Acetate Groups Research Articles

Flavin-Catalyzed, Photochemical Conversion of Dehydroalanine into 4,5-Dihydroxynorvaline.

The chemical synthesis of unnatural amino acids (UAA) is a key strategy for preparing designed peptides, including pharmaceutically active compounds. Alterations of existing amino acid residues such as dehydroalanine (Dha) are particularly important since selected positions can be addressed without the necessity of a complete de novo synthesis. The intriguing UAA 4,5-dihydroxynorvaline (Dnv) is found in a variety of naturally occurring peptides and biologically active compounds. However, no method is currently available to modify an existing peptide with this residue. We report the use of flavin catalysts and visible light irradiation for this challenge, which serves as a versatile strategy for converting Dha into Dnv. Our study shows that excited flavins are competent hydrogen atom abstraction catalysts for ethers and acetals, which allows masked 1,2-dihydroxyethylene functionalization from 2,2-dimethyl-1,3-dioxolane. The masked diol was successfully coupled to Dha residues, and a series of Dnv-containing products is reported. A mild and orthogonal protocol for deprotection of the acetal group was also identified, allowing free Dnv-modified peptides to be obtained. This method provides a straightforward strategy for Dnv functionalization, which is envisioned to be crucial for accessing natural products and synthetic analogues with pharmaceutical activity.

Crop growth scenario-based pH/temperature dual-responsive degradable polyurea nano/microcapsules: Smart pesticide delivery and sustainable control of Fusarium crown rot in wheat

Designing smart pesticide delivery systems in response to the environmental factors of disease occurrence is critical to achieving targeted pesticide delivery, improving effective pesticide utilization and reducing environmental pollution. Herein, we prepared a novel chemically degradable pH/temperature dual-responsive polyurea capsule (Pyr@PU). The Pyr@PU was based on the diamine cross-linking agent 2,2-diethoxypropane (DAKT) containing acetal groups unstable to acids and isophorone diisocyanate (IPDI), and the phase change material methyl myristate (melting point: 18°C) was used as the oil phase. Owing to the acetal structure in the capsular shell and methyl myristate in the core, Pyr@PU has excellent acidic pH responsiveness and temperature sensitivity. 95.0 % of the fungicidewas released within 48 h at a weakly acidic condition (pH = 5.0), and the fungicide release rate at 35°C was 3.6 and 10.4 times higher than that at 25°C and 15°C, respectively. Bioactivity assays showed a longer duration of Pyr@PU compared to the commercial emulsion (Pyr EC). The degradation rate of Pyr@PU microcapsules (Pyr@PU-Micro) (64.5 %) was significantly lower than Pyr EC (98.6 %) after 24-h UV irradiation. In the 96-h acute toxicity test, Pyr@PU-Micro (LC50 = 0.695 mg·L−1) exhibited a lower toxicity to zebrafish than the Pyr (LC50 = 0.076 mg·L−1), Pyr EC (LC50 = 0.108 mg·L−1), and commercialized microcapsules (Pyr CS) (LC50 = 0.209 mg·L−1). In summary, the new chemically degradable polyurea microcapsules improved the stability and duration of fungicide efficacy and provided a new solution for the effective control of Fusarium crown rot and the reduction of environmental pollution caused by microplastics.

Effects of long-term high-dose medroxyprogesterone acetate use on bone mineral density in postmenopausal women

Aims: The aim of this study was to investigate the relationship between long-term depot medroxyprogesterone acetate (DMPA) use and bone mineral density (BMD) in postmenopausal women. Methods: This study was conducted on 40 postmenopausal women who presented at the SSK Okmeydanı Training and Research Hospital Gynecology and Obstetrics Polyclinic. The sample for the study was randomly selected from postmenopausal women and divided into the control group (N=20) and the medroxyprogesterone acetate group (N=19). Results: A total of 39 participants were included in this study, 19 cases and 20 controls. Long-term DMPA users had higher BMD compared with the control group. These differences from the control group were statistically and potentially clinically significant. The BMD in the control group has decreased significantly during one year of study. Based on the results, the longterm use of DMPA significantly affects the bone mineral density in postmenopausal women, increasing BMD. Conclusion: Long-term use of DMPA was associated with improved BMD after treatment. The findings demonstrate the need for long-term, controlled, prospective studies with adequate sample size to evaluate the potential clinical impact of DMPA use on bone health outcomes in postmenopausal women.

Synthesis and Bioevaluation of New Stable Derivatives of Chrysin-8-C-Glucoside That Modulate the Antioxidant Keap1/Nrf2/HO-1 Pathway in Human Macrophages

Background/Objectives: The beneficial effects of the flavonoid chrysin can be reduced by its poor oral bioavailability. It has been shown that chrysin-8-C-glucoside (1) has a better absorption capability. The aim of this study was to evaluate the antioxidant and anti-inflammatory activity of this glucoside, as well as the respective hexa-acetate derivative 1a and the hexa-ethyl carbonate derivative 1b since the inclusion of moieties in bioactive molecules may increase or modify their biological effects. Methods: THP-1 macrophages were used to determine the viability in the presence of chrysin derivatives, and non-cytotoxic concentrations were selected. Subsequently, lipopolysaccharide (LPS)-induced reactive oxygen species (ROS) production and inflammatory mediators were examined. The involvement of chrysin derivatives with the Keap1 and Nrf2 antioxidant system was determined by docking and Western blotting studies. Results: Our data demonstrated, for the first time, that pretreatment with the three compounds caused a significant reduction in LPS-induced reactive oxygen species (ROS) production and pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin 1β (IL-1β) levels, as well as in cyclooxygenase 2 (COX-2) expression. The mechanisms underlying these protective effects were related, at least in part, to the competitive molecular interactions of these phenolic compounds with Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2-related factor 2 (Nrf2), which would allow the dissociation of Nrf2 and its translocation into the nucleus and the subsequent up-regulation of hemo-oxygenase 1 (HO-1) expression. Conclusions: Compared to the 8-C-glucoside parent chrysin, compound 1a exhibited the strongest antioxidant and anti-inflammatory activity. We hypothesized that the incorporation of an acetate group (1a) may reduce its polarity and, thus, increase membrane permeability, leading to better pharmacological activity. These findings support the potential use of these phenolic compounds as Nrf2 activators against oxidative-stress-related inflammatory diseases.

Metabolomic Profiling and Network Toxicology: Mechanistic Insights into Effect of Gossypol Acetate Isomers in Uterine Fibroids and Liver Injury

Objective: Gossypol is a natural polyphenolic dialdehyde product that is primarily isolated from cottonseed. It is a racemized mixture of (−)-gossypol and (+)-gossypol that has anti-infection, antimalarial, antiviral, antifertility, antitumor and antioxidant activities, among others. Gossypol optical isomers have been reported to differ in their biological activities and toxic effects. Method: In this study, we performed a metabolomics analysis of rat serum using 1H-NMR technology to investigate gossypol optical isomers’ mechanism of action on uterine fibroids. Network toxicology was used to explore the mechanism of the liver injury caused by gossypol optical isomers. SD rats were randomly divided into a normal control group; model control group; a drug-positive group (compound gossypol acetate tablets); high-, medium- and low-dose (−)-gossypol acetate groups; and high-, medium- and low-dose (+)-gossypol acetate groups. Result: Serum metabolomics showed that gossypol optical isomers’ pharmacodynamic effect on rats’ uterine fibroids affected their lactic acid, cholesterol, leucine, alanine, glutamate, glutamine, arginine, proline, glucose, etc. According to network toxicology, the targets of the liver injury caused by gossypol optical isomers included HSP90AA1, SRC, MAPK1, AKT1, EGFR, BCL2, CASP3, etc. KEGG enrichment showed that the toxicity mechanism may be related to pathways active in cancer, such as the PPAR signaling pathway, glycolysis/glycolysis gluconeogenesis, Th17 cell differentiation, and 91 other closely related signaling pathways. Conclusions: (−)-gossypol acetate and (+)-gossypol acetate play positive roles in the treatment and prevention of uterine fibroids. Gossypol optical isomers cause liver damage through multiple targets and pathways.

5-Diethoxymethyl-1,1-diethoxy-5-hydroxyundeca-3,6-diyn-2-one

As an extension of our study of the reactivity of derivatives of 3,3,4,4-tetraethoxybut-1-yne, attempts have been made to achieve acid-catalyzed deacetalization of the diethoxymethyl moieties in 5-diethoxymethyl-1,1,2,2-tetraethoxyundeca-3,6-diyn-5-ol. That was not achieved; instead, only deketalization occurred and afforded the title compound, indicating that the triple bond activates the propargylic diethoxy moiety relative to the other acetal groups.

Protective effect of evodiamine on acetic acid-induced gastric ulcers in rats through regulation of ROS/ICAM1/Nrf2 signaling pathway

Purpose: To study the effect of evodiamine on the signaling pathway of ROS/ICAM-1/Nrf2 in rats with acetic acid-induced stomach ulcers. Methods: The rats were randomly assigned to five groups containing 10 rats each. Prior to acetic acidinduction of gastric ulcers, omeprazole (4.0 mg/kg/day), low-dose evodiamine (L-EVD, 20 mg/kg/day), and high-dose evodiamine (H-EVD, 40 mg/kg/day) were orally administered to the respective groups for 15 days. Following ulcer induction, the same treatments continued for an additional 7 days, for a total treatment duration of 22 days. The control (0.9 % saline) and acetic acid (model) groups were administered 0.9 % sodium chloride solution (10 mL/kg) for the same period. Thereafter, oxidative stress, inflammatory markers, macroscopic and microscopic evaluations were conducted on the gastric mucosa. Results: The acetic acid group showed significantly higher levels of oxidative and inflammatory markers, as well as damage and degeneration of the gastric mucosa when compared to control group (p < 0.05). However, both low-dose and high-dose evodiamine treatment groups demonstrated significant gastric healing. Administration of low-dose and high-dose evodiamine resulted in significantly lower levels of malondialdehyde (MDA), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), myeloperoxidase (MPO) and intracellular adhesion molecule-1 (ICAM-1, p < 0.05). Furthermore, evodiamine treatment led to significantly increased levels of glutathione (GSH) and nuclear facterythroid factor 2 (Nrf2). Conclusion: Evodiamine reduces oxidative stress, suppresses inflammatory reactions, and exerts an anti-ulcer effect on acetic acid-induced gastric ulcers in rats by modulating ROS/ ICAM-1/Nrf2 signaling pathway. More studies into the integration of evodiamine into conventional pharmaceutical treatments for gastric ulcers should be conducted.

Opuntia ficus-indica cladodes extract inhibits human neutrophil pro-inflammatory functions and protects rats from acetic acid-induced ulcerative colitis.

The increased production of reactive oxygen species (ROS) by human neutrophils can lead to oxidative imbalances and several diseases, such as inflammatory bowel disease (IBD). Opuntia ficus-indica (O. ficus-indica) is rich in bioactive substances with anti-inflammatory properties. This study aimed to identify the bioactive compounds present in aqueous cladodes extract (ACE) of O. ficus-indica using high-performance liquid chromatography (HPLC) and to test its effects on human neutrophil inflammatory functions and on ulcerative colitis (UC) induced by acetic acid (Aa) in rats. ROS production and degranulation by neutrophils were assessed by luminol-amplified chemiluminescence, enzymatic techniques, and western blotting. In vivo, the experiment involved seven groups of rats: a negative control group (NaCl), the acetic acid group (Aa), and groups treated with oral sulfasalazine (150mg/kg) or various doses of ACE for 7days. Colonic lesions were induced by an intra-rectal Aa injection, and inflammation was assessed. HPLC analysis identified gallic acid, catechin, caffeic acid, and ferulic acid as major compounds in ACE. In vitro, ACE inhibited neutrophil ROS production, including superoxide anion produced by NADPH oxidase, and significantly reduced myeloperoxidase activity and neutrophil degranulation. In vivo, ACE protected rats from Aa-induced histopathological damage of the colonic mucosa, significantly increased catalase, superoxide dismutase and reduced glutathione levels, and significantly suppressed the increases of plasma cytokines (TNF-α and IL-1β) observed in the Aa group. In conclusion, O. ficus-indica ACE has significant anti-inflammatory properties by restoring oxidative balance, indicating that it could be a potential source of therapeutic agents for inflammatory diseases, particularly UC.

5065 Cyproterone Acetate Versus Spironolactone In Transgender Women Commencing Estradiol: A Randomized Controlled Trial

Abstract Disclosure: L.M. Angus: Advisory Board Member; Self; Kirin Brewery. Speaker; Self; Kirin Brewery. S. Leemaqz: None. A. Kasielska-Trojan: None. M. Mikołajczyk: None. J. Doery: None. J.D. Zajac: None. A.S. Cheung: None. Background: Transgender women commonly use cyproterone acetate or spironolactone as anti-androgens with estradiol to assist with feminization. However, the optimal anti-androgen is unclear. We aimed to assess the effect of these anti-androgens on breast development and hypothesized that cyproterone acetate would result in greater breast development than spironolactone due to greater androgen receptor antagonism and suppression of serum total testosterone. Design: Double-blind, randomised controlled trial Methods: Transgender women newly commencing estradiol were randomized to spironolactone 100mg daily or cyproterone acetate 12.5mg daily for six months. The primary outcome was measurement of breast development via breast chest distance with secondary outcomes of estimated breast volume using the BreastIdea Volume Estimator application and serum total testosterone using LCMS. Results: Fifty-five participants were included in per protocol analysis (cyproterone acetate group n=28, spironolactone group n=27). Baseline age, body mass index, breast indices, serum estradiol and serum total testosterone were comparable. At six months, the mean (standard deviation) breast chest distance was 9.2cm (3.0) in the cyproterone group versus 8.3cm (2.7) in the spironolactone group (p=0.27). The mean (SD) estimated breast volume was 190.25 mL (158.60) in the cyproterone acetate group and 157.84mL (112.03) in the spironolactone group (p=0.39) with significant inter-individual variation (range 20.27 - 787.77 mL). The mean (SD) serum total testosterone was 1.48 nmol/L (3.45) in the cyproterone acetate group and 4.29 nmol/L (5.44) in the spironolactone group (p=0.04). Serum estradiol levels were comparable. Use of cyproterone acetate was associated with mild hyperprolactinaemia and spironolactone with an increase in serum urea and creatinine. Conclusions: Choice of anti-androgen should be individualised based on clinician and patient preference, with consideration of associated side effects. Further research is needed to optimise breast development in transgender women. Presentation: 6/3/2024

Dynamics of Lanthanide(III) complexes from crystallographic data and computational studies

In this study we take advantage of the large body of X-ray data reported for lanthanide complexes, as well as their similar coordination chemistry properties, to gain insight on the dynamic processes involving λ ↔ δ configurational changes leading to isomer interconversion. The analysis of X-ray data reveals that different donor groups are characterized by Gaussian distributions of the dihedral N–C–X–Y angles ϕ. In the case of ethylenediamine groups (X = C; Y = N) Gaussian distributions are very narrow, while acetates (X = C; Y = O) provide very broad distributions. The analysis of the potential energy surfaces (PESs) using DFT reveals that ethylenediamine groups are characterised by well-defined deep energy minima, while those of acetate groups are rather swallow. Other donor groups like acetamide, pyridine or phosphinate show intermediate Gaussian distributions with respect to ethylenediamine and acetates. The PESs were fitted to a potential incorporating quadratic, cubic and quartic terms. The quadratic force constants k11 obtained for the different donor types follow the trend of the full width at half maxima (FWHM) of Gaussian distributions obtained from X-ray data. The k11 values are very similar for a given donor group, while the anharmonic cubic (k111) and quartic (k1111) force constants vary significantly depending on the environment of the donor group. Overall, this work demonstrates that the analysis of X-ray crystallographic data in lanthanide complexes can provide very useful information on their coordination chemistry preferences and dynamic processes.

Synthesis, Characterization, Crystal structure determination and DFT study of a six coordinated Cu (II) complex of a phosphorous based tris-(2-pyridinylamino) phosphene sulphide ligand and its acid catalysed hydrolysis

One mono nuclear copper(II) complex (Cu-TPPS-OOCCH3 with structural formula C17H19CuN6O3PS) is synthesized using a novel tripodal tetradentate ligand, tris-(2-pyridinylamino)phosphene sulphide (TPPS), which has three pyridinylamino groups attached to a phosphorus atom connected to a sulphur atom (PS). The equatorial positions of the complex are occupied by three amino N-atoms of three aminopyridyl groups and one O-atom of the acetate group. The apical position is occupied by other O-atom of acetate group and one secondary N-atom of the tripodal ligand. The complex has been synthesized and purified as green solid and characterized by various spectroscopic techniques and the structure has been determined by X-ray single crystal diffraction study. The geometry optimizations and calculations of energies of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) of the compounds are performed by using the hybrid B3LYP density functional theory (DFT) along with the def2TZVP basis set.

How does the integration of amino acids enhance the bonding ability of triazine-based inhibitors with iron surfaces: Insights from SCC-DFTB, COSMO-RS and molecular dynamics simulations

Theoretical investigations into the adsorption of molecules on metal surfaces play a pivotal role in the development of more efficient corrosion inhibitors. This study offers a novel approach by combining Density Functional Tight Binding (DFTB), Molecular Dynamics (MD) simulations, and conductor-like screening model for realistic solvation (COSMO-RS) calculations to comprehensively assess the interaction and diffusion properties of glycine (Gly), 2,2′-azanediyldiacetic acid (IDA), and 5-aminopentanoic acid (5-APA) with two 1,3,5-triazine (Tris) derivatives (Tris-Gly and Tris-IDA) for corrosion protection of carbon steel in acidic medium. The solvation properties of these molecules were evaluated alongside their interaction strength with the Fe(1 1 0) surface, considering both neutral and protonated forms. DFTB simulations revealed a clear trend in interaction energies, following the order: Tris-IDA > Tris-Gly > 5-APA > IDA > Gly. It ranges from −1.191 eV to −1.853 eV, with the highest stability observed for protonated Tris-IDA (−1.853 eV), while neutral Glycine exhibits the lowest interaction energy (−1.263 eV). While these theoretical results diverged slightly from experimental observations, with Tris-Gly outperforming Tris-IDA, this discrepancy was attributed to steric effects and solvent interactions. The DFTB results also indicated strong covalent interactions, particularly involving acetic groups, between the inhibitors’ orbitals and the iron’s 3d orbitals. MD simulations further demonstrated the impact of protonation on inhibitor mobility, with reduced diffusion coefficients due to enhanced electrostatic interactions and hydrogen bonding. COSMO-RS solvation analysis confirmed the strong hydrogen bonding capabilities of these molecules with water. Overall, this study elucidates the mechanisms of corrosion inhibition by integrating multiple simulation techniques, providing key molecular insights that can guide the design of more effective corrosion inhibitors. The findings emphasize the significance of electronic interactions and molecular structure in enhancing inhibitor performance, making this a valuable contribution to corrosion science.

Flavin‐Catalyzed, Photochemical Conversion of Dehydroalanine into 4,5‐Dihydroxynorvaline

The chemical synthesis of unnatural amino acids (UAA) is a key strategy for preparing designed peptides, including pharmaceutically active compounds. Alterations of existing amino acid residues such as dehydroalanine (Dha) are particularly important since selected positions can be addressed without the necessity of a complete de novo synthesis. The intriguing UAA 4,5‐dihydroxynorvaline (Dnv) is found in a variety of naturally occurring peptides and biologically active compounds. However, no method is currently available to modify an existing peptide with this residue. We report the use of flavin catalysts and visible light irradiation for this challenge, which serves as a versatile strategy for converting Dha into Dnv. Our study shows that excited flavins are competent hydrogen atom abstraction catalysts for ethers and acetals, which allows masked 1,2‐dihydroxyethylene functionalization from 2,2‐dimethyl‐1,3‐dioxolane. The masked diol was successfully coupled to Dha residues, and a series of Dnv‐containing products is reported. A mild and orthogonal protocol for deprotection of the acetal group was also identified, allowing free Dnv‐modified peptides to be obtained. This method provides a straightforward strategy for Dnv functionalization, which is envisioned to be crucial for accessing natural products and synthetic analogues with pharmaceutical activity.

Comparative study on the immune surveillance injury of blood cerebrospinal fluid barrier induced by exposure to lead acetate and nano-lead sulfide

Objective: To investigate the differences in terms of blood cerebrospinal fluid barrier immune surveillance injury by lead acetate and nano-lead sulfide exposure in order to provide basis for the study of their mechanism of nerve injury caused by exposure to lead and nano lead. Methods: In June 2015, forty-five SPF SD male rats were randomly divided into control group, lead acetate group (20 mg/kg) and nano-lead sulfide group (20 mg/kg), with 15 rats in each group. The rats were intragastric five times a week, for nine weeks. The numbers of CD4(+) T lymphocytes in blood and cerebrospinal fluid were detected by flow cytometry. The levels of interleukin-4 (IL-4) and interferon-γ (IFN-γ) in serum and cerebrospinal fluid were detected by ELISA. The expressions and distribution of intercellular cell adhesion molecule-1 (ICAM-1) and CD4(+) T lymphocytes in choroid plexus were detected by laser confocal fluorescence immunoassay. The mRNA expression levels of IL-4, IFN-γ and ICAM-1 in the choroid plexus were detected by real-time PCR. Results: Compared with the control group, the proportion of CD4(+) T lymphocytes in blood of rats in lead acetate group was increased, the proportions of CD4(+) T lymphocytes in cerebrospinal fluid of rats in lead acetate group and nano-lead sulfide group were increased, the contents of IL-4 and IFN-γ in serum of rats in lead acetate group and nano-lead sulfide group were increased, the content of IL-4 in cerebrospinal fluid of rats in lead acetate group and the contents of IL-4 and IFN-γ in cerebrospinal fluid of rats in nano-lead sulfide group were increased, the differences were statistically significant (P<0.05). The fluorescence intensity of ICAM-1 and CD4(+) T lymphocytes in choriochoroid plexus of rats in lead acetate group and nano-lead sulfide group were stronger than those in control group, and the fluorescence intensity of CD4(+) T lymphocytes of rats in nano-lead sulfide group was weaker than that in lead acetate group. Compared with the control group, the mRNA expression levels of ICAM-1, IL-4 and IFN-γ in choriochoroids plexus of rats in lead acetate group and nano-lead sulfide group were increased, and the mRNA expression levels of ICAM-1 and IL-4 in nano-lead sulfide group were higher than those in lead acetate group, while the mRNA expression level of IFN-γ in nano-lead sulfide group was lower than that in lead acetate group (P<0.05) . Conclusion: Exposure to lead and nano-lead sulfide can cause the increase of CD4(+) T lymphocytes, IL-4, IFN-γ and ICAM-1, which may be related to the damage to the immune surveillance of the blood cerebrospinal fluid barrier. And there is a difference in the injury caused by lead and nano-lead sulfide exposure.

Behind the Scenes: Metagenomic Analysis of Bacterial Communities in Sustainable Depilation of Sheepskin.

The leather industry is embracing eco-friendly technologies for both regulatory compliance and sustainable growth. While enzymatic depilation provides a greener alternative to traditional beamhouse methods, its complexity often leads to higher costs. To address this, we examined the performance of sheepskins' native bacterial flora in acetic acid conditions with low environmental impact. Utilizing metagenomic techniques, we analyzed the bacterial community dynamics during the depilation process. This investigation revealed a notable increase in microbial diversity and richness in acetic acid treatments compared to water treatments. At the class level, a post-processing decrease in Gammaproteobacteria dominance was observed, while Actinomycetia numbers surged in the acetic acid group. In contrast, the water group showed an increase in Bacteroidia. Order-level analysis indicated reductions in Pseudomonadales and increases in Actinomycetales with acetic acid treatment, whereas Flavobacteriales was more prevalent in water-treated liquors. At the family level, Moraxellaceae decreased and Micrococcaceae increased in the acetic acid group, in contrast to the marked rise of Weeksellaceae in the water group. Temporal analyses further highlighted the evolving bacterial landscapes under different treatments. Moreover, acetic acid treatment fostered a stable microbial community, beneficial for sustainable leather processing. Functional pathways were predicted using PICRUSt2. It showed that significantly enriched degradation pathways in the water group were less abundant in the acetic acid group, potentially preventing substrate matrix damage during depilation. The study underscores the transformative potential of acetic acid for the leather industry, offering a pathway to reduce pollution while maintaining economic viability. By enhancing our understanding of microbial interactions during depilation, this study opens avenues for refining these eco-friendly techniques. Our findings advocate for a shift towards greener depilation methods and contribute to the broader dialogue on sustainable manufacturing practices, emphasizing the importance of leveraging indigenous microbial communities for environmental and economic gains.

Acetate attenuates hypothalamic pyroptosis in experimentally induced polycystic ovarian syndrome

This study hypothesized that SCFA, acetate impacts positively on hypothalamic pyroptosis and its related abnormalities in experimentally induced PCOS rat model, possibly through NrF2/HIF1-α modulation. Eight-week-old female Wister rats were divided into groups (n = 5), namely control, PCOS, acetate and PCOS + acetate groups. Induction of PCOS was performed by administering 1 mg/kg body weight of letrozole for 21 days. After PCOS confirmation, the animals were treated with 200 mg/kg of acetate for 6 weeks. Rats with PCOS were characterized with insulin resistance, leptin resistance, increased plasma testosterone as well as degenerated ovarian follicles. There was also a significant increase in hypothalamic triglyceride level, triglyceride-glucose index, inflammatory biomarkers (SDF-1 and NF-kB) and caspase-6 as well as plasma LH and triglyceride. A decrease was observed in plasma adiponectin, GnRH, FSH, and hypothalamic GABA with severe inflammasome expression in PCOS rats. These were accompanied by decreased level of NrF2/HIF1-α, and the alterations were reversed when treated with acetate. Collectively, the present results suggest the therapeutic impact of acetate on hypothalamic pyroptosis and its related comorbidity in PCOS, a beneficial effect that is accompanied by modulation of NrF2/HIF1-α.

In Silico Structure-Activity Study of Selected Triterpenoids as Potential Inhibitors of Mycolic Acid Transporter of Mycobacterial MmpL3 Receptor Protein

Structural features of the triterpenoid skeleton that are necessary for antimycobacterial activity are not well understood. Following the isolation of the triterpenoids ergosterol-5,8-endoperoxide, 6β-hydroxykulactone, 12β-hydroxykulactone, (24R)-24,25-epoxycycloartan-3-one and (3β,24R)-24,25-epoxycycloartan-3-ol, and (3β,24R)-24,25-epoxycycloartan-3-acetate with varying antimycobacterial activity ranging between MIC of 1 µg/ml to128 µg/ml prompted us to study this class of compounds further to shade light on the structural features necessary for their antimycobacterial activity. This in silico study involved docking the triterpenoids on the mycobacterial multi-pharmacophore receptor protein MmpL3. The docking results were compared with the MmpL3 receptor protein co-crystallized TB drug candidate, AU1235, (1-(2-adamantyl)-3-[2,3,4-tris(fluoranyl)phenyl] urea). The virtual screening revealed key structural features in the triterpenoid skeleton, including the C-3 keto and β-hydroxy group on C-3 or C-6, as important for antimycobacterial activity. Also, the decreased binding affinity for compounds 2 and 7 with an acetate group on C-3 were in tandem with those observed in vitro. Toxicity predictions revealed that this class of compounds had no mutagenic effects and displayed favorable pharmacokinetic parameters. The study reveals the potential of the triterpenoid skeleton exemplified by the readily available ergosterol-5,8-endoperoxide as a useful scaffold in searching and developing effective therapeutic lead entities to facilitate anti-tuberculosis drug discovery.

Potent and Selective Oxidatively Labile Ether‐Based Prodrugs through Late‐Stage Boronate Incorporation

AbstractThis manuscript describes a new strategy for prodrug synthesis in which a relatively inert ether group is introduced at an early stage in a synthetic sequence and functionalized in the final step to introduce a prodrug‐activating group through a chemoselective process. Boryl allyloxy (BAO) ether groups are synthesized through several metal‐mediated processes to form entities that are readily cleaved under oxidative conditions commonly found in cancer cells. The high cleavage propensity of the BAO group allows for ether cleavage, making these compounds substantially more hydrolytically stable in comparison to acyl‐linked prodrugs while retaining the ability to release alcohols. We report the preparation of prodrug analogues of the natural products camptothecin and pederin from acetal precursors that serve as protecting groups in their synthetic sequences. The BAO acetal groups cleave in the presence of hydrogen peroxide to release the cytotoxic agents. The pederin‐based prodrug shows dramatically greater cytotoxicity than negative controls and outstanding selectivity and potency toward cancer cell lines in comparison to non‐cancerous cell lines. This late‐stage functionalization approach to prodrug synthesis should be applicable to numerous systems that can be accessed through chemoselective processes.

Potent and Selective Oxidatively Labile Ether-Based Prodrugs through Late-Stage Boronate Incorporation.

This manuscript describes a new strategy for prodrug synthesis in which a relatively inert ether group is introduced at an early stage in a synthetic sequence and functionalized in the final step to introduce a prodrug-activating group through a chemoselective process. Boryl allyloxy (BAO) ether groups are synthesized through several metal-mediated processes to form entities that are readily cleaved under oxidative conditions commonly found in cancer cells. The high cleavage propensity of the BAO group allows for ether cleavage, making these compounds substantially more hydrolytically stable in comparison to acyl-linked prodrugs while retaining the ability to release alcohols. We report the preparation of prodrug analogues of the natural products camptothecin and pederin from acetal precursors that serve as protecting groups in their synthetic sequences. The BAO acetal groups cleave in the presence of hydrogen peroxide to release the cytotoxic agents. The pederin-based prodrug shows dramatically greater cytotoxicity than negative controls and outstanding selectivity and potency toward cancer cell lines in comparison to non-cancerous cell lines. This late-stage functionalization approach to prodrug synthesis should be applicable to numerous systems that can be accessed through chemoselective processes.

The Preparation and Crystal Structures of Octaoxoketocalix[8]arene Derivatives: The Ketocalixarene Counterparts of the Largest "Major" Calixarene.

The purpose of this study was to synthesize and structurally characterize ketocalixarenes (i.e., calixarenes where the bridging methylene bridges are replaced by carbonyl groups) derived from the largest "major" calixarene, namely p-tert-butylcalix[8]arene 3a. Ketocalix[8]arenes were synthesized by the oxidation of protected p-tert-butylcalix[8]arene derivatives. Octamethoxy-p-tert-butylketocalix[8]arene 6b was prepared by the photochemical reaction of the calixarene 3b with NBS in a CHCl3/H2O mixture. The oxidation of the methylene groups of octaacetoxy-p-tert-butylcalix[8]arene 3c was conducted by a reaction with CrO3 in Ac2O/AcOH. The basic hydrolysis of the acetate groups of the oxidation product yielded octahydroxy-p-tert-butylketocalix[8]arene 6a. In the crystal, the molecule adopts a saddle-like conformation of crystallographic C2 and idealized S4 symmetry. Strikingly, the array of OH/OH intramolecular hydrogen bonds present in the parent 3a is completely disrupted in 6a.