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Current Opinion in Chemical Biology Jun 2024Reactive amino acid side chains play important roles in the binding of peptides to specific targets. In addition, their reactivity enables selective peptide conjugation... (Review)
Review
Reactive amino acid side chains play important roles in the binding of peptides to specific targets. In addition, their reactivity enables selective peptide conjugation and functionalization for pharmaceutical purposes. Diverse reactive amino acids are incorporated into nonribosomal peptides, which serve as a source for drug candidates. Notable examples include (poly)unsaturated (enamine, alkyne, and furyl) and halogenated residues, strained carbacycles (cyclopropyl and cyclopropanol), small heterocycles (oxirane and aziridine), and reactive N-N functionalities (hydrazones, diazo compounds, and diazeniumdiolates). Their biosynthesis requires diverse biocatalysts for sophisticated reaction mechanisms. Several avenues have been identified for their incorporation into peptides, the recruitment by adenylation domains or ligases, on-line modifications, and enzymatic tailoring reactions. Combined with protein engineering approaches, this knowledge provides new opportunities in synthetic biology and bioorthogonal chemistry.
PubMed: 38936328
DOI: 10.1016/j.cbpa.2024.102494 -
International Journal of Molecular... Jun 2024Bacterial nitroreductase enzymes capable of activating imaging probes and prodrugs are valuable tools for gene-directed enzyme prodrug therapies and targeted cell...
Bacterial nitroreductase enzymes capable of activating imaging probes and prodrugs are valuable tools for gene-directed enzyme prodrug therapies and targeted cell ablation models. We recently engineered a nitroreductase ( NfsB F70A/F108Y) for the substantially enhanced reduction of the 5-nitroimidazole PET-capable probe, SN33623, which permits the theranostic imaging of vectors labeled with oxygen-insensitive bacterial nitroreductases. This mutant enzyme also shows improved activation of the DNA-alkylation prodrugs CB1954 and metronidazole. To elucidate the mechanism behind these enhancements, we resolved the crystal structure of the mutant enzyme to 1.98 Å and compared it to the wild-type enzyme. Structural analysis revealed an expanded substrate access channel and new hydrogen bonding interactions. Additionally, computational modeling of SN33623, CB1954, and metronidazole binding in the active sites of both the mutant and wild-type enzymes revealed key differences in substrate orientations and interactions, with improvements in activity being mirrored by reduced distances between the N5-H of isoalloxazine and the substrate nitro group oxygen in the mutant models. These findings deepen our understanding of nitroreductase substrate specificity and catalytic mechanisms and have potential implications for developing more effective theranostic imaging strategies in cancer treatment.
Topics: Nitroreductases; Nitroimidazoles; Metronidazole; Prodrugs; Escherichia coli Proteins; Positron-Emission Tomography; Escherichia coli; Catalytic Domain; Protein Engineering; Models, Molecular; Aziridines
PubMed: 38928299
DOI: 10.3390/ijms25126593 -
Organic & Biomolecular Chemistry Jun 2024Brønsted acid catalyzed regioselective ring opening of aziridines by phenols and thiophenols have been reported. Involvement of a series of aziridines with a range of...
Regioselective Brønsted acid catalyzed ring opening of aziridines by phenols and thiophenols; a gateway to access functionalized indolines, indoles, benzothiazines, dihydrobenzo-thiazines, benzo-oxazines and benzochromenes.
Brønsted acid catalyzed regioselective ring opening of aziridines by phenols and thiophenols have been reported. Involvement of a series of aziridines with a range of phenols and thiophenols offer the generality of the reported protocol. Completion of the reaction at room temperature within very short time brings the uniqueness of the developed technique. To emphasis on the application of the developed methodology, the products have been used for the further synthesis of a range of useful and novel heterocyclic molecules such as indolines, indoles, benzothiazines, dihydrobenzothiazines, benzo-oxazines and benzochromenes.
PubMed: 38919997
DOI: 10.1039/d4ob00196f -
Materials (Basel, Switzerland) Jun 2024To use polylactic acid in demanding technical applications, sufficient long-term thermal stability is required. In this work, the thermal aging of polylactic acid (PLA)...
To use polylactic acid in demanding technical applications, sufficient long-term thermal stability is required. In this work, the thermal aging of polylactic acid (PLA) in the solid phase at 100 °C and 150 °C is investigated. PLA has only limited aging stability without the addition of stabilizers. Therefore, the degradation mechanism in thermal aging was subsequently investigated in more detail to identify a suitable stabilization strategy. Investigations using nuclear magnetic resonance spectroscopy showed that, contrary to expectations, even under thermal aging conditions, hydrolytic degradation rather than oxidative degradation is the primary degradation mechanism. This was further confirmed by the investigation of suitable stabilizers. While the addition of phenols, phosphites and thioethers as antioxidants leads only to a limited improvement in aging stability, the addition of an additive composition to provide hydrolytic stabilization results in extended durability. Efficient compositions consist of an aziridine-based hydrolysis inhibitor and a hydrotalcite co-stabilizer. At an aging temperature of 100 °C, the time until significant polymer chain degradation occurs is extended from approx. 500 h for unstabilized polylactic acid to over 2000 h for stabilized polylactic acid.
PubMed: 38894026
DOI: 10.3390/ma17112761 -
Medical Oncology (Northwood, London,... Jun 2024Treating metastatic malignancies to the central nervous system (CNS) is challenging because many drugs cannot cross the blood-brain-barrier (BBB). Direct intrathecal... (Review)
Review
Treating metastatic malignancies to the central nervous system (CNS) is challenging because many drugs cannot cross the blood-brain-barrier (BBB). Direct intrathecal (IT) drug administration into the cerebrospinal fluid (CSF) is a strategy to overcome this problem. Thiotepa has effective CNS penetration but its popularity has waned over the last two decades due to concerns about its efficacy and potential systemic toxicity. This review evaluates the available evidence for the use of IT thiotepa in hematologic malignancies and non-CNS solid tumors with leptomeningeal disease metastases (LMD). Our search shows that IT thiotepa is a reasonable alternative in hematologic malignancies and LMD due to solid organ malignancies. This suggests a potential role of IT thiotepa in second-or third-line treatment or a substitute role in cases of drug-shortages and adverse effects with other agents. Future research should focus on rigorous comparative trials to establish its definitive role in the evolving landscape of CNS-directed chemotherapy.
Topics: Humans; Thiotepa; Injections, Spinal; Central Nervous System Neoplasms; Antineoplastic Agents, Alkylating; Hematologic Neoplasms; Meningeal Neoplasms
PubMed: 38884819
DOI: 10.1007/s12032-024-02401-w -
Organic & Biomolecular Chemistry Jun 2024This review explores the significance of trifluoromethylnitrones in synthesizing fluorine-containing compounds, with a particular focus on trifluoromethylated... (Review)
Review
This review explores the significance of trifluoromethylnitrones in synthesizing fluorine-containing compounds, with a particular focus on trifluoromethylated heterocycles. It explores the versatility of trifluoromethylnitrones, especially in [3 + 2] cycloaddition reactions, highlighting their unique reactivity with various dienophile substrates. Trifluoromethylnitrones are valuable precursors for the rapid synthesis of medicinally important trifluoromethylated heterocycles, including isoxazolidines, dihydroisoxazoles, oxathiazolidines, β-lactams, and aziridines. These heterocycles, in turn, serve as synthons for synthesizing trifluoromethylated lactams and aminoalcohols. Additionally, nitrone chemistry extends to synthesizing trifluoromethylated nucleosides and trifluorinated organoborane heterocycles, demonstrating their versatility. While sharing similarities with trifluorodiazoethane reactivity, trifluoromethylnitrones offer distinct advantages by enabling the synthesis of heterocycles typically inaccessible with trifluorodiazoethane.
PubMed: 38881404
DOI: 10.1039/d4ob00849a -
Chemical Communications (Cambridge,... Jun 2024The switchable synthesis of 3-aminoindolines and 2'-aminoaryl acetic acids from the same substrates, 3-azido-2-hydroxyindolines, was developed through denitrogenative...
The switchable synthesis of 3-aminoindolines and 2'-aminoaryl acetic acids from the same substrates, 3-azido-2-hydroxyindolines, was developed through denitrogenative electrophilic amination of Grignard reagents. The key to success is the serendipitous discovery that the reaction conditions, including solvents and reaction temperature, can affect the chemoselectivity. It is noteworthy that isotope-labeling experiments revealed the occurrence of the aziridine intermediate in the production of 2'-aminoaryl acetic acids.
PubMed: 38847113
DOI: 10.1039/d4cc01448k -
The Journal of Organic Chemistry Jun 2024The nucleophilic ring-opening of aziridine derivatives provides an important synthetic tool for the preparation of various β-functionalized amines. Amines as...
The nucleophilic ring-opening of aziridine derivatives provides an important synthetic tool for the preparation of various β-functionalized amines. Amines as nucleophiles are employed to prepare synthetically useful 1,2-diamines in the presence of various catalysts or activators. Herein, the B(OH)-mediated reductive ring-opening transformation of -tosyl aziridines by nitroarenes was developed. This aqueous protocol employed nitroarenes as cheap and readily available amino sources and proceeds under external catalyst-free conditions. Control experiments and DFT calculations pointed to the reduction of nitroarenes to aryl amines via -aryl boramidic acid () and an S1-type ring-opening of -tosylaziridines by the resultant aryl amines with high regioselectivity.
PubMed: 38831644
DOI: 10.1021/acs.joc.4c00591 -
Chembiochem : a European Journal of... Jun 2024Only 0.016% of all known natural products contain an aziridine ring, but this unique structural feature imparts high reactivity and cytotoxicity to the compounds in...
Only 0.016% of all known natural products contain an aziridine ring, but this unique structural feature imparts high reactivity and cytotoxicity to the compounds in which it is found. Until 2021, no naturally occurring azirdine-forming enzymes had been identified. Since 2021, the biosynthetic enzymes for ~10% of known aziridine containing natural products have been identified and characterized. This article describes the recent advances in our understanding of enzyme-catalyzed aziridine formation in the context of historical means of azirdine formation through synthetic chemistry.
PubMed: 38830838
DOI: 10.1002/cbic.202400295 -
Trends in Chemistry Feb 2024
PubMed: 38827493
DOI: 10.1016/j.trechm.2023.12.003