Design, synthesis and evaluation of acridone-2-carbohydrazide derivatives as p-AKT Ser473 kinase inhibitors.

Aim: A series of benzylidene- and phenylethylidene-substituted acridone-2-carbohydrazide derivatives were designed, synthesized and evaluated for their cytotoxicity and response to p-AKT Ser473. Methods: The structures of the synthesized compounds were confirmed by spectroscopic techniques and evaluated for AKT enzyme inhibition activities. Molecular docking and in silico absorption, distribution, metabolism, elimination and toxicity studies were also performed. Results: Compounds 8k, 8v and 9h demonstrated good cytotoxicity against breast cancer cell lines. Especially, compounds 8v and 9h exhibited remarkable inhibition, with IC50 values of 1.75 and 2.40 µM, respectively. These compounds inhibited p-AKT Ser473 more specifically than total AKT in a dose-dependent manner. Moreover, they caused G0/G1-phase cell cycle arrest and cell apoptosis. Conclusion: This study identified compound 8v as a potent p-AKT Ser473 inhibitor.

Transition-Metal-Free Approach to Acridone Derivatives by TBHP-Promoted Oxidative Annulation of Isatins with Arynes.

A tert-butyl hydroperoxide-promoted oxidative annulation reaction of isatins with 2-(trimethylsilyl)aryl triflates for the convenient synthesis of acridone derivatives has been established. Mechanistic investigation suggested that the reaction may proceed via consecutive Baeyer-Villiger-type rearrangement followed by an intermolecular cyclization. This synthetic approach offers several advantages, including broad substrate scope, good functional group tolerance, and simplicity of operation. Additionally, successful late-stage modification of the obtained compounds was achieved, expanding the application potential of this methodology in organic synthesis.

Syntheses and evaluation of acridone derivatives as anticancer agents targeting Kras promoter i-motif structure.

Two series of novel acridone derivatives were designed and synthesized, with their anticancer activity evaluated. Most of these compounds showed potent antiproliferative activity against cancer cell lines. Among them, compound C4 with dual 1,2,3-triazol moieties exhibited the most potent activity against Hep-G2 cells with IC50 value determined to be 6.29 ± 0.93 µM. Subsequent experiments showed that C4 could bind to and destabilize Kras gene promoter i-motif structure without significant interaction with its corresponding G-quadruplex. C4 could down-regulate Kras expression in Hep-G2 cells, possibly due to its interaction with the Kras i-motif. Further cellular studies indicated that C4 could induce apoptosis of Hep-G2 cells, possibly related to its effect on mitochondrial dysfunction. These results indicated that C4 could be further developed as a promising anticancer agent.

Acridine/Acridone-Carborane Conjugates as Strong DNA-Binding Agents with Anticancer Potential.

Synthesis of acridine derivatives that act as DNA-targeting anticancer agents is an evolving field and has resulted in the introduction of several drugs into clinical trials. Carboranes can be of importance in designing biologically active compounds due to their specific properties. Therefore, a series of novel acridine analogs modified with carborane clusters were synthesized. The DNA-binding ability of these analogs was evaluated on calf thymus DNA (ct-DNA). Results of these analyses showed that 9-[(1,7-dicarba-closo-dodecaborane-1-yl)propylamino]acridine (30) interacted strongly with ct-DNA, indicating its ability to intercalate into DNA, whereas 9-[(1,7-dicarba-closo-dodecaborane-1-yl)propanamido]acridine (29) changed the B-form of ct-DNA to the Z form. Compound 30 demonstrated cytotoxicity, was able to inhibit cell proliferation, arrest the cell cycle in the S phase in the HeLa cancer cell line, and induced the production of reactive oxygen species (ROS). In addition, it was specifically localized in lysosomes and was a weak inhibitor of Topo IIα.

A FRET-based ratiometric fluorescent probe for Hg2+ detection in aqueous solution and bioimaging in multiple samples.

Mercury ion, as a metal cation with great toxic effect, is widely present in various production and living environments. It seriously threatens human health and environmental safety. It is of great significance to develop convenient and effective methods for mercury ion detection. Here, we designed and synthesized a new ratiometric fluorescent probe (namely APS-NA) for the detection of mercury ions in the environment and multiple biological samples. The probe is constructed by covalently connecting two fluorophores with lipolic acid to achieve fluorescence resonance energy transfer (FRET). In the molecular structure of APS-NA, acridone is used as an energy donor, 1,8-naphthalimide is used as an energy acceptor, and a dithioacetal group is used as the reaction site for Hg2+. The intact APS-NA mainly shows the green fluorescence from the acceptor moiety 1,8-naphthalimide; the presence of Hg2+ ions would break the dithioacetal linkage between acridone and 1,8-naphthalimide; the defunctionalization of FRET would lead to bright blue fluorescence emission of acridone; thus ratiometric fluorescent detection of Hg2+ can be achieved by this recognition process. The probe not only has a large Stokes shift (Δλ = 110 nm), but also has high selectivity, high sensitivity (low detection limit 30 nM) and naked eye visualization. In addition, we have successfully used this probe for the detection Hg2+ of actual samples and imaging of a variety of organisms. These results indicate that the probe has broad application prospects.

Development of new 1, 3-dihydroxyacridone derivatives as Akt pathway inhibitors in skeletal muscle cells.

In the present work, four new compounds based on the privileged structure acridone were efficiently synthesized following simple operational techniques and biologically tested on proliferative skeletal muscle cells (C2C12) and rhabdomyosarcoma cells (RD) showing no significant changes in the number of dead or viable cells at 1 µM during 24 or 48 h of treatment. Of relevance, acridone derivatives 3a-3d at 0.5 µM for 24 h effectively inhibited Akt activation in C2C12, while at 1 µM only compounds 3a and 3b have effect. RD cells showed a different response pattern. These cells treated with 3a (0.5 µM), 3b (0.5 µM) or 3d (0.5 or 1 µM) for 24 h shown significant Akt inhibition. In addition, 3a-3d assayed at 1 µM for 48 h were highly successful in inhibiting Akt phosphorylation. Finally, based on molecular docking and molecular dynamics simulations, we rationalize the experimental results mentioned above and propose that 3-phosphoinositide-dependent kinase-1 (PDK1) could be one of the molecular targets of this new series of 1, 3-dihydroxyacridone derivatives. Biological and in silico studies revealed that 3b could be considered as the most promising prototype for the development of new antitumor agents.

Effect of Lysine Acridone Acetate on the Level of Apoptosis and Expression of Apoptosis-Associated Proteins during Antioncogenic Therapy in Colorectal Cancer in Mice.

We studied the mechanism of action of cytostatics with the addition of lysine acridone acetate to evaluate the possibility of its use for improving the effectiveness of antioncogenic therapy in colorectal cancer. In Nude mouse model, the level of apoptosis (TUNEL) and expression of proteins CD95, p53, Bcl-2, histone H3, and Ki-67 (immunohistochemistry) were assessed in primary tumor biopsy specimens. It has been shown that cytostatic treatment led to stimulation of p53-mediated apoptosis and suppression of proliferation (Ki-67 expression) of tumor cells, and apoptosis level was increased in groups receiving lysine acridone acetate. H3 expression in the experimental groups was changed.

Anti-inflammatory constituents from the stems and leaves of Glycosmis ovoidea Pierre.

Seven undescribed compounds, including four acridones, two coumarins, and a phenylpropanoid, together with 13 known acridone analogues were isolated from the ethanolic extract of the stems and leaves of Glycosmis ovoidea Pierre. Their structures were elucidated on the basis of comprehensive analysis of 1D and 2D NMR and HRESIMS spectroscopic data, and the absolute configurations were assigned by comparison of the experimental and calculated ECD data. Five compounds showed moderate inhibitory effects on nitric oxide production stimulated by lipopolysaccharide in BV-2 microglial cells with IC50 values in the range of 18.30-30.84 µM, and three compounds showed potent inhibition on 5-lipoxygenase (5-LOX) with IC50 values in the range of 2.08-10.26 µM. The possible binding sites of the active compounds with 5-LOX were further performed by molecular docking.

Acridone Derivatives from Atalantia monophyla Inhibited Cancer Cell Proliferation through ERK Pathway.

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.

A comprehensive review on acridone based derivatives as future anti-cancer agents and their structure activity relationships.

The development of drug resistance and severe side-effects has reduced the clinical efficacy of the existing anti-cancer drugs available in the market. Thus, there is always a constant need to develop newer anti-cancer drugs with minimal adverse effects. Researchers all over the world have been focusing on various alternative strategies to discover novel, potent, and target specific molecules for cancer therapy. In this direction, several heterocyclic compounds are being explored but amongst them one promising heterocycle is acridone which has attracted the attention of medicinal chemists and gained huge biological importance as acridones are found to act on different therapeutically proven molecular targets, overcome ABC transporters mediated drug resistance and DNA intercalation in cancer cells. Some of these acridone derivatives have reached clinical studies as these heterocycles have shown huge potential in cancer therapeutics and imaging. Here, the authors have attempted to compile and make some recommendations of acridone based derivatives concerning their cancer biological targets and in vitro-cytotoxicity based on drug design and novelty to increase their therapeutic potential. This review also provides some important insights on the design, receptor targeting and future directions for the development of acridones as possible clinically effective anti-cancer agents.

A dual-modal aptasensor based on a multifunctional acridone derivate for exosomes detection.

Exosomes are promising biomarkers for cancer screening, but the development of a robust approach that can sensitively and accurately detect exosomes remains challenging. In the present study, an aptasensor based on the multifunctional signal probe 10-benzyl-2-amino-acridone (BAA) was developed for the colorimetric and photoelectrochemical detection and quantitation of exosomes. Exosomes are captured by cholesterol DNA anchor-modified magnetic beads (MBs) through hydrophobic interactions. This capture process can be monitored under a confocal fluorescence microscope using BAA as the fluorescent signal probe. The aptamer modified copper oxide nanoparticles (CuO NPs) then bind to mucin 1 (MUC1) on the surface of the exosomes to form a sandwich structure (MBs-Exo-CuO NPs). Finally, the MBs-Exo-CuO NPs are dissolved in nitric acid to generate Cu2+, which inhibits the visible-light-induced oxidase mimic activity and photoelectrochemical activity of BAA simultaneously. The changes in absorbance and photocurrent intensities are directly proportional to the concentration of exosomes. In this dual-modal aptasensor, the colorimetric assay can achieve rapid screening and identification, which is especially useful for point-of-care testing. The UV-vis absorbance and photocurrent assays then provide quantitative information, with a limit of detection of 1.09 × 103 particles µL-1 and 1.38 × 103 particles µL-1, respectively. The proposed aptasensor thus performs dual-modal detection and quantitation of exosomes. This aptasensor provides a much-needed toolset for exploring the biological roles of exosomes in specific diseases, particularly in the clinical setting.

Structural optimizations and bioevaluation of N-substituted acridone derivatives as strong topoisomerase II inhibitors.

Previously, an array of N-substituted acridone derivatives have been reported as potent topoisomerase II (topo II) inhibitors, and preliminary structure-activity relationship (SAR) outcomes revealed that the linker between 1-NH and N-methyl piperazine motif of the tricyclic acridone scaffold significantly affected their anti-proliferative potencies. To further explore the SARs of acridone-derived topo II inhibitors, a wider range of novel acridone derivatives were herein synthesized via two rounds of structural optimizations on two validated hits, E17 and E24. Initially, the linker length was optimized, and then influences of N-methyl piperazinyl moiety and disposition of three N atoms on the bioactivity were investigated. As a result, a newly developed topo II inhibitor 6 h was found to be more potent than E17 and E24, thereby serving as a tool compound for the follow-up mechanistic study. Compound 6 h functioned as a strong topo IIα/ß inhibitor, caused obvious DNA damage, and induced apoptosis by triggering the loss of mitochondrial membrane potential (Δψm). Further molecular docking and MD study illustrated the favorable interactions of 6 h with both topo IIα and topo IIß subtypes.

Acridone alkaloids and flavones from the leaves of Citrus reticulata.

A new acridone alkaloid, reticarcidone A (1), decorated with an oxygenated isopentenyl group between C-1 and C-2, was isolated from the leaves of Citrus reticulata Blanco, together with nine known acridone alkaloids (2-10) and fifteen flavones compounds (11-25). The structure of those compounds were confirmed by analysis of comprehensive 1D and 2D NMR, and MS data. Reticarcidone A (1) was the first pyrano[2,3-a]acridone isolated from the genus Citrus. Some of these compounds showed moderated cytotoxicity against the five human tumor cell lines MCF-7, SMMC-7721, HL-60, A549 and SW480.

Direct Observation of Ultrafast Access to a Solvent-Independent Singlet-Triplet Equilibrium State in Acridone Solutions.

Acridone and its derivatives have potential application as emitters for highly efficient blue organic light-emitting diodes (OLEDs). In this paper, we demonstrated ultrafast access of a solvent-independent singlet-triplet equilibrium state in acridone solutions by using femtosecond time-resolved spectroscopy. Our spectral data show that due to highly effective forward and reverse intersystem crossing (both kISC and krISC over 1010 s-1), a singlet-triplet equilibrium state is always populated in acridone in all solvents studied. However, the lifetimes of the equilibrium state varied a lot in different solvent environments and the final decay pathway of this state can switch between high quantum yield fluorescence emission and further internal conversion to the lowest triplet state. These findings provide direct experimental evidence to understand the distinct photophysical behaviors of acridone and also provide guidance for further design of acridone and its derivatives as blue OLED emitters.

Room Temperature Phosphorescence vs Triplet-Triplet Annihilation in N-Substituted Acridone Solids.

Organic room temperature phosphorescent (ORTP) compounds have recently emerged as a promising class of emissive materials with a multitude of potential applications. However, the number of building blocks that give rise to efficient ORTP materials is still limited, and the rules for engineering phosphorescent properties in organic solids are not well understood. Here, we report ORTP in a series of N-substituted acridone derivatives with electron-donating, electron-withdrawing, and sterically bulky substituents. X-ray crystallography shows that the solid-state packing varies progressively between coparallel and antiparallel π-stacking and separated π-dimers, depending on the size of the substituent. The detailed photophysical studies supported by DFT calculations reveal complex dynamics of singlet and triplet excited states, depending on the electronic effects of substituents and solid-state packing. The programmable molecular packing provides a lever to control the triplet-triplet annihilation that is manifested as delayed fluorescence in acridone derivatives with continuous (both parallel and antiparallel) π-stacking.

Design and Synthesis of New Acridone-Based Nitric Oxide Fluorescent Probe.

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.

Acridones: Strongly Emissive HIGHrISC Fluorophores.

An acridone derivative (N-methyl-difluoro-acridone, NMA-dF) is characterized with respect to its utility as an emitter in organic light emitting diodes (OLEDs). Using steady-state and time-resolved spectroscopy as well as quantum chemistry, its ability to convert singlet and triplet excitons into light was scrutinized. NMA-dF emits in the deep blue range of the visible spectrum. Its fluorescence emission occurs with quantum yields close to 1 and a radiative rate constant of ≈5 × 108 s-1. So, it processes singlet excitons very efficiently. Using 1,4-dichlorobenzene as a sensitizer, it is shown that NMA-dF also converts triplet excitons into light. With the aid of quantum chemistry, this is related to a reverse intersystem crossing starting from a higher triplet state (HIGHrISC).

A New Coumarin-Acridone Compound as a Fluorescence Probe for Fe3+ and Its Application in Living Cells and Zebrafish.

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.

Synthesis of Xanthones, Thioxanthones and Acridones by a Metal-Free Photocatalytic Oxidation Using Visible Light and Molecular Oxygen.

9H-Xanthenes, 9H-thioxanthenes and 9,10-dihydroacridines can be easily oxidized to the corresponding xanthones, thioxanthones and acridones, respectively, by a simple photo-oxidation procedure carried out using molecular oxygen as oxidant under the irradiation of visible blue light and in the presence of riboflavin tetraacetate as a metal-free photocatalyst. The obtained yields are high or quantitative.

A colorimetric sensor for acid phosphatase activity detection based on acridone derivative as visible-light-stimulated oxidase mimic.

Currently, organic artificial enzymes as biocatalysts have been extensively used to construct various colorimetric sensors. However, exploiting a potential organic artificial enzyme with high catalytic efficiency still remains a challenge. To address this issue, herein, we synthesize an acridone derivative 10-benzyl-2-amino-acridone (BAA). The synthesized BAA exhibits an intrinsic visible-light-stimulated oxidase-like activity, which is capable of oxidizing various chromogenic substrates without destructive hydrogen peroxide (H2O2) under visible light stimulation, resulting in colored products. The reaction system can be regulated by switching light on and off, which is milder and more reliable means than others H2O2-dependent. The photocatalytic mechanism of BAA is investigated in detail. However, l-ascorbic acid (AA), an antioxidant generating from the acid phosphatase (ACP)-mediated hydrolysis of 2-phospho-l-ascorbic acid (AAP), is able to inhibit the catalytic activity of BAA. Based on the above properties, a facile, photo-switchable and low-cost colorimetric sensing strategy is developed for ACP detection. The linear range is 0.05-2.5 U/L (r = 0.9994), and the limit of detection (LOD) is 0.0415 U/L. Moreover, the proposed sensing system can be applied for monitoring ACP activity in practical samples, demonstrating promising applications in clinical analysis and biosensor platform.