Search Results (28)

Acute kidney injury (AKI) is a global public health problem with its pathogenesis not fully understood. Excessive apoptosis of renal tubular epithelial cells is an important feature of AKI patients, and therefore an anti-apoptotic approach could be used in the treatment for AKI. Up-regulation of B-cell lymphoma-2 (BCL-2) gene and protein has been found to be correlated with anti-apoptosis of cells. It has been found that the presence of the C-rich sequence on the upstream region of the BCL-2 gene promoter could form DNA secondary i-motif structure, and its stabilization by small molecules could up-regulate gene transcription and translation. In the present study, we constructed AKI models through folic acid (FA) induction. With these in vitro and in vivo models, we demonstrated that the acridone derivative A22 could up-regulate the expression of BCL-2 by targeting its gene promoter i-motif to reduce renal tubular epithelial cell apoptosis and improve renal function in many ways. A22 could alleviate FA-induced oxidative stress injury, inflammatory response, and endoplasmic reticulum stress in mouse kidneys. Our results provided a potentially new anti-apoptotic approach for the treatment of early stages of AKI. Our employed model focused on its short-term effect on AKI, while its long-term efficacy and safety, particularly regarding the regeneration of renal tubular epithelial cells, require further investigation before clinical application. This study further demonstrated that promoter i-motif could be targeted for up-regulating BCL-2 expression for the treatment of important diseases caused by excessive apoptosis. Full article

In this work, two novel acridone-based photoinitiators were designed and synthesized for the free radical polymerization of acrylates with a light-emitting diode emitting at 405 nm. These acridone derivatives were employed as mono-component Type II photoinitiators and as multicomponent photoinitiating systems in the presence of an iodonium salt or an amine synergist (EDB) in which they achieved excellent polymerization initiating abilities and high final conversions of the acrylate group. Photoinitiation mechanisms through which reactive species are produced were investigated employing different complementary techniques including steady-state photolysis, steady-state fluorescence, cyclic voltammetry, UV–visible absorption spectroscopy, and electron spin resonance spectroscopy. Finally, these molecules were also used in the direct laser writing process for the fabrication of 3D objects. Full article

Because of environmental impact, there is a great need for chemosensors, especially for toxic heavy metals such as lead. The conventional instrumental analytical techniques rarely provide an available real-time sensing platform, thus the development of highly selective and stable synthetic chemosensor molecules is of great importance. Acridono-18-crown-6 ethers have such properties, and much research has proven their outstanding applicability in various supramolecular devices. In this present work, we aimed to enable their covalent immobilization capability by synthesizing functionalized derivatives while preserving the favored molecular recognition ability. Several new macrocycle analogues were synthesized, while synthetization difficulties and design aspects were also dealt with. The selectivity of the macrocycle analogues was studied using UV–Vis spectroscopy and compared with that of the parent compounds. The ultimate crown ether derivative showed high Pb²⁺-selectivity, reversibility (decomplexation by extraction with water) and stability. Full article

Breast cancer, especially the aggressive triple-negative subtype, poses a serious health threat to women. Unfortunately, effective targets are lacking, leading to a grim prognosis. Research highlights the crucial role of c-MYC overexpression in this form of cancer. Current inhibitors targeting c-MYC focus on stabilizing its G-quadruplex (G4) structure in the promoter region. They can inhibit the expression of c-MYC, which is highly expressed in triple-negative breast cancer (TNBC), and then regulate the apoptosis of breast cancer cells induced by intracellular ROS. However, the clinical prospects for the application of such inhibitors are not promising. In this research, we designed and synthesized 29 acridone derivatives. These compounds were assessed for their impact on intracellular ROS levels and cell activity, followed by comprehensive QSAR analysis and molecular docking. Compound N8 stood out, significantly increasing ROS levels and demonstrating potent anti-tumor activity in the TNBC cell line, with excellent selectivity shown in the docking results. This study suggests that acridone derivatives could stabilize the c-MYC G4 structure. Among these compounds, the small molecule N8 shows promising effects and deserves further investigation. Full article

Artur Silva’s research group has a long history in the field of medicinal chemistry. The development of new synthetic methods for oxygen (mostly polyphenols, e.g., 2- and 3-styrylchromones, xanthones, flavones) and nitrogen (e.g., pyrazoles, triazoles, acridones, 4-quinolones) heterocyclic compounds in order to be assessed as antioxidant, anti-inflammatory, antidiabetic, and anticancer agents has been the main core work of our research interests. Additionally, the synthesis of steroid-type compounds as anti-Alzheimer drugs as well as of several chromophores as important dyes for cellular imaging broadened our research scope. In this review article, we intend to provide an enlightened appraisal of all the bioactive compounds and their biological properties that were synthesized and studied by our research group in the last two decades. Full article

A total of 21 novel xanthone and acridone derivatives were synthesized using the reactions of 1,2,4-triazine derivatives with 1-hydroxy-3-methoxy-10-methylacridone, 1,3-dimethoxy-, and 1,3-dihydroxanthone, followed by optional dihydrotiazine ring aromatization. The synthesized compounds were evaluated for their anticancer activity against colorectal cancer HCT116, glioblastoma A-172, breast cancer Hs578T, and human embryonic kidney HEK-293 tumor cell lines. Five compounds (7a, 7e, 9e, 14a, and 14b) displayed good in vitro antiproliferative activities against these cancer cell lines. Compounds 7a and 7e demonstrated low toxicity for normal human embryonic kidney (HEK-293) cells, which determines the possibility of further development of these compounds as anticancer agents. Annexin V assay demonstrated that compound 7e activates apoptotic mechanisms and inhibits proliferation in glioblastoma cells. Full article

Boron neutron capture therapy (BNCT) is a re-emerging technique for selectively killing tumor cells. Briefly, the mechanism can be described as follows: after the uptake of boron into cells, the thermal neutrons trigger the fission of the boron atoms, releasing the α-particles and recoiling lithium particles and high-energy photons that damage the cells. We performed a detailed study of the reactor dosimetry, cellular dose assessment, and radiobiological effects induced by BNCT in glioblastoma (GBM) cells. At maximum reactor power, neutron fluence rates were ϕ₀ = 6.6 × 10⁷ cm⁻² s⁻¹ (thermal) and θ = 2.4 × 10⁴ cm⁻² s⁻¹ with a photon dose rate of 150 mGy·h⁻¹. These values agreed with simulations to within 85% (thermal neutrons), 78% (epithermal neutrons), and 95% (photons), thereby validating the MCNPX model. The GEANT4 simulations, based on a realistic cell model and measured boron concentrations, showed that >95% of the dose in cells was due to the BNC reaction. Carboranylmethylbenzo[b]acridone (CMBA) is among the different proposed boron delivery agents that has shown promising properties due to its lower toxicity and important cellular uptake in U87 glioblastoma cells. In particular, the results obtained for CBMA reinforce radiobiological effects demonstrating that damage is mostly induced by the incorporated boron with negligible contribution from the culture medium and adjacent cells, evidencing extranuclear cell radiosensitivity. Full article

Aromatic heterocycles can be found in many molecules endowed with specific properties, in particular for applications in the fields of medicinal chemistry and materials science. In this group, we notably develop synthetic methodologies to selectively introduce iodine onto aromatic compounds and to use this heavy halogen in order to build heterocycles of interest. While we sometimes employed direct iodinations on electron-enriched aromatic compounds, we mainly optimized deprotometallation–iodolysis sequences to functionalize substrates sensitive to nucleophilic attacks. In particular, hindered lithium amide–metal trap tandems have been designed to overcome the low tolerance of some functional groups (e.g., ketones or sensitive diazines) toward organolithiums. The aromatic iodides generated in these ways have been involved in transition metal–catalyzed cross-couplings to access original scaffolds (oxazoloquinoxalines, pyrazinoisatins, pyrazinocarbazoles, etc.). We specifically developed the use of aromatic iodides in the copper-mediated N-arylation of anilines, e.g., to reach triarylamines. Combined with subsequent cyclizations, these reactions allowed access to numerous heterocyclic compounds (such as acridones, acridines, other aza-aromatic polycycles and helicene-like structures) with potential applications. From some of the scaffolds obtained, biological evaluation in the frame of collaborations allowed properties of interest to be discovered (e.g., specific inhibition of protein kinases GSK-3 or PIM, related to cancer development). Full article

The present study aimed to investigate the effect of acridone alkaloids on cancer cell lines and elucidate the underlying molecular mechanisms. The ten acridone alkaloids from Atalantia monophyla were screened for cytotoxicity against LNCaP cell lines by a WST-8 assay. Then, the most potential acridone, buxifoliadine E, was evaluated on four types of cancer cells, namely prostate cancer (LNCaP), neuroblastoma (SH SY5Y), hepatoblastoma (HepG2), and colorectal cancer (HT29). The results showed that buxifoliadine E was able to significantly inhibit the proliferation of all four types of cancer cells, having the most potent cytotoxicity against the HepG2 cell line. Western blotting analysis was performed to assess the expression of signaling proteins in the cancer cells. In HepG2 cells, buxifoliadine E induced changes in the levels of Bid as well as cleaved caspase-3 and Bax through MAPKs, including Erk and p38. Moreover, the binding interaction between buxifoliadine E and Erk was investigated by using the Autodock 4.2.6 and Discovery Studio programs. The result showed that buxifoliadine E bound at the ATP-binding site, located at the interface between the N- and C-terminal lobes of Erk2. The results of this study indicate that buxifoliadine E suppressed cancer cell proliferation by inhibiting the Erk pathway. Full article

Type II DNA topoisomerase (topo II) is an essential nuclear enzyme and a well-validated anticancer drug target. Previously, we have carried out several rounds of structural optimizations on our in-house topo II inhibitor E17, which was shown to have superior anticancer activity and less risk of multidrug resistance (MDR). Among the newly developed acridone derivatives, 6h displayed significant anticancer efficacy with unique mechanisms of action. At low concentrations, it arrested cancer cell cycles and triggered cell apoptosis, which is similar to the action of the well-known topo II inhibitor VP16. By contrast, 6h showed significant and long-term anti-proliferative activity at relatively high concentrations, with negligible influence on apoptosis. In addition, 6h exhibited no serious cardiotoxicity compared to doxorubicin (DOXO), a widely used topo II-targeting antineoplastic drug in clinic, but with damaging myocardial side effects. Collectively, our present work has supported the therapeutic value of 6h as a promising chemotherapy for cancers. Full article

Ten acridones isolated from Atalantia monophylla were evaluated for effects on Alzheimer’s disease pathogenesis including antioxidant effects, acetylcholinesterase (AChE) inhibition, prevention of beta-amyloid (Aβ) aggregation and neuroprotection. To understand the mechanism, the type of AChE inhibition was investigated in vitro and binding interactions between acridones and AChE or Aβ were explored in silico. Drug-likeness and ADMET parameters were predicted in silico using SwissADME and pKCSM programs, respectively. All acridones showed favorable drug-likeness and possessed multifunctional activities targeting AChE function, Aβ aggregation and oxidation. All acridones inhibited AChE in a mixed-type manner and bound AChE at both catalytic anionic and peripheral anionic sites. In silico analysis showed that acridones interfered with Aβ aggregation by interacting at the central hydrophobic core, C-terminal hydrophobic region, and the key residues 41 and 42. Citrusinine II showed potent multifunctional action with the best ADMET profile and could alleviate neuronal cell damage induced by hydrogen peroxide and Aβ_1-42 toxicity. Full article

Nitric oxide (NO) is an important signaling molecule involved in a wide range of physiological and pathological processes. Fluorescent imaging is a useful tool for monitoring NO concentration, which could be essential in various biological and biochemical studies. Here, we report the design of a novel small-molecule fluorescent probe based on 9(10H)acridone moiety for nitric oxide sensing. 7,8-Diamino-4-carboxy-10-methyl-9(10H)acridone reacts with NO in aqueous media in the presence of O₂, yielding a corresponding triazole derivative with fivefold increased fluorescence intensity. The probe was shown to be capable of nitric oxide sensing in living Jurkat cells. Full article

A synthetic route to new heterocyclic 1,1-donor–acceptor-substituted alkenes starting with N-methyl-acridone, xanthone, and thioxanthone was investigated, leading to the acridone- and xanthone-derived products methyl 2-methoxy-2-(10-methylacridin-9 (10H)-ylidene)acetate (7) and methyl 2-methoxy-2-(9H-xanthen-9-ylidene)acetate (10) in low yields with the de-methoxylated product methyl 2-(10-methylacridin-9 (10H)-ylidene)acetate (8) and the reduced compound methyl 2-methoxy-2-(9H-xanthen-9-yl)acetate (11) as the major products from N-methyl acridone and xanthone. From thioxanthone, only the rearrangement and reduction products (14) and (15) resulted. The photophysical properties of compounds (7), (8), and (10) were investigated in the presence and absence of the Brønsted acid TFA by NMR, UV–VIS absorption, and fluorescence spectroscopy. Protonation of the acridone-derived alkenes (7) and (8) led to strong bathochromic and hyperchromic fluorescence shifts and a substantial increase in Stokes shift. The photooxygenation experiments with these substrates showed an unusual reactivity pattern in the singlet oxygen processes: whereas the electron-rich enolether (7) was chemically unreactive, (8) and (10) were oxidatively cleaved, presumably via intermediate 1,2-dioxetanes. Full article

N-alkylated amino acids occur widely in nature and can also be found in bioactive secondary metabolites such as the glycopeptide antibiotic vancomycin and the immunosuppressant cyclosporine A. To meet the demand for N-alkylated amino acids, they are currently produced chemically; however, these approaches often lack enantiopurity, show low product yields and require toxic reagents. Fermentative routes to N-alkylated amino acids like N-methyl-l-alanine or N-methylantranilate, a precursor of acridone alkaloids, have been established using engineered Corynebacterium glutamicum, which has been used for the industrial production of amino acids for decades. Here, we describe metabolic engineering of C. glutamicum for de novo production of N-methylphenylalanine based on reductive methylamination of phenylpyruvate. Pseudomonas putida Δ-1-piperideine-2-carboxylate reductase DpkA containing the amino acid exchanges P262A and M141L showed comparable catalytic efficiencies with phenylpyruvate and pyruvate, whereas the wild-type enzyme preferred the latter substrate over the former. Deletion of the anthranilate synthase genes trpEG and of the genes encoding branched-chain amino acid aminotransferase IlvE and phenylalanine aminotransferase AroT in a strain engineered to overproduce anthranilate abolished biosynthesis of l-tryptophan and l-phenylalanine to accumulate phenylpyruvate. Upon heterologous expression of DpkA^P262A,M141L, N-methylphenylalanine production resulted upon addition of monomethylamine to the medium. In glucose-based minimal medium, an N-methylphenylalanine titer of 0.73 ± 0.05 g L⁻¹, a volumetric productivity of 0.01 g L⁻¹ h⁻¹ and a yield of 0.052 g g⁻¹ glucose were reached. When xylose isomerase gene xylA from Xanthomonas campestris and the endogenous xylulokinase gene xylB were expressed in addition, xylose as sole carbon source supported production of N-methylphenylalanine to a titer of 0.6 ± 0.04 g L⁻¹ with a volumetric productivity of 0.008 g L⁻¹ h⁻¹ and a yield of 0.05 g g⁻¹ xylose. Thus, a fermentative route to sustainable production of N-methylphenylalanine by recombinant C. glutamicum has been established. Full article

A new coumarin-acridone fluorescent probe S was designed and synthesized, and the structure was confirmed with ¹H/¹³C NMR spectrometry, single-crystal X-ray diffraction, and high-resolution mass spectrometry. This probe has high sensitivity and selectivity for Fe³⁺ over other testing metal ions at 420 or 436 nm in acetonitrile–MOPS (3-Morpholinopropanesulfonic Acid) buffer solution (20.0 μM, pH = 6.9, 8:2 (v/v)). Under physiological conditions, the probe displayed satisfying time stability with a detection limit of 1.77 µM. In addition, probe S was successfully used to detect intracellular iron changes through a fluorescence-off mode, and the imaging results of cells and zebrafish confirmed their low cytotoxicity and satisfactory cell membrane permeability, as well as their potential biological applications. Full article