isopropyl ester
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Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2110
Author(s):  
Ewelina Świątek ◽  
Paula Ossowicz-Rupniewska ◽  
Ewa Janus ◽  
Anna Nowak ◽  
Peter Sobolewski ◽  
...  

The paper presents the synthesis, full identification, and characterization of new salts-L-proline alkyl ester naproxenates [ProOR][NAP], where R was a chain from ethyl to butyl (including isopropyl). All obtained compounds were characterized by Nuclear Magnetic Resonance (NMR), Fourier transform infrared spectroscopy (FTIR), X-ray powder diffractometry (XRD), and in vitro dissolution studies. The specific rotation, phase transition temperatures (melting point), and thermal stability were also determined. In addition, their lipophilicity, permeability, and accumulation in pigskin were determined. Finally, toxicity against mouse L929 fibroblast cells was tested. The obtained naproxen derivatives showed improved solubility and higher absorption of drug molecules by biological membranes. Their lipophilicity was lower and increased with the increase in the alkyl chain of the ester. The derivative with isopropyl ester had the best permeability through pigskin. The use of L-proline isopropyl ester naproxenate increased the permeation of naproxen through the skin almost four-fold. It was also shown that the increase in permeability is not associated with additional risk: all compounds had a similar effect on cell viability as the parent naproxen.


Animals ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 3311
Author(s):  
Yuchao Zhao ◽  
Md Sazzadur Rahman ◽  
Mengmeng Li ◽  
Guangyong Zhao

The objective of the experiment was to investigate the effects of dietary supplementation with 2-hydroxy-4-(methylthio)-butanoic acid isopropyl ester (HMBi) on the nitrogen (N) metabolism in beef steers. The plasma metabolites analyzed by metabolome profiling were used to clarify the impact mechanism. Three Simmental steers (body weight, 593 ± 23 kg) were used as experimental animals. Three levels of HMBi (i.e., 0, 12, and 24 g d−1) were added in a basal ration as experimental treatments. The steers and the dietary treatments were randomly allocated in a 3 × 3 Latin square design. The results showed that supplementing HMBi up to 24 g d−1 did not affect the N retention and N retention rate (NRR), and the fecal N/urinary N ratio even though it tended to linearly increase the uric acid N/urinary N ratio in steers. The results of plasma metabolome profiling showed that supplementing HMBi at 24 g d−1 upregulated the plasma concentrations of L-methionine (Met); Met-related metabolites including betaine, Met sulfoxide, and taurine; and L-isoleucine and tyrosine, whereas it downregulated L-serine, glycine, diaminopimelic acid, and other metabolites. The reason for the nonsignificant effect of HMBi on improving the N utilization in steers could be that the steers used in the experiment were in the fattening period. It is suggested to evaluate the effects of the dietary addition of HMBi using growing cattle in further research.


Polymers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 3801
Author(s):  
Sherif M. El-Kadi ◽  
Mohssen Elbagory ◽  
Hassan A. H. EL-Zawawy ◽  
Hossam F. A. EL-Shaer ◽  
Adel A. Shoukry ◽  
...  

Thirty bacterial isolates were tested on three different media for Poly-ß-hydroxybutyrate (PHB) production. The best bacterial isolates for producing PHB were screened and identified based on molecular biology; then, using three different alternative carbon sources (dried whey, sugar beet molasses and date molasses), physical properties were evaluated by Infrared (IR) spectrometry and Gas chromatography–mass spectrometry (GC-MS/MS) analysis. Our results showed that the best isolates identified based on molecular biology were Bacillus paramycoides MCCC 1A04098, Azotobacter salinestris NBRC 102611 and Brevundimonas naejangsanensis BIO-TAS2-2. The addition of sugar beet molasses to the medium of A. salinestris increased the cell dry weight (CDW), PHB concentration, PHB% and conversion coefficient (4.97 g/L, 1.56 g/L, 31.38% and 23.92%, respectively). The correlation coefficient values between PHB g/L and CDW g/L varied between very strong and moderate positive correlation. IR of the produced PHB from B. paramycoides and A. salinestris showed similar bands which confirmed the presence of PHB; however, B. naejangsanensis showed weak bands, indicating lower PHB concentration. The chemical composition obtained showed that the GC-MS of the PHB extracted represents 2, 4-ditert-butylphenol for B. paramycoides and isopropyl ester of 2-butenoic acid for both of A. salinestris and Brevundimonas naejangsanensis. Therefore, PHB produced by microorganisms can be considered a biodegradable polyester, and represents a promising technique for the development of eco-friendly and fully biodegradable plastics.


Author(s):  
Zhuowei Shen ◽  
Haihong Hu ◽  
Jie Pan ◽  
Mingcheng Xu ◽  
Fengting Ou ◽  
...  

Abstract Objectives 6-Hydroxykynurenic acid (6-HKA) is an organic acid component in extracts of Ginkgo biloba leaves and acts as a major contributor to neurorestorative effects, while its oral bioavailability was low. Therefore, using prodrug method to improve the bioavailability and brain content of 6-HKA is significant. Methods Three structural modified compounds of 6-HKA were synthesized, and ultra performance liquid chromatography-tandem mass spectrometry methods for quantification of these structural modified compounds in rat plasma and rat brain homogenate were established and comprehensively validated. The methods were effectively applied to investigate the effects of structural modification on apparent permeability coefficients in cells, the pharmacokinetics and the brain distribution in rats. Key findings The results illustrated that esterification can greatly improve the apparent permeability coefficient and bioavailability of 6-HKA. Comparing with direct oral administration of 6-HKA, the bioavailability of isopropyl ester was greatly improved (from 3.96 ± 1.45% to 41.8 ± 15.3%), and the contents of 6-HKA in rat brains (49.7 ± 9.2 ng/g brain) were significantly higher after oral administration. Conclusions The bioavailability and the brain content of 6-HKA can be improved by the prodrug method. Among three structural modified compounds, isopropyl-esterified 6-HKA was the most promising treatment.


Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1357
Author(s):  
Matthijs J. van Haren ◽  
Yongzhi Gao ◽  
Ned Buijs ◽  
Roberto Campagna ◽  
Davide Sartini ◽  
...  

A recently discovered bisubstrate inhibitor of Nicotinamide N-methyltransferase (NNMT) was found to be highly potent in biochemical assays with a single digit nanomolar IC50 value but lacking in cellular activity. We, here, report a prodrug strategy designed to translate the observed potent biochemical inhibitory activity of this inhibitor into strong cellular activity. This prodrug strategy relies on the temporary protection of the amine and carboxylic acid moieties of the highly polar amino acid side chain present in the bisubstrate inhibitor. The modification of the carboxylic acid into a range of esters in the absence or presence of a trimethyl-lock (TML) amine protecting group yielded a range of candidate prodrugs. Based on the stability in an aqueous buffer, and the confirmed esterase-dependent conversion to the parent compound, the isopropyl ester was selected as the preferred acid prodrug. The isopropyl ester and isopropyl ester-TML prodrugs exhibit improved cell permeability, which also translates to significantly enhanced cellular activity as established using assays designed to measure the enzymatic activity of NNMT in live cells.


2021 ◽  
Vol 45 (1) ◽  
Author(s):  
Olumuyiwa Moses Adeyemo ◽  
Mohammed Inuwa Ja’afaru ◽  
Feyisayo Victoria Adams

Abstract Background Actinomycetes are prolific producers of bioactive compounds which can be used to combat microbial infections. Microbial infections have resulted to increase in mortality and morbidity rates world-wide, especially in developing nations. This study was carried out to isolate and identify actinomycetes with potentials of synthesizing bioactive compounds, to produce and partially purify antimicrobial extracts, to characterize bioactive compounds in the extracts, to assess their antibacterial activity and to profile other biological properties of the bioactive compounds synthesized by the actinomycetes. Results Streptomyces sp. SUI (MT584797), Streptomyces sp. SW72IV (MT584818) and Streptomyces sp. SW72VII (MT584816) were isolated and identified. Ultraviolet–visible spectra absorption ranged between 241 and 251 nm wavelengths showing the polyene or chromone and unsaturation nature of the natural compounds. Infrared (IR) spectra indicated functional groups such as hydroxyl, aliphatic bromo, carbonyls, esters, carboxylic acids and silicon oxy compounds in the compounds produced by the three strains. Gas Chromatography-Mass Spectrum (GC–MS) identified elaidic acid isopropyl ester (32.11%), Octadec-9-enoic acid (17.44%) and 2, 3-dihydroxyl elaidate (10%) to be mostly produced by Streptomyces sp. SUI, Streptomyces sp. SW72IV and Streptomyces sp. SW72VII respectively. The three strains exhibited antimicrobial activity against Bacillus sp. Pseudomonas aeruginosa ATCC 9077, Staphylococcus aureus ATCC 700699, Candida albicans and Aspergilus flavus. Conclusion The results showed that the three strains of Streptomyces could be sources of antimicrobial bioactive compounds and other secondary metabolites that can be used in the production of pharmaceutical bioactive agents that are effective against pathogens, and production of biological materials that can be used in cosmetics and food industries.


Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1073
Author(s):  
Mark R. Hellmich ◽  
Celia Chao ◽  
Katalin Módis ◽  
Ye Ding ◽  
John R. Zatarain ◽  
...  

Upregulation of hydrogen sulfide (H2S) biosynthesis, at least in part related to the upregulation of cystathionine β-synthetase (CBS) in cancer cells, serves as a tumor-promoting factor and has emerged as a possible molecular target for antitumor drug development. To facilitate future clinical translation, we have synthesized a variety of novel CBS-targeting, esterase-cleavable prodrugs based on the structure of the prototypical CBS inhibitor aminooxyacetic acid (AOAA). The pharmacological properties of these compounds were evaluated in cell-free assays with recombinant human CBS protein, the human colon cancer cell line HCT116, and in vivo using various tumor-bearing mice models. The prodrug YD0251 (the isopropyl ester derivative of AOAA) was selected for detailed characterization. YD0251 exhibits improved antiproliferative efficacy in cell culture models when compared to AOAA. It is up to 18 times more potent than AOAA at suppressing HCT116 tumor growth in vivo and is effective when administered to tumor-bearing mice either via subcutaneous injection or oral gavage. Patient-derived xenografts (PDTXs) with higher levels of CBS protein grew significantly larger than tumors with lower levels, and YD0251 treatment inhibited the growth of PDTXs with elevated CBS, whereas it had no significant effect on PDTXs with low CBS protein levels. The toxicity of YD0251 was assessed in mice subjected to subchronic administration of supratherapeutic doses the inhibitor; no significant alteration in circulating markers of organ injury or histopathological alterations were noted, up to 60 mg/kg/day × 5 days. In preparation to a future theranostic concept (to match CBS inhibitor therapy to high-CBS expressors), we identified a potential plasma marker of CBS-expressing tumors. Colon cancer cells produced significant levels of lanthionine, a rare metabolic intermediate of CBS-mediated H2S biosynthesis; forced expression of CBS into non-transformed epithelial cells increased lanthionine biogenesis in vitro and in vivo (measured in the urine of tumor-bearing mice). These current results may be useful to facilitate the translation of a CBS inhibition-based antitumor concept into the clinical space.


2021 ◽  
Vol 22 (12) ◽  
pp. 6252
Author(s):  
Paula Ossowicz-Rupniewska ◽  
Rafał Rakoczy ◽  
Anna Nowak ◽  
Maciej Konopacki ◽  
Joanna Klebeko ◽  
...  

The potential of bacterial cellulose as a carrier for the transport of ibuprofen (a typical example of non-steroidal anti-inflammatory drugs) through the skin was investigated. Ibuprofen and its amino acid ester salts-loaded BC membranes were prepared through a simple methodology and characterized in terms of structure and morphology. Two salts of amino acid isopropyl esters were used in the research, namely L-valine isopropyl ester ibuprofenate ([ValOiPr][IBU]) and L-leucine isopropyl ester ibuprofenate ([LeuOiPr][IBU]). [LeuOiPr][IBU] is a new compound; therefore, it has been fully characterized and its identity confirmed. For all membranes obtained the surface morphology, tensile mechanical properties, active compound dissolution assays, and permeation and skin accumulation studies of API (active pharmaceutical ingredient) were determined. The obtained membranes were very homogeneous. In vitro diffusion studies with Franz cells were conducted using pig epidermal membranes, and showed that the incorporation of ibuprofen in BC membranes provided lower permeation rates to those obtained with amino acids ester salts of ibuprofen. This release profile together with the ease of application and the simple preparation and assembly of the drug-loaded membranes indicates the enormous potentialities of using BC membranes for transdermal application of ibuprofen in the form of amino acid ester salts.


2021 ◽  
Vol 33 (2) ◽  
pp. 126
Author(s):  
M. Ritz ◽  
A. Gonzalez ◽  
A.-S. Fries ◽  
T. Scheu ◽  
N. Blad-Stahl ◽  
...  

Supplementation of rumen-protected amino acids (RPAA) has proven to be an effective tool to supply limiting AA in dairy diets. Methionine and lysine are the two most limiting AA for lactating dairy cows. Recently, it has been shown that methionine supplementation seems to affect pre-implantation embryos collected from superovulated cows enhancing their developmental competence because there is strong evidence that endogenous lipid reserves serve as an energy substrate (Acosta et al. 2016 Theriogenology 85, 1669–1679). Moreover, higher concentrations of methionine were determined in the follicular fluid of the first dominant follicle postpartum in cows supplemented with rumen-protected methionine and rumen-protected choline from 21 days before calving to 30 days postpartum and it was assumed that higher methionine concentrations in the follicular fluid could affect oocyte quality (Acosta et al. 2017 Theriogenology 96, 1–9). There is no information available so far regarding the effect of a combined methionine and lysine supplementation (each rumen-protected) on oocyte quality. Therefore, the objective of this study was to evaluate the effect of a combined methionine and lysine supplementation during early to mid-lactation on the developmental competence of oocytes collected from lactating dairy cows (days 0 to 100 p.p.). Thirty pregnant multiparous German Holstein dairy cows were grouped 3 weeks before their expected calving date, receiving identical diets. After calving, they were randomly allocated to 2 groups fed a total mixed ration supplemented with (N=14 cows; RPAA) or without (N=16 cows; CON) LysiGEMTM (encapsulated lysine; Kemin Industries) and Metasmart DryTM (isopropyl ester of the hydroxylated analogue of methionine adsorbed onto a silicon dioxide carrier; Adisseo). Starting from 45 days p.p., animals from both groups were submitted to an ovum pickup (OPU) session once a week for at least 8 weeks. Collected cumulus–oocyte complexes (COC) were subjected to a standard invitro production (IVP) protocol (Stinshoff et al. 2014 Reprod. Fertil. Dev. 26, 502–10) including IVM, IVF, and invitro culture (IVC). Cleavage and developmental rates up to the morula/blastocyst stage were recorded on Days 3, 7, and 8. In total, 1211 follicles have been aspirated from RPAA animals compared with 1413 from CON animals, from which 742 and 885 COC were collected, respectively. The calculated recovery rate based on the number of aspirated follicles and collected COC was similar for both groups (61.3±29.4% vs. 62.6±33.5%). Cleavage and developmental rates based on 240 (RPAA group) and 299 (CON group) COC also showed similar results [RPAA: 84.1±5.9% (202/240), 18.3±4.4% (44/240), 18.8±4.7% (45/240); CON: 81.9±8.6% (245/299), 15.4±8.9% (46/299), 16.7±8.4% (50/299)]. In conclusion, supplementation of RPAA (methionine and lysine) had no beneficial effect on the developmental competence of COC obtained from these animals compared with those collected from cows fed the diet without RPAA supplementation.


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