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Drug Metabolism and Disposition: the... May 2024Cantharidin is a terpenoid from coleoptera beetles. Cantharidin has been used to treat molluscum contagiosum and some types of tumors. Cantharidin is highly toxic and...
Cantharidin is a terpenoid from coleoptera beetles. Cantharidin has been used to treat molluscum contagiosum and some types of tumors. Cantharidin is highly toxic and cantharidin poisoning and fatal cases have been reported worldwide. The mechanisms underlying cantharidin-induced toxicity remain unclear. Cantharidin contains anhydride, which may react with biological amines. This study aimed to examine the chemical reactivity of cantharidin toward nucleophiles and characterize adducts of cantharidin with biological amines and in mice. Here, two types of conjugates were formed in the incubation of cantharidin under physiologic conditions with free amino acids, a mimic peptide, or amine-containing compounds, respectively. Amide-type conjugates were produced by the binding of cantharidin anhydride with the primary amino group of biological amines. Imide-type conjugates were generated from the dehydration and cyclization of amide-type conjugates. The structure of the conjugates was characterized by using the high-resolution mass spectrometry. We introduced the N/N and Br/Br isotope signatures to confirm the formation of conjugates using L-(ε)N-lysine, L-lysine-N, and bromine-tagged hydrazine, respectively. The structure of imide conjugate was also confirmed by NMR experiments. Furthermore, the amide and imide conjugates of cantharidin with amino acids or -acetyl-lysine were detected in mouse liver and urine. Cantharidin was found to modify lysine residue proteins in mouse liver. Pan-P450 inhibitor 1-aminobenzotriazole significantly increased the urine cantharidin--acetyl-lysine conjugates whereas decreased cantharidin metabolites. In summary, cantharidin anhydride can covalently bind to biological amines nonenzymatically, which facilitates a better understanding of the role of nonenzymatic reactivity in cantharidin poisoning. Anhydride moiety of cantharidin can covalently bind to the primary amino group of biological amines nonenzymatically. Amide and imide conjugates were generated after the covalent binding of cantharidin anhydride with the primary amino groups of amino acids, a mimic peptide, and protein lysine residues. The structure of conjugates was confirmed by N/N and Br/Br isotope signatures using isotope-tagged reagents and NMR experiments. This study will facilitate the understanding of the role of nonenzymatic reactivity in cantharidin poisoning.
PubMed: 38811155
DOI: 10.1124/dmd.123.001637 -
ChemistryOpen May 2024Among the natural tetramic acids with a decalinoyl part, signermycin B is unique because it contains a cis-decalin. In this paper, we demonstrate that the cis-decalin...
Among the natural tetramic acids with a decalinoyl part, signermycin B is unique because it contains a cis-decalin. In this paper, we demonstrate that the cis-decalin section of signermycin B can be accessed by an anionic oxy-Cope rearrangement. The substrate, a tricyclic dienol was prepared by an intramolecular Diels-Alder reaction of a masked ortho-benzoquinone, generated by oxidation of an α-methoxyphenol in presence of cis-2-hexenol. After a superfluous bromine on the cycloadduct was removed, reaction of the tricyclic ketone with isopropenylmagnesium bromide led to the tricyclic trienol that underwent the oxy-Cope rearrangement to a cis-decalinone. While we could show, that introduction of the 4-ethyl substituent (signermycin B numbering) is possible by enolate alkylation, the 4-epi-isomer was formed.
PubMed: 38809061
DOI: 10.1002/open.202400103 -
Frontiers in Bioengineering and... 2024Bacterial natural products (BNPs) are very important sources of leads for drug development and chemical novelty. The possibility to perform late-stage diversification of... (Review)
Review
Bacterial natural products (BNPs) are very important sources of leads for drug development and chemical novelty. The possibility to perform late-stage diversification of BNPs using biocatalysis is an attractive alternative route other than total chemical synthesis or metal complexation reactions. Although biocatalysis is gaining popularity as a green chemistry methodology, a vast majority of orphan sequenced genomic data related to metabolic pathways for BNP biosynthesis and its tailoring enzymes are underexplored. In this review, we report a systematic overview of biotransformations of 21 molecules, which include derivatization by halogenation, esterification, reduction, oxidation, alkylation and nitration reactions, as well as degradation products as their sub-derivatives. These BNPs were grouped based on their biological activities into antibacterial (5), antifungal (5), anticancer (5), immunosuppressive (2) and sensing modulating (4) compounds. This study summarized 73 derivatives and 16 degradation sub-derivatives originating from 12 BNPs. The highest number of biocatalytic reactions was observed for drugs that are already in clinical use: 28 reactions for the antibacterial drug vancomycin, followed by 18 reactions reported for the immunosuppressive drug rapamycin. The most common biocatalysts include oxidoreductases, transferases, lipases, isomerases and haloperoxidases. This review highlights biocatalytic routes for the late-stage diversification reactions of BNPs, which potentially help to recognize the structural optimizations of bioactive scaffolds for the generation of new biomolecules, eventually leading to drug development.
PubMed: 38807651
DOI: 10.3389/fbioe.2024.1351583 -
Journal of Xenobiotics May 2024Disinfection during tertiary municipal wastewater treatment is a necessary step to control the spread of pathogens; unfortunately, it also gives rise to numerous...
Disinfection during tertiary municipal wastewater treatment is a necessary step to control the spread of pathogens; unfortunately, it also gives rise to numerous disinfection byproducts (DBPs), only a few of which are regulated because of the analytical challenges associated with the vast number of potential DBPs. This study utilized polydimethylsiloxane (PDMS) passive samplers, comprehensive two-dimensional gas chromatography (GC×GC) coupled with time-of-flight mass spectrometry (TOFMS), and non-negative matrix factorization (NMF) spectral deconvolution for suspect screening of DBPs in treated wastewater. PDMS samplers were deployed upstream and downstream of the chlorination unit in a municipal wastewater treatment plant located in Abu Dhabi, and their extracts were analyzed using GC×GC-TOFMS. A workflow incorporating a multi-tiered, eight-filter screening process was developed, which successfully enabled the reliable isolation of 22 candidate DBPs from thousands of peaks. The NMF spectral deconvolution improved the match factor score of unknown mass spectra to the reference mass spectra available in the NIST library by 17% and facilitated the identification of seven additional DBPs. The close match of the first-dimension retention index data and the GC×GC elution patterns of DBPs, both predicted using the Abraham solvation model, with their respective experimental counterparts-with the measured data available in the NIST WebBook and the GC×GC elution patterns being those observed for the candidate peaks-significantly enhanced the accuracy of peak assignment. Isotopic pattern analysis revealed a close correspondence for 11 DBPs with clearly visible isotopologues in reference spectra, thereby further strengthening the confidence in the peak assignment of these DBPs. Brominated analogues were prevalent among the detected DBPs, possibly due to seawater intrusion. The fate, behavior, persistence, and toxicity of tentatively identified DBPs were assessed using EPI Suite™ and the CompTox Chemicals Dashboard. This revealed their significant toxicity to aquatic organisms, including developmental, mutagenic, and endocrine-disrupting effects in certain DBPs. Some DBPs also showed activity in various CompTox bioassays, implicating them in adverse molecular pathways. Additionally, 11 DBPs demonstrated high environmental persistence and resistance to biodegradation. This combined approach offers a powerful tool for future research and environmental monitoring, enabling accurate identification and assessment of DBPs and their potential risks.
PubMed: 38804286
DOI: 10.3390/jox14020033 -
ACS Omega May 2024This work reports a theoretical investigation of the solvent polarity as well as the halogenation of benzimidazole derivatives during excited state intramolecular proton...
This work reports a theoretical investigation of the solvent polarity as well as the halogenation of benzimidazole derivatives during excited state intramolecular proton transfer (ESIPT). It details how the environment and halogen substitution may contribute to the efficiency of ESIPT upon keto-enol tautomerism and exploits this effect to design fluorescence sensing. For this purpose, we first examine the conformational equilibrium of benzimidazole derivatives containing different halogen atoms, which results in intramolecular proton transfer, using density-functional theory (DFT) combined with the polarizable continuum model (PCM). Then we evaluate the fluorescence of the benzimidazole derivatives in different dielectric constants within time-dependent DFT (TD-DFT) approaches. Our results quantitatively allow the determination of large Stokes shifts in nonpolar solvents around 100 nm. These theoretical results are in agreement with experimental solvatochromism studies of benzimidazoles. The effect of halogenation, with fluorine, chlorine, and bromine, is less important than solvent polarization when ESIPT takes place. Thus, halogenation can be properly chosen depending on the interest of the synthesis of benzimidazole-based turn-on fluorescence in appropriate solvents.
PubMed: 38799309
DOI: 10.1021/acsomega.4c00488 -
BioRxiv : the Preprint Server For... May 2024Hemolysins are lytic exotoxins expressed in most strains of , but hemolytic activity varies between strains. We have previously reported several novel anti-virulence...
Hemolysins are lytic exotoxins expressed in most strains of , but hemolytic activity varies between strains. We have previously reported several novel anti-virulence compounds that disrupt the transcriptome, including hemolysin gene expression. This report delves further into our two lead compounds, loratadine and a structurally related brominated carbazole, and their effects on hemolysin production in MRSA. To gain understanding into how these compounds affect hemolysis, we analyzed these exotoxins at the DNA, RNA, and protein level after in vitro treatment. While lysis of red blood cells varied between strains, DNA sequence variation did not account for it. We hypothesized that our compounds would modulate gene expression of multiple hemolysins in a laboratory strain and a clinically relevant hospital-acquired strain of MRSA, both with SCC type II. RNA-seq analysis of differential gene expression in untreated and compound-treated cultures revealed hundreds of differentially expressed genes, with a significant enrichment in genes involved in hemolysis. The brominated carbazole and loratadine both displayed the ability to reduce hemolysis in the laboratory strain, but displayed differential activity in a hospital-acquired strain. These results corroborate gene expression studies as well as western blots of alpha hemolysin. Together, this work suggests that small molecules may alter exotoxin production in MRSA, but that the directionality and/or magnitude of the difference is likely strain-dependent.
PubMed: 38798408
DOI: 10.1101/2024.05.15.594412 -
Molecules (Basel, Switzerland) May 2024The FDA has approved several drugs based on the fluorinated nucleoside pharmacophore, and numerous drugs are currently in clinical trials. Fluorine-containing... (Review)
Review
The FDA has approved several drugs based on the fluorinated nucleoside pharmacophore, and numerous drugs are currently in clinical trials. Fluorine-containing nucleos(t)ides offer significant antiviral and anticancer activity. The insertion of a fluorine atom, either in the base or sugar of nucleos(t)ides, alters its electronic and steric parameters and transforms the lipophilicity, pharmacodynamic, and pharmacokinetic properties of these moieties. The fluorine atom restricts the oxidative metabolism of drugs and provides enzymatic metabolic stability towards the glycosidic bond of the nucleos(t)ide. The incorporation of fluorine also demonstrates additional hydrogen bonding interactions in receptors with enhanced biological profiles. The present article discusses the synthetic methodology and antiviral activities of FDA-approved drugs and ongoing fluoro-containing nucleos(t)ide drug candidates in clinical trials.
Topics: Humans; Antiviral Agents; Fluorine; Halogenation; Nucleosides; Nucleotides; Clinical Trials as Topic
PubMed: 38792251
DOI: 10.3390/molecules29102390 -
Molecules (Basel, Switzerland) May 2024Methyl 4-(1,3a,6a-triazapentalen-3-yl)benzoate () shows interesting properties as a small molecule fluorophore. In the search for post-functionalization methods,...
Methyl 4-(1,3a,6a-triazapentalen-3-yl)benzoate () shows interesting properties as a small molecule fluorophore. In the search for post-functionalization methods, palladium-catalyzed arylation reactions were demonstrated. Direct CH arylation reactions of with various aryl halides resulted in 3,6-diaryltriazapentalenes , although mostly in poor yields. Bromination of followed by Suzuki coupling, on the other hand, requires a more delicate procedure, but gave arylated products with the same regiochemistry () in moderate to good yields. The structure of 6-phenyltriazapentalene was confirmed by crystallographic analysis. In addition, the effect of the C6 arylation on the fluorescent properties of 3-aryl-1,3a,6a-triazapentalenes was studied in dichloromethane at room temperature and in 2-methyltetrahydrofuran at 77 K, while the photophysical properties of two saponified derivatives were measured in acetonitrile.
PubMed: 38792091
DOI: 10.3390/molecules29102229 -
International Journal of Molecular... May 2024The search for new substances of natural origin, such as flavonoids, is necessary in the fight against the growing number of diseases and bacterial resistance to...
The search for new substances of natural origin, such as flavonoids, is necessary in the fight against the growing number of diseases and bacterial resistance to antibiotics. In our research, we wanted to check the influence of flavonoids with chlorine or bromine atoms and a nitro group on pathogenic and probiotic bacteria. We synthesized flavonoids using Claisen-Schmidt condensation and its modifications, and through biotransformation via entomopathogenic filamentous fungi, we obtained their glycoside derivatives. Biotransformation yielded two new flavonoid glycosides: 8-amino-6-chloroflavone 4'---D-(4″--methyl)-glucopyranoside and 6-bromo-8-nitroflavone 4'---D-(4″--methyl)-glucopyranoside. Subsequently, we checked the antimicrobial properties of the aforementioned aglycon flavonoid compounds against pathogenic and probiotic bacteria and yeast. Our studies revealed that flavones have superior inhibitory effects compared to chalcones and flavanones. Notably, 6-chloro-8-nitroflavone showed potent inhibitory activity against pathogenic bacteria. Conversely, flavanones 6-chloro-8-nitroflavanone and 6-bromo-8-nitroflavanone stimulated the growth of probiotic bacteria ( and ). Our research has shown that the presence of chlorine, bromine, and nitro groups has a significant effect on their antimicrobial properties.
Topics: Flavonoids; Chlorine; Biotransformation; Bromine; Microbial Sensitivity Tests; Anti-Infective Agents; Bacteria; Anti-Bacterial Agents
PubMed: 38791577
DOI: 10.3390/ijms25105540 -
International Journal of Molecular... May 2024The development of photocurable compositions is in high demand for the manufacture of functional materials for electronics, optics, medicine, energy, etc. The properties...
Soluble Fluorinated Cardo Copolyimide as an Effective Additive to Photopolymerizable Compositions Based on Di(meth)acrylates: Application for Highly Thermostable Primary Protective Coating of Silica Optical Fiber.
The development of photocurable compositions is in high demand for the manufacture of functional materials for electronics, optics, medicine, energy, etc. The properties of the final photo-cured material are primarily determined by the initial mixture, which needs to be tuned for each application. In this study we propose to use simple systems based on di(meth)acrylate, polyimide and photoinitiator for the preparation of new photo-curable compositions. It was established that a fluorinated cardo copolyimide (FCPI) based on 2,2--(3,4-dicarboxydiphenyl)hexafluoropropane dianhydride, 9,9--(4-aminophenyl)fluorene and 2,2--(4-aminophenyl)hexafluoropropane (1.00:0.75:0.25 mol) has excellent solubility in di(met)acrylates. This made it possible to prepare solutions of FCPI in such monomers, to study the effect of FCPI on the kinetics of their photopolymerization in situ and the properties of the resulting polymers. According to the obtained data, the solutions of FCPI (23 wt.%) in 1,4-butanediol diacrylate (BDDA) and FCPI (15 wt.%) in tetraethylene glycol diacrylate were tested for the formation of the primary protective coatings of the silica optical fibers. It was found that the new coating of poly(BDDA-FCPI) can withstand prolonged annealing at 200 °C (72 h), which is comparable or superior to the known most thermally stable photo-curable coatings. The proposed approach can be applied to obtain other functional materials.
Topics: Polymerization; Silicon Dioxide; Optical Fibers; Solubility; Imides; Temperature; Acrylates; Polymers; Halogenation; Photochemical Processes
PubMed: 38791532
DOI: 10.3390/ijms25105494