Methyl Ester Derivatives Research Articles

Chemoreversal Agents from Taiwanofungus Genus and Their More Potent Methyl Derivatives Targeting Signal Transducer and Activator of Transcription 3 (STAT3) Phosphorylation.

Multidrug resistance (MDR), for which the mechanisms are not yet fully clear, is one of the major obstacles to cancer treatment. In recent years, signal transducer and activator of transcription 3 (STAT3) were found to be one of the important MDR mechanism pathways. Based on the previous research, zhankuic acid A, B, and C were found to have collateral sensitivity effects on MDR cancer cells, and MDR inhibitory activity of zhankuic acid methyl ester was found to be better than that of its acid. Therefore, we executed a systematic examination of the structure–activity relationship of zhankuic acid methyl ester derivatives to collateral sensitivity in MDR cancer cells. The results showed that compound 12 is the best in terms of chemoreversal activity, where the reversal fold was 692, and the IC50 value of paclitaxel combined with 10 μM compound 12 treatment was 1.69 nM in MDR KBvin cells. Among all the derivatives, methyl ester compounds were found to be better than their acids, and a detailed discussion of the structure–activity relationships of all of the derivatives is provided in this work. In addition, compounds 8, 12, and 26 were shown to influence the activation of STAT3 in KBvin cells, accounting for part of their chemoreversal effects. Our results may provide a new combined therapy with paclitaxel to treat multidrug-resistant cancers and provide a new therapy option for patients.

Antibacterial activity and inhibition against Staphylococcus aureus NorA efflux pump by ferulic acid and its esterified derivatives

Objective: To evaluate the inhibitory activity of ferulic acid and four of its esterified derivatives (methyl, ethyl, propyl, and butyl) against resistance mechanisms in Staphylococcus aureus strains. Methods: Ferulic acid derivatives were obtained by esterification with methanol, ethanol, propanol, and butanol, and then characterized by hydrogen and carbon-13 nuclear magnetic resonance analysis. The minimum inhibitory concentrations (MIC) of ferulic acid and its esterified derivatives, ethidium bromide, and norfloxacin were obtained using the microdilution test, while the efflux pump inhibition test was conducted by examining reduction in the MICs of norfloxacin and ethidium bromide. Molecular docking was also carried out using the Schrodinger Suite 2015 molecular modeling software. A three-dimensional model of NorA efflux pump was generated using I-TASSER. The best scoring model was used as a receptor for ligand-receptor docking. Results: The methyl and butyl ester derivatives did not demonstrate significant antimicrobial activity. However, a significant synergic effect was evidenced when norfloxacin was combined with the ethyl and propyl esterified derivatives. The docking study demonstrated favorable energy of interaction between ferulate derivatives and NorA, and amino acid residues TYR57, TYR58, and LEU255 were present commonly in stabilizing all complexes. The PCA analysis corroborated the docking hypothesis that the lipophilic character and hydrogen bond interactions were the most relevant characteristics involved with NorA inhibitors. The pharmacokinetic parameters of ferulic acid derivatives showed good ADMET properties, demonstrating that they can be easily absorbed and have no effect or inhibit the cytochrome P450 enzyme complex, revealing their potential as drug candidates. Conclusions: This study provides strong evidence that the molecular basis for this activity is potentially due to the NorA efflux pump.

Six novel complexes based on 5-Acetoxy-1-(6-chloro-pyridin-2-yl)-1H-pyrazole-3-carboxylic acid methyl ester derivatives: Syntheses, crystal structures, and anti-cancer activity

Abstract A novel 5-Acetoxy-1-(6-chloropyridin-2-yl)-1H-pyrazole-3-carboxylic acid methyl ester derivatives Htcdodtta (1), and it’s five complexes, [Cu2(L1)2]·(CH3CN) (2), [Cu2(L2)1.63(L3)0.37]·(CH3OH)0.5 (3), [Cu2(L3)(L4)]·(C2H5OH)0.5·(CH3OH)0.5 (4), [Cu2(L4)(L5)]·(H2O) (5) and [Cu2(L1)1.18(L2)0.82] (6) have been synthesized. The Htcdodtta, HL1-HL5 were formed in-situ reaction. HL1-HL5 are homologues which possess two chiral carbons. Compounds 1–6 were characterized using single-crystal X-ray diffraction, IR, and elemental analysis. Compounds 2–6 are dinuclear copper complexes. The in vitro cytotoxicities of compounds 1–4 against a variety of cell lines were evaluated by MTT assays. Hela cancer cell apoptosis assay of 1 and 2 were examined by flow cytometry. The cell apoptosis in NP69, A549, Capan-2, Hela, HepG2, and HUVECs cell lines induced by compound 2 was further affirmed by cellular morphology observations.

Methanofullerene Synthesis via Photogenerated Fullerene Radical Anion Intermediates.

This work describes the synthesis of PCBM ([6,6]-phenyl-C61-butyric acid methyl ester) derivatives and other methanofullerene derivatives via generation of fullerene radical anions under photoirradiation and controlled by photoswitching, without preparation, a strong reducing agent, or precise control of the reaction conditions.

Azetidine-Bearing Non-Ribosomal Peptides, Bonnevillamides D and E, Isolated from a Carrion Beetle-Associated Actinomycete.

Two new nonribosomal peptides, bonnevillamides D and E (1 and 2), have been discovered in Streptomyces sp. UTZ13 isolated from the carrion beetle, Nicrophorus concolor. Combinational analysis of the UV, MS, and NMR spectroscopic data revealed that their planar structures were comprised of dichlorinated linear peptides containing nonproteinogenic amino acid residues, such as 4-methylazetidinecarboxylic acid and 4-O-acetyl-5-methylproline. The configurations of bonnevillamides D and E (1 and 2) were determined based on ROESY correlations, the advanced Marfey's method, phenylglycine methyl ester derivatization, molecular modeling, and circular dichroism spectroscopy. The nonribosomal peptide synthetase biosynthetic pathway of bonnevillamides D and E has been proposed using bioinformatic analysis of the whole-genome sequence data of Streptomyces sp. UTZ13. Their biological activity toward the aggregation of amyloid-β, which is one of the key pathogenic proteins in Alzheimer's disease, was evaluated using a thioflavin T assay and gel electrophoresis. Bonnevillamides D and E reversed the fibril formation by inducing the monomerization of amyloid-β aggregates.

Structure Determination, Biosynthetic Origin, and Total Synthesis of Akazaoxime, an Enteromycin-Class Metabolite from a Marine-Derived Actinomycete of the Genus Micromonospora.

A new enteromycin-class antibiotic, akazaoxime (1), possessing an aldoxime functionality in place of O-methyl nitronic acid, was isolated from the cultured extract of a marine-derived actinomycete of the genus Micromonospora, along with known A-76356 (2). The structure of 1, including the absolute stereochemistry of three chiral centers, was established by comprehensive analysis of nuclear magnetic resonance (NMR) and mass spectrometry data coupled with magnetic anisotropy analysis of its phenylglycine methyl ester derivatives. The stereochemistry of 2, not determined previously, was proven to be the same as that of 1 on the basis of the similarity of their NMR and specific rotation data. Precursor feeding experiments using 13C-labeled compounds elucidated that the carbon skeletons of 1 and 2 are constructed from propionate (methylmalonate), leucine, and glycine. Establishment of the concise and flexible synthetic route to 1 enabled us to implement biological evaluation of 1 and its unnatural analogues, demonstrating weak to moderate antimicrobial activities of 1 against Gram-positive Kocuria rhizophila [minimum inhibitory concentration (MIC) of 50 μg/mL] and those of synthetic analogues against a plant pathogen Glomerella cingulata (MIC of 50 μg/mL) and a human pathogen Trichophyton rubrum (MIC of 25-50 μg/mL).

Structure activity relationship of 3-nitro-2-(trifluoromethyl)-2H-chromene derivatives as P2Y6 receptor antagonists

Various 6-alkynyl analogues of a known 3-nitro-2-(trifluoromethyl)-2H-chromene antagonist 3 of the Gq-coupled P2Y6 receptor (P2Y6R) were synthesized using a Sonogashira reaction to replace a 6-iodo group. The analogues were tested in a functional assay consisting of inhibition of calcium mobilization in P2Y6R-expressing astrocytoma cells elicited by native P2Y6R agonist UDP. 6-Ethynyl and 6-cyano groups were installed, and the alkynes were extended through both alkyl and aryl spacers. The most potent antagonists, with IC50 of ~1 µM, were found to be trialkylsilyl-ethynyl 7 and 8 (3–5 fold greater affinity than reference 3), t-butyl prop-2-yn-1-ylcarbamate 14 and p-carboxyphenyl-ethynyl 16 derivatives, and 3 and 8 displayed surmountable antagonism of UDP-induced production of inositol phosphates. Other chain-extended terminal carboxylate derivatives were less potent than the corresponding methyl ester derivatives. Thus, the 6 position in this chromene series is suitable for derivatization with flexibility of substitution, even with sterically extended chains, without losing P2Y6R affinity. However, a 3-carboxylic acid or 3-ester substitution did not serve as a nitro bioisostere, as the affinity was eliminated. These compounds provide additional ligand tools for the underexplored P2Y6R, which is a target for inflammatory, neurodegenerative and metabolic diseases.

Exploring the antiplasmodal efficacy of erucic acid and its derivative isolated from Thlaspi arvense D. C. (Brassicaceae)

Traditional medicinal plants are cardinal sources of new drug molecules for malaria treatment. The present study evaluates the antiplasmodial potential of erucic acid (EA) isolated from ethanolic whole plant extract of Thlaspi arvense (EWETA) and its synthetic methyl ester derivative (EA-OMe) and also confirms the in vivo efficacy of the crude extract. EA and EA-OMe exhibited considerable in vitro activity against chloroquine (CQ)-sensitive (IC50 5.80 μg/ml and 6.25 μg/ml) and CQ-resistant (IC50 6.07 µg/ml and 8.58 µg/ml) strains of P. falciparum, respectively. Both compounds were non-toxic to HeLa cells and normal dermal fibroblasts with high selectivity index. However, EA and EA-OMe exhibited moderate suppressive activity in vivo. Further, EWETA illustrated ED50 <50 mg/kg in the suppressive test and prolonged the survival of treated mice in comparison to infected control. It also showed considerable preventive (500 mg/kg) and curative (100 mg/kg) activity with 91.75% and 91.93% chemo-suppression, respectively. Biochemical analysis also highlights the safety of EWETA to the liver and kidney function of the rodent host. It can be concluded that EA and EA-OMe are contributing to the activity of EWETA besides other components, which are being characterized.

Development and validation of a gas chromatography with a flame ionization detector method for quantitative analysis of four major fatty acids extracted shark liver oil

Context: The shark liver of the species Ginglimostoma cirratun, Carcharhinus longimanus, and Carcharhinus falciformis, captured in the north-central coast of Cuba are a source of oil, whose content of major fatty acids could be used in its quality control. Aims: To develop a simple and robust gas chromatography with a flame ionization detector (GC-FID) method that is suitable for routine analysis of four major fatty acids extracted shark liver oil. Methods: Four major fatty acid content in shark liver oil pool of species Ginglimostoma cirratun, Carcharhinus longimanus, and Carcharhinus falciformis, was analyzed through the gas chromatography with a GC-FID. The fatty acids were analyzed as methyl esters derivatives, using 5% aqueous sulfuric acid in methanol. The method was validated in terms of linearity, precision, accuracy, specificity and limit of detection and quantitation. Results: Under the optimum analytical conditions, the analysis revealed that each target component was well separated with satisfactory recoveries and reproducibility. The method linearity was found to be high with good determination coefficient values for all target components. The evaluation of the matrix effect, demonstrated, that there is not interference from substances other than analysis. The method was also found to be accurate, precise and reproducible and it was applied to the quantitative determination of the fatty acid content in shark liver oil pool; oleic acid was the most abundant fatty acid (22.69%), followed by palmitic (18.85%), stearic (6.01 %) and myristic acid (0.40 %). Conclusions: The GC-FID developed method is reliable and suitable for determination of four major fatty acids in shark liver oil pool.

A New Ent-Kaurane from the Roots of Lasianthaea aurea

A known kaurenoic acid (1), together with a new kaurane derivative named 3α-isobutyryloxykaurenoic acid (2), was isolated from the roots of Lasianthaea aurea, a plant endemic to Mexico. The compounds were characterized using their physical and spectroscopic data. In order to verify the structure and absolute configuration of 2, the derived methyl ester 3, obtained after diazomethane treatment, was subjected to single-crystal X-ray diffraction analysis, whose Flack and Hooft parameter calculations evidenced that the new natural product is an ent-kaurane derivative.

Synthesis of Tetrazole and 1,2,4-Oxadiazole Derivatives of Maleopimaric Acid Methyl Ester

New tetrazole derivatives were synthesized by 1,3-dipolar cycloaddition of azide ion to N-(2-cyano­ethyl) and N-(2-cyanoethoxy) imides obtained from maleopimaric acid methyl ester. Amidoximation of the same nitriles gave the corresponding amidoximes, and treatment of the latter with acetyl chloride gave analogous 1,2,4-oxadiazole derivatives.

Determination of some biochemical parameters from leaves of Quercus ilex L.(Fagaceae), collected in Djabel Zagouan (Tunisia)

Biochemical characterization, such as, fatty acids, essential oils composition, polyphenols content and antioxidant activities, were investigated from leaves, of Quercus ilex L.(Fagaceae), collected in DjabelZagouan (Tunisia). Only the fatty acid composition was determined by gas chromatography after transformation of the fatty acids into methyl ester derivatives compatible for injection in a Gas Chromatograph,and determined by gas chromatography (GC-FID). Essential oils were extracted by hydrodistillation and, analyzed by gas chromatography (GC-FID). Total phenolic content, concentration of flavonoids and, in vitro, antioxidant activities were determined, using spectrophotometric methods. The antioxidant activities was tested by the DPPH (2, 2-diphenyl-1-picrylhydrazyl), free radical scavenging assay. Results showed that total fatty acid content varied from 1.78 to 4.86%, based on dry weight (dw) and the predominants fatty acids were oleic acid (63.43–59.76%), linoleic acid (14.93–16.05%) and palmitic acid (9.16–12.13%). The oils contain, an appreciable, amount of unsaturated fatty acids (73.86–85.59%).This study showed that Holm oak leaves, are rich in an unusual fatty acid, the oleic one. The essential oil yield varied, from 0.01 to 0.04%. So the major components, in leaves oils from Quercus ilex L., were trans -2-hexanal (14.89–16.93%), viridiflorol (12.94–15.24%) and sabinene (6.84–9.65%).The total phenolic, content of the samples, varied, from 2.93 to 3.40 mg/g of dry weight, expressed as gallic acid equivalents. The total flavonoid concentrations varied, from 1.83 to 2.72 mg/g, of dry weight quercetin equivalents. The extracts of the leaves were observed displaying strong DPPH free radical scavenging action, with IC 50 value, ranged, from 102.66 to 134.83 µg/mL, comparing to the IC 50 value (48.31µg/mL), of reference standard. These results suggest that phenolics, in this species, provide substantial antioxidant activity and Quercus. Ilex L. may be a potential source of natural antioxidants.

Plakortinic acids C and D: A pair of peroxide-polyketides possessing a rare 7,8-dioxatricyclo[4.2.2.02,5]dec-9-ene core from a two-sponge association of Plakortis symbiotica–Xestospongia deweerdtae

Plakortinic acids C (3) and D (4), two unprecedented peroxide-polyketides with 7,8-dioxatricyclo[4.2.2.02,5]dec-9-ene scaffold, as well as known biogenetically related congeners, plakortinic acids A (1) and B (2), were isolated from a two-sponge association of Plakortis symbiotica–Xestospongia deweerdtae. Upon chemical derivatization, the structures and relative configurations of 3 and 4 were characterized by analysis of HRESIMS and NMR spectroscopic data, molecular modeling studies, and chiroptical comparisons with known natural products and published values of [α]D of related synthetic analogs. A mixture of methyl ester derivatives 5 and 6 displayed negligible cytotoxicity against a panel of 60 cell lines of various human cancers at a concentration of 10 μM.

Structures and Biosynthetic Pathway of Coprisamides C and D, 2-Alkenylcinnamic Acid-Containing Peptides from the Gut Bacterium of the Carrion Beetle Silpha perforata.

Coprisamides C and D (1 and 2) were isolated from a gut bacterium, Micromonospora sp. UTJ3, of the carrion beetle Silpha perforata. Based on the combined analysis of UV, MS, and NMR spectral data, the planar structures of 1 and 2 were elucidated to be unreported derivatives of coprisamides A and B, cyclic depsipeptides bearing a 2-alkenylcinnamic acid unit and the unusual amino acids β-methylaspartic acid and 2,3-diaminopropanoic acid. The absolute configuration of 1 was determined using the advanced Marfey's method, phenylglycine methyl ester derivatization, and J-based configuration analysis. The biosynthetic gene clusters for the coprisamides were investigated based on genomic data from coprisamide-producing strains Micromonospora sp. UTJ3 and Streptomyces sp. SNU533. Coprisamide C (1) was active against the Mycobacterium tuberculosis mc2 6230 strain.

Paratrimerins J-Y, Dimeric Coumarins Isolated from the Stems of Paramignya trimera.

Paratrimerins J-Y (1-13 and 16-18), new dimeric coumarins, were obtained from the EtOH(aq) extract of the stems of Paramignya trimera (Rutaceae) utilizing LC/MS guided isolation. The structures of the dimeric coumarins were elucidated based on 1D/2D NMR spectroscopic and HR-ESIMS data analyses. The absolute configurations of paratrimerins J-Y along with those of two known dimers paratrimerins A (14) and B (15) were established on the basis of the experimental and simulated ECD data. In addition, the absolute configurations of the sugar units of paratrimerins A, B, and J-V (1-15) were confirmed by LC/MS analysis on l-cysteine methyl ester and phenyl isothiocyanate derivatives. The variety of the absolute configurations of the dimeric diastereomers 1-15 highlighted a diversity in stereochemical outcomes following a Diels-Alder biosynthesis in P. trimera. With regard to P. trimera being a recently emerging medicinal resource for liver cancer, the dimers 1-18 were evaluated for cytotoxicity against a wide panel of human cancer cell lines. Paratrimerin W (16) was cytotoxic toward Huh7 hepatocellular carcinoma, HT1080 fibrosarcoma, and HT29 colorectal cancer cells with IC50 values of 14.9, 18.4, and 22.5 μM, respectively.

Phospholipid fatty acids from Colombian Caribbean sea sponges

Five demosponges belonging to the order Axinellida: Axinella corrugata, Dragmacidon alvarezae, Dragmacidon reticulatum, Ptilocaulis walpersi, Myrmekioderma rea and one sponge belonging to the order Scopalinida: Scopalina ruetzleri were analyzed to assess their fatty acid composition in the phospholipid fraction. Additionally, the seasonal and intraspecific variation in fatty acids composition was assessed in M. rea and D. alvarezae. Fatty acid identification was conducted using an HRGC-MS with an ECL value of methyl ester derivatives, and analyzing their mass spectra. To confirm double bound location, N-acylpyrrolidide derivatives were used studying their mass spectra. In total, 83 fatty acids were identified with chain lengths ranging from C14 to C32. Interestingly, brominated fatty acids were identified, previously suggested for sponges. Polybranched fatty acids such as 4,8,12-trimethyltridecanoic acid (4,8,12-TMTD) and 3,7,11,15-tetramethylhexadecanoic (phytanic acid) were found, without a clear distribution pattern. A predominance of iso-acids (i-15:0 and i-17:0) on anteiso acids were observed. Some seasonal variations in fatty acid (FA) compositions for M. rea and D. alvarezae were observed. The hierarchical Clusters Analysis (HCA) showed that the FA composition was species-specific but not informative at the family or order level.

Oleanolic acid indole derivatives as novel α-glucosidase inhibitors: Synthesis, biological evaluation, and mechanistic analysis

Research efforts have been directed to the development of oleanolic acid (OA) based α-glucosidase inhibitors and various OA derivatives showed improved anti-α-glucosidase activity. However, the inhibitory effects of indole infused OA derivatives on α-glucosidase is unknown. Herein, we synthesized a series of indole-OA (2a-2o) and -OA methyl ester (3a-3 l) derivatives with various electron withdrawing groups inducted to indole benzene ring and evaluated their anti-α-glucosidase activity. Indole OA derivatives (2a-2o) exhibited superior α-glucosidase inhibitory effects as compared to OA methyl ester derivatives (3a-3l) and OA (with IC50 values of 4.02 μM-5.30 μM v.s. over 10 μM and 5.52 µM, respectively). In addition, mechanistic studies using biochemical (kinetic assay), biophysical (circular dichroism), and computational (docking) methods revealed that OA-indole derivatives (2a and 2f) are mixed type of α-glucosidase inhibitors and their inhibitory effects were attributed to their capacity of forming the ligand-enzyme complex with α-glucosidase enzyme. Findings from this study support that OA indole derivatives are promising α-glucosidase inhibitors as a potential management of diabetes mellitus.

Virulence profiles of some Pseudomonas aeruginosa clinical isolates and their association with the suppression of Candida growth in polymicrobial infections.

Pseudomonas aeruginosa is an opportunistic pathogen that can cause a variety of diseases especially in the hospital environment. However, this pathogen also exhibits antimicrobial activity against Gram-positive bacteria and fungi. This study aimed to characterize different virulence factors, secreted metabolites and to study their role in the suppression of Candida growth. Fifteen P. aeruginosa isolates were tested for their anticandidal activity against 3 different Candida spp. by the cross-streak method. The effect on hyphae production was tested microscopically using light and scanning electron microscopy (SEM). Polymerase chain reaction was used in the detection of some virulence genes. Lipopolysaccharide profile was performed using SDS-polyacrylamide gel stained with silver. Fatty acids were analyzed by GC-MS as methyl ester derivatives. It was found that 5 P. aeruginosa isolates inhibited all tested Candida spp. (50-100% inhibition), one isolate inhibited C. glabrata only and 3 isolates showed no activity against the tested Candida spp. The P. aeruginosa isolates inhibiting all Candida spp. were positive for all virulence genes. GC-Ms analysis revealed that isolates with high anticandidal activity showed spectra for several compounds, each known for their antifungal activity in comparison to those with low or no anticandidal activity. Hence, clinical isolates of P. aeruginosa showed Candida species-specific interactions by different means, giving rise to the importance of studying microbial interaction in polymicrobial infections and their contribution to causing disease.

Evaluation of Lotions of Botanical-Based Repellents Against Aedes aegypti (Diptera: Culicidae).

Thirteen botanical product repellent compounds such as 2-undecanone, capric, lauric, coconut fatty acids (and their methyl ester derivatives), and catnip oil were formulated in either Coppertone or Aroma Land lotions and evaluated against laboratory-reared Aedes aegypti L. (Diptera: Culicidae) mosquitoes. These formulations contained 7-15 wt/wt of the botanical repellent as the major active ingredient either pure or as mixtures. USDA standard repellent test cages were used to determine the complete protection time (CPT) of the different formulated repellents. Two of the evaluated formulations, a 7% capric acid in Coppertone (CPT 2.7 ± 0.6 h) and 7% coconut fatty acids containing carrylic acid, capric acid, and lauric acid in Coppertone (CPT 2.3 ± 2.0 h), provided strong repellency against mosquitoes up to 3 h, which was equivalent to the (N,N-diethyl-m-toluamide) DEET control (CPT 2.7 ± 0.6 h). This work suggests future potential for these botanical product-based repellents as alternatives to commercial DEET-containing products.

Spectroscopic characterization of dipicolinic acid and its photoproducts as thymine photosensitizers.

Dipicolinic acid (DPA), present in large amount in bacterial spores, has been proposed to act as an endogenous photosensitizer in spore photoproduct formation. The proposed mechanism involves a triplet-triplet energy transfer from DPA to thymine. However, up to now, no spectroscopic studies have been performed to determine the interaction between the endogenous compound and the nucleobase, probably due to its photolability in aqueous solutions. Here, triplet excited state properties of DPA are reported together with its bimolecular quenching rate constant by thymidine, kq of ca. 5.3×109M-1s-1. To run more reliable studies, a stable methyl ester derivative of DPA, which exhibits the same spectroscopic properties as the parent compound, is also described. Finally, DPA photoproducts are characterized. Studies of their triplet excited state properties have demonstrated that, interestingly, one of them is able to photosensitize thymidine triplet excited state formation.