Bioorganic Chemistry最新文献

In this study, a series of BODIPY dyes were synthesized, containing various substituents at meso position. Further functionalization of the BODIPY framework at C2 and C2-C6 position(s) by palladium-catalysed cross-coupling reactions using organoindium reagents (R₃In) was efficiently assessed, starting from C2(6)-halogenated BODIPYs, and their optical properties were measured. The cytotoxicity of BODIPY dyes on SH-SY5Y neuronal cells by MTT assay showed that those compounds bearing thien-2-yl and benzonitrile moieties at meso position, exhibited great efficiency in maintaining cell viability under all tested conditions (up to 50 µM for 24 h and 48 h). Furthermore, nanoliposomal encapsulation of a hydrophobic BODIPY, incorporating bis(trifluoromethyl)phenyl substituents at C2 and C6 positions, through the lipid-extrusion method was addressed. The liposomes exhibited spherical shape as observed in cryo-TEM image, with average particle size of 120 nm (average PdI 0.05) and Zeta potential 54.69 mV by DLS measurements. Simple incubation of gliobastoma U-87 cells with prepared liposomes led to efficient internalization, and visualization of brightness BODIPY in cytoplasm using fluorescence confocal microscopy, demonstrating encapsulation enhance biocompatibility of the hydrophobic BODIPY as preliminary approximation for further biomedical applications.

Background: Tumor-specific molecular probe-based imaging strategies have shown great potential for tumor diagnosis. However, the sensitivity and contrast of imaging may interfere with the complex labeling process and degradation of tumor-specific imaging probes. We sought to adapt a pretargeting strategy and an in vivo bioorthogonal reaction to improve hyaluronan (HA)-based tumor multimodal imaging diagnosis.

Methods: Transcyclooctene-labeled HA (HA-TCO) and tetrazine-labeled NODA (NODA-Tz) were synthesized and purified. Probes Gd-NODA-Tz and [¹⁸F]AlF-NODA-Tz for magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging were prepared. The bioorthogonal reaction of HA-TCO with NODA-Tz and the stability of the products were confirmed and analyzed. CD44 + A549 tumor-bearing mice were injected with HA-TCO via the tail vein, followed by Gd-NODA-Tz or [¹⁸F]AlF-NODA-Tz administration half an hour later, and subsequently imaged by MR or PET. The images were analyzed and tumor uptake was quantified.

Results: HA-TCO efficiently bound to CD44-overexpressing A549 cells and selectively reacted with the Tz-imaging group. In vivo MR and PET images were obtained after probe injection and subsequent bioorthogonal labeling. The images showed a tumor mass with a high target background ratio (TBR) and clear boundaries.

Conclusion: In situ labeling of pretargeted HA-TCO enabled MRI and PET imaging of tumor tissues in mice with high sensitivity and improved TBR.

Positron Emission Tomography (PET) has emerged as a powerful imaging technique in molecular medicine, enabling the non-invasive visualisation and quantification of biological processes at the molecular level. Antibody-based PET imaging has recently gained prominence, offering specific targeting capabilities for various diseases. This scientific article delves into the intricate chemistry underlying antibody conjugation strategies for PET, providing a comprehensive understanding of the key principles and advancements in this rapidly evolving field. The article begins with a detailed exploration of various antibody conjugation methodologies, encompassing both covalent and non-covalent approaches. The chemical intricacies of bioconjugation reactions, such as amine and thiol chemistry, click chemistry, and bioorthogonal chemistry, are thoroughly discussed in the context of antibody modification. Additionally, the article critically analyses recent advancements in radiolabeling strategies for PET, including using radionuclides with favourable decay characteristics. This discussion covers both traditional radioisotopes and emerging alternatives, demonstrating their potential to raise the effectiveness of PET imaging agents based on antibodies. Ultimately, this article aims to contribute to the ongoing efforts to advance the field toward more effective diagnostic tools for personalized medicine.

Eudesmane-type sesquiterpene lactone isoalantolactone 1 is of great interest due to its availability, biological activity and synthetic application. Respective series of original spirocyclic (11S,5') (1,2,3-triazoline-eudesma-4,15-enolides) and (11S)-aziridine-eudesma-4,15-enolides were efficiently synthesized via a chemoselective 1,3-dipolar cycloaddition reaction of organic azides to the exocyclic double bond of the lactone ring of isoalantolactone or 13E-(aryl)isoalantolactones by heating in DMF or toluene. The thermal reactions of isoalantolactone with benzyl azide, 2-azidoethanol, or n-butyl azide in 2-methoxyethanol afforded 13-(alkyamino)isoalantolactones formed as a mixture of (Z) and (E)-isomers. The results of in vitro biological assays showed that novel spirocyclic isoalantolactone derivatives exhibited cytotoxicity against human breast cancer and glioblastoma cells at low micromolar concentrations. The most cytotoxic and selective (11S,5')-spiro-1,2,3-triazoline from 13E-(fluorophenyl)isoalantolactone 20 (IC₅₀^(MCF-7) = 8 ± 0.1 µM, SI^(MCF-7) > 12.5) was found to induce ROS-dependent death of MCF-7 human breast cancer cells via mitochondrial apoptosis. The corresponding (11S)-spiroaziridine derivatives 21 at non-toxic concentrations (10 and 20 µM) effectively suppressed motility, clonogenicity and adhesion of glioblastoma cells and exhibited synergistic cytotoxicity in combination with temozolomide. In silico analysis revealed the potential ability of the 13-aryl (11S)-spiroaziridine derivative 21 to bypass the blood-brain barrier and exhibit anti-glioblastoma activity probably based on the direct interaction with Hsp90α.

This study presents the development and evaluation of triphenylphosphine-modified cyclometalated iridium^III complexes as selective anticancer agents targeting mitochondria. By leveraging the mitochondrial localization capability of the triphenylphosphine group, these complexes displayed promising cytotoxicity in the micromolar range (3.12-7.24 μM) against A549 and HeLa cancer cells, these complexes exhibit significantly higher activity compared to their unmodified counterparts lacking the triphenylphosphine moiety. Moreover, they demonstrate improved specificity for cancer cells over normal cells, achieving selectivity index in the range of 5.46-14.83. Mechanistic studies confirmed that these complexes selectively target mitochondria rather than DNA, as shown by confocal microscopy and flow cytometry, where they accumulate to induce mitochondrial dysfunction. This disruption leads to mitochondrial membrane depolarization (MMP), elevated reactive oxygen species (ROS) levels, and activation of intrinsic apoptosis pathways. Furthermore, the complexes induce cell cycle arrest at the G₂/M phase and suppress the migration of A549 cells.

Background: Hederagenin (HG), derived from ivy seeds, is known to offer protection against Alzheimer's disease (AD). However, the specific molecular pathways through which it counters ferroptosis-induced neurotoxicity are not fully elucidated. This investigation seeks to delineate the processes by which HG mitigates neurotoxic effects in HT22 cells subjected to glutamate (Glu)-induced ferroptosis.

Methods: HT22 cell ferroptosis was prompted by Glu exposure. Cell viability was assessed using CCK-8 and LDH assays, while Fe²⁺ fluorescence and assays of iron-related proteins served to gauge intracellular Fe²⁺ concentrations. Evaluations of mitochondrial structure and functionality employed JC-1 staining and transmission electron microscopy. Assessments of ROS, lipid peroxidation, MDA, 4-HNE, and the GSSG/GSH ratio were conducted to ascertain HG's antioxidative efficacy. The expression of proteins within the PPARα/Nrf2/GPX4 pathway was quantified via western blotting, with molecular docking (MD), and molecular dynamics simulations (MDS) used to explore protein interactions.

Results: HG diminished the cellular toxicity triggered by Glu in HT22 cells, lowered Fe²⁺ within cells, and rejuvenated mitochondrial morphology and performance. Concurrently, it modulated proteins critical to Fe²⁺ metabolism, diminished ROS and lipid peroxidation, and elevated GSH/GSSG ratios. Enhanced PPARα/Nrf2/GPX4 protein levels were corroborated by western blot results. Furthermore, molecular docking revealed favorable binding of HG to the proteins PPARα, Nrf2, and GPX4, with binding energies of -7.751, -7.535, and -7.414 kcal/mol, respectively. MDS confirmed robust interactions between HG and these pivotal targets.

Conclusion: The evidence suggests that HG effectively mitigates Glu-induced ferroptosis in HT22 cells by activating the PPARα/Nrf2/GPX4 signaling pathway. These findings endorse HG's potential as a nutritional adjunct for AD management.

Dysregulation of the fibroblast growth factor receptor 1 (FGFR1) signaling has prompted efforts to develop therapeutic agents, which is a carcinogenic driver of many cancers, including breast, prostate, bladder, and chronic myeloid leukemia. Despite significant progress in the development of potent and selective FGFR inhibitors, the long-term efficacy of these drugs in cancer therapy has been hampered by the rapid onset of acquired resistance. Therefore, more drug discovery strategies are needed to promote the development of FGFR-targeted drugs. Here, we discovered compound S2h, a compound that selectively and effectively degrades FGFR1 at nanomolar concentrations in KG1a cells (IC₅₀ = 26.81 nM; DC₅₀ = 39.78 nM), which incorporates an essential, nine atom-long linkers. The importance of linker length, composition, and tethering site proteolysis-targeting chimeras (PROTACs) design is emphasized, and slight modifications can significantly affect degradation potency. Meanwhile, it was verified that the degradation of FGFR1 protein at compound S2h was concentration- and time-dependent and that the protein degradation occurred through the ubiquitin-proteasome system (UPS). In summary, the newly designed heterobifunctional FGFR1 degrader, compound S2h, provides new ideas and references for the research of FGFR small-molecule degraders.

The objective of this review was to explore the trends and chemical characteristics of acridines and their derivatives, analyze their contribution to the scientific literature and international cooperation, identify the most influential authors and articles, and provide an overview of the knowledge produced in elucidating their mechanisms of action. To this end, a bibliometric analysis was performed using RStudio software, along with a systematic review focusing on articles indexed in the "Web of Science" and "Scopus" databases. The keywords used were "acridine$", "Synthesi$", "Structure$", and "Biologic* Application$" for the period from 2020 to 2024. Relevant articles were carefully selected from these databases, and a bibliometric analysis was carried out to comprehensively discuss the most relevant biological activities associated with acridines. The results showed that, during the analyzed period, China and India led in the number of publications, followed by Brazil in third place. However, a decline in the number of publications was observed in the last two years of the period. Keyword analysis revealed that antitumor activity remains the most extensively studied aspect of acridines and their derivatives.

Prostate cancer (PCa) has emerged to be the second leading cause of cancer-related deaths in men. Molecular imaging of PCa using targeted radiopharmaceuticals specifically to PCa cells promises accurate staging of primary disease, detection of localized and metastasized tumours, and helps predict the progression of the disease. Glutamate urea heterodimers have been popularly used as high-affinity small molecules in the binding pockets of popular and well-characterized PCa biomarker, prostate specific membrane antigen (PSMA). However, extensive studies in molecular docking and the QSAR model have predicted that bioisotere substitution of an oxygen atom with sulfur in the glutamate urea heterodimer molecules would yield a new library of high-affinity ligands in the nanomolar range to target PSMA. Based on these predictions, a new class of glutamate thiourea derivatives has been designed and developed for binding with PSMA. The in silico guided selection and chemical synthesis of glutamate thiourea small molecule PSMA inhibitors by a new methodology is described in this report. One of the high-affinity glutamate thiourea ligands was further chelated to radioisotopes such as ^99mTechnetium using a chelating moiety via a peptide spacer and targeted to PSMA⁺ LNCaP and 22Rv1 cells. The newly synthesized ^99mTc-bioconjugate has shown nanomolar affinity to selectively target PSMA⁺ cancers during in vitro studies. Collectively, these PSMA-specific small molecule radio-imaging agents show significant promise in monitoring disease prognosis and treatment selection of PCa patients.

Tuberculosis (TB) remains a global health challenge, claiming numerous lives each year, despite recent advancements in drug discovery and treatment strategies. Current TB treatment typically involves long-duration chemotherapy regimens that are often accompanied by adverse effects. The introduction of new anti-TB drugs, such as Bedaquiline, Delamanid, and Pretomanid, offers hope for more effective treatment, although challenges persist keeping the quest to find new anti-TB chemotypes an incessant exercise of medicinal chemists. Towards this initiative, the benzazoles continue to draw attention and have been recognised as new anti-TB scaffolds. Benzazole-containing compounds emerged as new chemotypes with potential to offer a versatile platform for new anti-TB drug design to generate new leads for further optimization. The elucidation of their chemical properties, biological effects, and potential mechanisms of action, would lead to identify innovative candidates for TB therapy. As medicinal chemists delve deeper into the SARs and mechanisms of action of benzazole derivatives, new opportunities for creating effective and safe anti-TB medications arise. This review highlights the potential impact of benzazole-based compounds on the search for new therapeutic agents against tuberculosis, emphasizing the importance of continued research and innovation in the field.