colon and human myeloma cells.

Design of Dimeric Bile Acid Derivatives as Potent and Selective Human NTCP Inhibitors.

Dimeric bile acid derivatives (DBADs) were developed and tested for their anti-HBV and anti-HDV activities as sodium taurocholate cotransporting polypeptide (NTCP) inhibitors. DBADs exhibited strong and persistent potency of NTCP inhibition, whereas diverse linkers and constitutions showed distinct inhibition features. Motif aa157-165 on NTCP was shown to be a possible binding site of DBADs; therefore, we determined DBADs' selectivity among NTCPs from different species. A cyclized DBAD scaffold DBA-41 exhibited a high affinity to human NTCP (hNTCP). Intraperitoneal administration of DBA-41 to hNTCP-tg mice induced serum total bile acid elevation. DBA-41 may serve as a biological tool to study NTCP physiological function.

Ardeemins and citrinin dimer derivatives from Aspergillus terreus harbored in Pinellia ternate

One new alkaloid, 15b-β-hydroxy-16α-hydroxy-5-N-acetylardeemin (1), and one new dimeric derivative of citrinin, penicitrinol Q (5), together with three known alkaloids (2–4) and two citrinin dimers (6–7), were isolated from the solid culture of an endophytic Aspergillus terreus resided in Pinellia ternata. Their structures were established by detailed spectroscopic analysis, and the absolute configurations were determined by single crystal X‑ray diffraction and the comparison of ECD spectra. Penicitrinol Q (5) exhibited inhibitory effects against Staphylococcus aureus and Bacillus subtilis with MIC50 values of 4.3 and 6.2 μg/mL, respectively. When using a concentration of 30 μM, compound 2 showed 2.1-fold enhancement of doxorubicin susceptibility in treating doxorubicin-resistant human breast cancer cell line.

Onion Peel: Turning a Food Waste into a Resource.

Food waste is a serious problem for food processing industries, especially when it represents a loss of a valuable source of nutrients and phytochemicals. Increasing consumer demand for processed food poses the problem of minimizing waste by conversion into useful products. In this regard, onion (Allium cepa) waste consisting mainly of onion skin is rich in bioactive phenolic compounds. Here, we characterized the flavonoid profiles and biological activities of onion skin wastes of two traditional varieties with protected geographical indication (PGI), the red “Rossa di Tropea” and the coppery “Ramata di Montoro”, typically cultivated in a niche area in southern Italy. The phytochemical profiles of exhaustive extracts, characterized by ultra-high-performance liquid chromatography coupled with ultraviolet (UV) detection and high-resolution mass spectrometry, revealed that flavonols and anthocyanins were the characteristic metabolite classes of onion skins. Quercetin, quercetin glucosides and their dimer and trimer derivatives, and, among anthocyanins, cyanidin 3-glucoside, were the most abundant bioactive compounds. The potential of onion skins was evaluated by testing several biological activities: ABTS/oxygen radical absorbance capacity (ORAC) and in vitro alpha-glucosidase assays were performed to evaluate the antioxidant and anti-diabetic properties of the extracts and of their main compounds, respectively, and proliferative activity was evaluated by MTT assay on human fibroblasts. In the present study, by observing various biological properties of “Rossa di Tropea” and “Ramata di Montoro” onion-dried skins, we clearly indicated that this agricultural waste can provide bioactive molecules for multiple applications, from industrial to nutraceutical and cosmetical sectors.

Electrospun wound dressings containing bioactive natural products: physico-chemical characterization and biological assessment

BackgroundCurrent research on skin tissue engineering has been focusing on novel therapies for the effective management of chronic wounds. A critical aspect is to develop matrices that promote growth and uniform distribution of cells across the wound area, and at the same time offer protection, as well as deliver drugs that help wound healing and tissue regeneration. In this context, we aimed at developing electrospun scaffolds that could serve as carriers for the bioactive natural products alkannin and shikonin (A/S).MethodsA series of polymeric nanofibers composed of cellulose acetate (CA) or poly(ε-caprolactone) (PCL) and varying ratios of a mixture of A/S derivatives, has been successfully fabricated and their physico-chemical and biological properties have been explored.ResultsScanning electron microscopy revealed a uniform and bead-free morphology for CA scaffolds, while for PCL beads along the fibers were observed. The average diameters for all nanofibers ranged between 361 ± 47 and 487 ± 88 nm. During the assessment of physicochemical characteristics, CA fiber mats exhibited a more favored profile, while the assessment of the biological properties of the scaffolds showed that CA samples containing A/S mixture up to 1 wt.% achieved to facilitate attachment, survival and migration of Hs27 fibroblasts. With respect to the antimicrobial properties of the scaffolds, higher drug-loaded (1 and 5 wt.%) samples succeeded in inhibiting the growth of Staphylococcus epidermidis and S. aureus around the edges of the fiber mats. Finally, carrying out a structure-activity relationship study regarding the biological activities (fibroblast toxicity/proliferation and antibacterial activity) of pure A/S compounds – present in the A/S mixture – we concluded that A/S ester derivatives and the dimeric A/S augmented cell proliferation after 3 days, whereas shikonin proved to be toxic at 500 nM and 1 μM and alkannin only at 1 μM. Additionally, alkannin, shikonin and acetyl-shikonin showed more pronounced antibacterial properties than the other esters, the dimeric derivative and the A/S mixture itself.ConclusionsTaken together, these findings indicate that embedding A/S derivatives into CA nanofibers might be an advantageous drug delivery system that could also serve as a potential candidate for biomedical applications in the field of skin tissue engineering.

A fluorescence biosensor for therapeutic drug monitoring of vancomycin using in vivo microdialysis

Clinical vancomycin (Van) treatment is administered over a prolonged period to achieve a sustained therapeutic effect. Accurate, rapid, and continuous Van detection is an unmet medical monitoring need that can provide data-based guidance for doctors to adjust the dosage and treatment plan in real-world settings. In this study, we created a Van-specific, fluorescent biosensor that was combined with a microdialysis sampling technique to develop a rapid, simple, accurate, and sensitive detection method, which was validated for Van in vivo. A Van-specific probe was created by separately conjugating each of the two peptide chains of a dimeric derivative of the Van binding peptide L-Lys-D-Ala-D-Ala to a fluorescent dansyl chloride group. Subject-specific pharmacokinetics of Van was recorded in normal rabbits and rabbits with adenine-induced chronic renal failure (CRF), which indicated the feasibility of therapeutic drug monitoring in vivo. The area under the concentration–time curve (AUC0–last) was 10,715 min μg mL−1 (95% CI = 8,892 to 12,538) in the normal rabbits, and 14,822 and 19,025 min μg mL−1 in two selected CRF rabbits. Furthermore, using pharmacokinetic dosing of Van in a rabbit study, we designed the dosage and drug administration interval to achieve a sustained therapeutic effect. The normal rabbits received three Van doses, 20, 5, and 5 mg kg−1, administered at 0, 500, and 900 min, respectively. The CRF rabbits received two Van doses, 20 and 5 mg kg−1, administered at 0 and 600 min, respectively. Thus, we established an effective method for the continuous monitoring of Van. This method facilitates the detection of Van in clinical treatment and provides the scientific basis for an effective approach to monitor blood drug levels during the clinical treatment of various diseases.

Quantitative analysis of palladacycle-tagged PLGA nanoparticle biodistribution in rat organs by means of atomic absorption spectrometry and inductively coupled plasma mass spectrometry

The biodistribution of PLGA nanoparticles labelled with Pd in the form of a dimeric cyclopalladated derivative of N,N-dimethyldiphenylmethylamine was investigated in rats using graphite furnace atomic absorption spectrometry and inductively coupled plasma mass spectrometry.

Nonpeptide small molecules with a ten-membered macrolactam or a morpholine motif from the insect American cockroach and their antiangiogenic activity

(±)-Periplactam A (1), a rare ten-membered macrolactam composed of lignan and putrescine, (±)-periplanol E (2), a dimeric phenethyl alcohol derivative formed via morpholine, and periplactams B (3) and C (4) were isolated from American cockroach.

Manilkzapotane, a novel dimeric alkylresorcinol derivative from the stem bark of Manilkara zapota

A novel dimeric alkylresorcinol derivative, manilkzapotane (1), along with seven known compounds, lupeol acetate (2), lupeol (3), arjunolic acid (4), ergosterol peroxide (5), taraxerol (6), hederagonic acid (7), and glochidiol (8) were isolated from the stem bark of Manilkara zapota. Their structures were determined on the basis of spectroscopic data. DFT-NMR chemical shift calculations and a modified probability (DP4+) method were applied to define the relative configuration of 1. To the best of our knowledge, this represents the first isolation of a dimeric alkylresorcinol derivative from the Sapotaceae family.

Induction of differentiation of the acute myeloid leukemia cell line (HL-60) by a securinine dimer

Differentiation therapy has been successfully applied clinically in cases of acute promyelocytic leukemia (APL), but few differentiation-induction agents other than all-trans retinoic acid (ATRA) have been discovered clinically. Based on our previously reported neuritogenic differentiation activity of synthetic dimeric derivatives of securinine, we explored the leukemia differentiation-induction activity of such as compound, SN3-L6. It was found that SN3-L6 induces transdifferentiation of both acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML) cells but unexpectedly, a new transdifferentiation pathway from APL cells to morphologically and immunologically normal megakaryocytes and platelets were discovered. SN3-L6 fails to induce transdifferentiation of ATRA–produced mature granulocytes into megakaryocytes, indicating its selectivity between mature and immature cells. SN3-L6 induces CML K562 cells to transdifferentiate into apoptotic megakaryocytes but without platelet formation, indicating a desirable selectivity between different leukemia cells. Our data illuminate a differentiation gap between AML cells and platelets, and promises applications in leukemia differentiation therapy strategy.

Dimeric γ-lactone derivatives from the soil-derived fungus Lasiodiplodia theobromae NSTRU-PN1.4

Investigation of the soil-derived fungus Lasiodiplodia theobromae NSTRU-PN1.4 resulted in the isolation of five dimeric γ-lactones including two new botryosphaerilactones D and E (4 and 5) and three known structurally related analogoues (1–3) along with seven known compounds. Their structures were elucidated by extensive spectroscopic analysis. The absolute configuration of 1–5 was determined by comparison of the ECD data with those of the structurally related monomeric γ-lactones. For biological evaluation, this is the first report on antifungal activity of the known (3 R,4R)-4-acetyl-3-methyl-2(3H)-dihydrofuranone which displayed weak antifungal activity against Cryptococcus neoformans with an MIC value of 200 µg/mL.

Dimer Indolizine Derivatives of Quaternary Salt Corrosion Inhibitors: Enlightened High-Effective Choice for Corrosion Prevention of Steel in Acidizing

Summary For decades, increasingly severe downhole conditions call for superior and less-expensive corrosion inhibitors (CIs) for acidizing in petroleum production. Inhibitors that exhibit satisfactory protective ability at relatively low concentration are of great interest to most scholars in this area. In this work, two newly obtained dimer indolizine derivatives that were derived from the conventional quaternary quinolinium salts were introduced as potential highly efficient acidizing CIs. The indolizine derivatives could perform well alone, even without any synergistic component, in concentrated hydrochloric acid (HCl). Two quinoline ammonium salts, ethyl acetate quinolinium chloride (EAQC) and n-butyl quinolinium chloride (BuQC), were synthesized in advance by means of the quaternarization process. Afterward, in the presence of alkali, the ammonium salts could then get converted into the corresponding novel dimer indolizine derivatives easily by means of a 1,3-dipolar cycloaddition reaction in a relatively high yield. The derivatives were purified and their accurate chemical structures were confirmed by elementary analysis, nuclear magnetic resonance (NMR), and mass spectrometry (MS). Dimer derivatives of two quinoline salts were prepared successfully and characterized separately as C26H23N2O4Cl and C26H27N2Cl. Corrosion-inhibition performance of the quaternary quinoline salts as well as the related dimer indolizine derivatives in concentrated HCl for N80 steel was investigated by gravimetric research, electrochemical method, and scanning electron microscopy (SEM) energy dispersive X-ray analysis. The thermodynamic aspect of the inhibition was also discussed. The structure of EAQC and BuQC are very close to the quinolinium salt inhibitors that are commonly used as key components in commercially accessible acid CI products. However, under alkaline condition, EAQC and BuQC would easily be transformed to dimer indolizine derivatives that possess a general “indolizine” structure. That is the reason why the targeted molecules are recognized as “dimer indolizine derivatives.” Both the derivatives have good thermal stability at approximately 248°F and are easily soluble in acid solution. The surprising difference in the anticorrosion effect between the original quinoline salts and their dimer derivatives was proved by weight-loss experiments in 15 wt% HCl at 194 and 248°F with dosage ranges from 0.01 to 0.5 wt%. The derivatives could retard the corrosion of steel considerably at a much lower concentration compared with their precursors. A 0.1-wt% dosage of indolizine derivatives could increase the inhibition efficiency (IE) of N80 steel remarkably, to approximately 99.0% in 15 wt% HCl at 194°F. Results obtained from gravimetric tests and electrochemical methods are in good agreement and confirmed the well-behaved inhibition of the derivatives. We predict that the inhibition will be enhanced apparently when similar quinoline or pyridine ammonium salt are converted via the similar 1,3-dipolar cycloaddition mechanism. We have determined that the use of dimer indolizine derivatives provides a creative new choice for low-cost corrosion prevention, and the protective compounds can be applied as main component of acidizing CIs in the coming years.

Bivalent HIV-1 fusion inhibitors based on peptidomimetics

Membrane fusion is a valid target for inhibition of HIV-1 replication. A 34-mer fragment peptide (C34), which is contained in the HIV-1 envelope protein gp41, has significant anti-HIV activity. Previously, a dimeric derivative of C34 linked by a disulfide bridge at its C-terminus was found to have more potent anti-HIV activity than the C34 peptide monomer. To date, several peptidomimetic small inhibitors have been reported, but most have lower potency than peptide derivatives related to C34. In the present study we applied this dimerization concept to these peptidomimetic small inhibitors and designed several bivalent peptidomimetic HIV-1 fusion inhibitors. The importance of the length of linkers crosslinking two peptidomimetic compounds was demonstrated and several potent bivalent inhibitors containing tethered peptidomimetics were produced.

Catalysis for Fine Chemicals

2′-Methoxyacetophenone (2M) presents improved UVA absorption as compared with other acetophenone derivatives. On the basis of transient infrared spectroscopy it has been previously claimed that 2M is an interesting photosensitiser for cyclobutane pyrimidine dimers (CPDs) formation. In the present paper, a complete UV–Vis transient absorption spectroscopic characterisation of this compound is provided, including triplet-triplet spectra, triplet lifetimes and rate constants for quenching of 2M by a dimeric thymine derivative. Furthermore, generation of singlet oxygen has been proven by time-resolved near IR phosphorescence measurements. Overall, the obtained results confirm the potential of 2M as a DNA photosensitiser, not only for CPDs formation, but also for oxidative damage.

Synthesis and characterization of single-bond fullerene dimer derivatives

Abstract

Regioselective Biomimetic Synthesis of Dimeric Oxyresveratrol Derivatives

AbstractOxyresveratrol and its methylated derivative as coupling precursors were efficiently prepared in four steps, with Wittig reactions and subsequent isomerization reactions as the key steps. The coupling reactions of oxyresveratrol under various oxidative conditions gave a complex and inseparable mixture of coupling products. The oxidative dimerizations of methylated oxyresveratrols catalyzed by horseradish peroxidase–H2O2 or FeCl3·6H2O in an acetone system predominantly produced the 8–5-coupled and 8–10-coupled dihydrobenzofuran-type dimers, respectively. This regioselective biomimetic strategy might be useful in synthesizing other dimeric oxyresveratrol derivatives.

Side‐chain engineering of perylene diimide dimers: Impact on morphology and photovoltaic performance

AbstractMorphology evolution of conjugated organic molecular materials in the solid state has important implications for optoelectronic applications. Two aspects that have a large impact on materials self‐assembly in the film are the nature of the side‐chains and the processing conditions. Films of N‐annulated perylene diimide (PDI) dimer derivatives with different side‐chains at the pyrrolic and imide N‐positions are herein studied after solution processing using the solvent additives 1,8‐diiodooctane (DIO) or diphenyl ether (DPE). Branched or cyclohexyl side‐chains are investigated at the imide position (compounds 1 vs. 2) while linear, cyclic or branched alkyl side‐chains are investigated at the pyrrolic position (compounds 1 vs. 3 vs. 4). Film morphology of the four materials were examined using polarized light, fluorescence, and atomic force microscopy (POM, FM, and AFM, respectively). Organic photovoltaic (OPV) devices using the donor polymer PTB7‐Th with each PDI dimer as a non‐fullerene acceptor (NFA) were fabricated and tested to correlate morphology to electronic performances. Cyclohexyl side‐chains at the imide position reduced PDI dimer (2) solubility, gave flower like crystals in the film, and overall poor OPV performance regardless of processing. Cyclic alkyl side‐chains at the pyrrolic position impeded PDI dimer (3) crystallization and lead to moderate OPV performance. A combination of branched and linear side‐chains on the PDI dimer (compounds 1 and 4) provided sufficient solubility in non‐halogenated solvents and best OPV performance without the use of processing additives. For 1 with linear side‐chains at the pyrrolic position, processing with additives lead to moderate crystallization and improved OPV performance. For 4 with branched‐side chains, processing with additives lead to major crystallization and poor OPV performance. Side‐chain engineering is critical for controlling the self‐assembly of N‐annulated PDI dimers and it was shown that the choice and volume of processing additive must be evaluated systematically for maximizing electronic performance.

Insight into Medicinal Chemistry Behind Traditional Chinese Medicines: p-Hydroxybenzyl Alcohol-Derived Dimers and Trimers from Gastrodia elata

From an aqueous extract of “tian ma” (the steamed and dried rhizomes of Gastrodia elata), ten new compounds gastrodibenzins A−D (1−4) and gastrotribenzins A−F (5−10), along with known analogues (11−20), having structure features coupling between two and three p-hydroxybenzyl-derived units via carbon- and/or ether-bonds, were isolated and characterized by spectroscopic data analysis. Meanwhile, the new compounds 5a, 6a, 8a, 22, and 23, as well as the known derivatives 13a, 14a, 15, 17−21, 24, 25, and p-hydroxybenzyl aldehyde were isolated and identified from a refluxed aqueous solution of p-hydroxybenzyl alcohol. Methylation of 5a and 6a in methanol and ethylation of 6a, 8a, 13a, and 14a in ethanol produced 5 and 6 and 7, 8, 13, and 14, respectively. using ultra-performance liquid chromatography high-resolution electrospray ionization mass spectrometry (UPLC-HRESIMS) analysis of the refluxed solutions of p-hydroxybenzyl alcohol and the refluxed extracts of the fresh G. elata rhizome and “tian ma” extracts indicated consistent production and variation of the dimeric and trimeric derivatives of p-hydroxybenzyl alcohol upon extracting solvents and refluxing time. In various assays, the dimeric and trimeric derivatives showed more potent activities than p-hydroxybenzyl alcohol itself and gastrodin, which are the main known active constituents of “tian ma”. These results revealed for the first time that the more effective dimers and trimers can be produced through condensation of the co-occurring p-hydroxybenzyl alcohol during processing and decocting of the G. elata rhizomes, demonstrating insights into medicinal chemistry behind application protocols of traditional Chinese medicines.Graphic

Dehydrodieugenol improved lung inflammation in an asthma model by inhibiting the STAT3/SOCS3 and MAPK pathways

BackgroundEugenol, a common phenylpropanoid derivative found in different plant species, has well-described anti-inflammatory effects associated with the development of occupational hypersensitive asthma. Dehydrodieugenol, a dimeric eugenol derivative, exhibits anti-inflammatory and antioxidant activities and can be found in the Brazilian plant species Nectandra leucantha (Lauraceae). The biological effects of dehydrodieugenol on lung inflammation remain unclear. PurposeThis study aimed to investigate the effects of eugenol and dehydrodieugenol isolated from N. leucantha in an experimental model of asthma. MethodsIn the present work, the toxic effects of eugenol and dehydrodieugenol on RAW 264.7 cells and their oxidant and inflammatory effects before lipopolysaccharide (LPS) exposure were tested. Then, male BALB/c mice were sensitized with ovalbumin through a 29-day protocol and treated with vehicle, eugenol, dehydrodieugenol or dexamethasone for eight days beginning on the 22nd day until the end of the protocol. Lung function; the inflammatory profile; and the protein expression of ERK1/2, JNK, p38, VAChT, STAT3, and SOCS3 in the lung were evaluated by immunoblotting. ResultsEugenol and dehydrodieugenol were nontoxic to cells. Both compounds inhibited NO release and the gene expression of IL-1β and IL-6 in LPS-stimulated RAW 264.7 cells. In OVA-sensitized animals, dehydrodieugenol reduced lung inflammatory cell numbers and the lung concentrations of IL-4, IL-13, IL-17, and IL-10. These anti-inflammatory effects were associated with inhibition of the JNK, p38 and ERK1/2, VAChT and STAT3/SOCS3 pathways. Moreover, treatment with dehydrodieugenol effectively attenuated airway hyperresponsiveness. Conclusion: The obtained data demonstrate, for the first time, that dehydrodieugenol was more effective than eugenol in counteracting allergic airway inflammation in mice, especially its inhibition of the JNK, p38 and ERK1/2, components of MAPK pathway. Therefore, dehydrodieugenol can be considered a prototype for the development of new and effective agents for the treatment of asthmatic patients.

Dimeric hexylitaconic acids from the marine-derived fungus Aspergillus welwitschiae CUGBMF180262

In the course of our efforts to search new secondary metabolites from marine-derived fungi, one new hexylitaconic acid derivative, 3-(5-methoxycarbonylpentyl)-4-methylfuran-2,5-dione (1), and two dimeric analogues asperwelwinates A and B (2 and 3), together with ten known compounds, asperitaconic acid C (4), kotanin (5) and orlandin (6), desertorin B (7), fonsecinone A (8), aurasperone A (9), asperpyrones B and C (10 and 11), aspernigrin B (12), and pyrophen (13), were isolated from a strain of Aspergillus welwitschiae CUGBMF180262. The structures of compounds 1–3 were determined by detailed analysis of HRMS, and 1D/2D NMR experiments, while the absolute configurations of 2 and 3 were determined by comparison of experimental and calculated electronic circular dichroism spectra. 2 and 3 were first reported dimeric hexylitaconic acid derivatives. Compounds 8, 9 and 11 showed moderate antibacterial activities against Helicobacter pylori with minimum inhibitory concentration (MIC) values of 16 μg/mL.