Advances in the total synthesis of bis- and tris-indole alkaloids containing N-heterocyclic linker moieties

Natural Product Reports, Год журнала: 2024, Номер 41(8), С. 1264 - 1293

Опубликована: Янв. 1, 2024

The past several years have seen an increase in the discovery and isolation of natural products indole alkaloid class. Bis- tris-indole alkaloids are classes that been shown to display diverse, potent biological activities. Of particular interest bis- containing N-heterocyclic linker moieties. It has reported more than 85% biologically active compounds contain one or heterocyclic moieties; these, N-heterocycles identified as most prevalent. goal this review is provide a detailed overview recent advances total synthesis known activities these will also be discussed.

Язык: Английский

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Advances in Enzymatic Incorporation of Small Fluorine Modules

European Journal of Organic Chemistry, Год журнала: 2024, Номер 27(17)

Опубликована: Март 29, 2024

Abstract Organofluorine compounds find extensive application in the fields of agrochemicals, pharmaceuticals, materials science, and molecular imaging. Introducing fluorine atoms can provide organic with unique physicochemical properties or improve their biological activity. Although significant progress has been made chemical synthesis fluorine‐containing compounds, achieving selective fluorination under mild conditions remains extremely challenging. biocatalytic approaches organofluorine chemistry is an important strategy given high efficiency, selectivity, environmental friendliness. In this review, we present discovery fluorinated natural products fluorinases, crystal structure directed evolution a focus on recent advances enzymatic years. It hoped that review will help to promote field compound synthesis.

Язык: Английский

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PK/PD investigation of antiviral host matriptase/TMPRSS2 inhibitors in cell models

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Июль 18, 2024

Abstract Certain corona- and influenza viruses utilize type II transmembrane serine proteases for cell entry, making these enzymes potential drug targets the treatment of viral respiratory infections. In this study, cytotoxicity inhibitory effects seven matriptase/TMPRSS2 inhibitors (MI-21, MI-463, MI-472, MI-485, MI-1900, MI-1903, MI-1904) on cytochrome P450 were evaluated using fluorometric assays. Additionally, their antiviral activity against A virus subtypes H1N1 H9N2 was assessed. The metabolic depletion rates in human primary hepatocytes determined over a 120-min period by LC–MS/MS, PK parameters calculated. tested compounds, with exception MI-21, displayed potent inhibition CYP3A4, while all compounds lacked CYP1A2, CYP2C9, CYP2C19, CYP2D6. differences between CYP3A4 within series rationalized ligand docking. Elucidation showed that MI-1900 MI-1904 more stable than MI-21 MI-1903. Anti-H1N1 properties MI-463 anti-H9N2 shown at 20 50 µM after 24 h incubation inhibitors, suggesting can be applied to block entry suppressing host matriptase/TMPRSS2-mediated cleavage.

Язык: Английский

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Cocrystallization of 5-FU and novel sulfathiazole Schiff bases: Synthesis, theoretical and experimental anticancer evaluation against MCF-7 and SW-480 cancer cell lines

Journal of Molecular Liquids, Год журнала: 2025, Номер 420, С. 126850 - 126850

Опубликована: Янв. 5, 2025

Язык: Английский

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Discovery, design, and engineering of enzymes based on molecular retrobiosynthesis

mLife, Год журнала: 2025, Номер 4(2), С. 107 - 125

Опубликована: Март 28, 2025

Abstract Biosynthesis—a process utilizing biological systems to synthesize chemical compounds—has emerged as a revolutionary solution 21st‐century challenges due its environmental sustainability, scalability, and high stereoselectivity regioselectivity. Recent advancements in artificial intelligence (AI) are accelerating biosynthesis by enabling intelligent design, construction, optimization of enzymatic reactions systems. We first introduce the molecular retrosynthesis route planning biochemical pathway including single‐step algorithms AI‐based design tools. highlight advantages large language models addressing sparsity data. Furthermore, we review enzyme discovery methods based on sequence structure alignment techniques. Breakthroughs structural prediction expected significantly improve accuracy discovery. also summarize for de novo generation nonnatural or orphan reactions, focusing functional annotation techniques reaction small molecule similarity. Turning engineering, discuss strategies thermostability, solubility, activity, well applications AI these fields. The shift from traditional experiment‐driven data‐driven computationally driven is already underway. Finally, present potential provide perspective future research directions. envision expanded biocatalysis drug development, green chemistry, complex synthesis.

Язык: Английский

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Quasi-intrinsic cytosine analogues for two-photon photodynamic therapy with Type I/II mechanism

Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy, Год журнала: 2025, Номер 340, С. 126330 - 126330

Опубликована: Май 3, 2025

Язык: Английский

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Oligomerization engineering of the fluorinase enzyme leads to an active trimer that supports synthesis of fluorometabolites in vitro

Microbial Biotechnology, Год журнала: 2022, Номер 15(5), С. 1622 - 1632

Опубликована: Янв. 27, 2022

Summary The fluorinase enzyme represents the only biological mechanism capable of forming stable C–F bonds characterized in nature thus far, offering a biotechnological route to biosynthesis value‐added organofluorines. is known operate hexameric form, but consequence(s) oligomerization status on activity and its catalytic properties remain largely unknown. In this work, aspect was explored by rationally engineering trimeric variants that retained same rate as wild‐type enzyme. These results ruled out hexamerization requisite for fluorination activity. Michaelis constant ( K M ) S ‐adenosyl‐ l ‐methionine, one substrates fluorinase, increased two orders magnitude upon hexamer disruption. Such shift ‐methionine affinity points long‐range effect substrate binding – likely decreasing dissociation release from active site. A practical application illustrated establishing vitro fluorometabolite synthesis bacterial cell‐free system.

Язык: Английский

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Photoinduced regioselective difluorination of secondary inert C(sp³)–H bonds in sulfonamides via 1,5-hydrogen-atom transfer

Organic Chemistry Frontiers, Год журнала: 2023, Номер 10(18), С. 4709 - 4717

Опубликована: Янв. 1, 2023

Difluorinated compounds are important structural motifs in organic synthesis and medicinal chemistry because fluoride can modulate the properties of various molecules.

Язык: Английский

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Identification of Genes Essential for Fluorination and Sulfamylation within the Nucleocidin Gene Clusters of Streptomyces calvus and Streptomyces virens

ChemBioChem, Год журнала: 2022, Номер 24(5)

Опубликована: Дек. 22, 2022

Abstract The gene cluster in Streptomyces calvus associated with the biosynthesis of fluoro‐ and sulfamyl‐metabolite nucleocidin was interrogated by systematic knockouts. Out 26 deletions, most did not affect fluorometabolite production, nine abolished sulfamylation but fluorination, three precluded had no effect on sulfamylation. In addition to nucI, nucG , nucJ nucK nucL nucN nucO nucQ nucP we identified two genes ( nucW nucA) belonging a phosphoadenosine phosphosulfate (PAPS) cluster, as required for sulfamyl assembly. Three orf(−3) orf2 orf3 ) were found be essential although activities their protein products are unknown. These well nucPNP whose knockouts produced results differing from those described recent report, also deleted virens – confirmatory outcomes. This genetic profile should inform biochemistry aimed at uncovering enzymology behind biosynthesis.

Язык: Английский

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Why Nonheme Iron Halogenases Do Not Fluorinate C–H Bonds: A Computational Investigation

Inorganic Chemistry, Год журнала: 2023, Номер 62(48), С. 19758 - 19770

Опубликована: Ноя. 16, 2023

Selective halogenation is necessary for a range of fine chemical applications, including the development therapeutic drugs. While synthetic processes to achieve C-H require harsh conditions, enzymes such as nonheme iron halogenases carry out some types halogenation, i.e., chlorination or bromination, with ease, while others, fluorination, have never been observed in natural engineered enzymes. Using density functional theory and correlated wave function theory, we investigate differences structural energetic preferences smaller fluoride larger chloride bromide intermediates throughout catalytic cycle. Although find that energetics rate-limiting hydrogen atom transfer are not strongly impacted by substitution, higher barriers during radical rebound reaction relative contribute difficulty fluorination. We also possibility isomerization playing role selectivity, our calculations reveal crucial terms isomer key ferryl intermediate between chloride/bromide intermediates. formation monodentate isomers believed be involved selective catalysis shown intermediates, possible calculations, which lack additional stabilizing interactions greater protein environment. Furthermore, shorter Fe-F bonds found increase barriers, suggesting incorporation residues form halogen bond F elongate could make fluorination halogenases. Our work highlights suggests potential steps toward engineering enable

Язык: Английский

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