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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.

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Dual inhibition of topoisomerase (topo) II and FLT3 kinase, as in the case of C-1311, was shown to overcome the shortcomings of using topo II inhibitors solely. In the present study, we designed and synthesized two series of pyrido-dipyrimidine- and pseudo-pyrido-acridone-containing compounds. The two series were evaluated against topo II and FLT3 as well as the HL-60 promyelocytic leukemia cell line in vitro. Compounds 6, 7, and 20 showed higher potency against topo II than the standard amsacrine (AMSA), whereas compounds 19 and 20 were stronger FLT3 inhibitors than the standard DACA. Compounds 19 and 20 showed to be dual inhibitors of both enzymes. Compounds 6, 7, 19, and 20 were more potent inhibitors of the HL-60 cell line than the standard AMSA. The results of the in vitro DNA flow cytometry analysis assay and Annexin V-FITC apoptosis analysis showed that 19 and 20 induced cell cycle arrest at the G2/M phase, significantly higher total percentage of apoptosis, and late-stage apoptosis in HL-60 cell lines than AMSA. Furthermore, 19 and 20 upregulated several apoptosis biomarkers such as p53, TNFα, caspase 3/7 and increased the Bax/Bcl-2 ratio. These results showed that 19 and 20 deserve further evaluation of their antiproliferative activities, particularly in leukemia. Molecular docking studies were performed for selected compounds against topo II and FLT3 enzymes to investigate their binding patterns. Compound 19 exerted dual fitting inside the active site of both enzymes.

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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.

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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.

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The precise knowledge of intracellular polarity, a physiological parameter that involves complex and intertwined intracellular mechanisms, may be relevant in the study of important diseases like cancer or Alzheimer's. In this technical note, we illustrate our recently developed, accurate method for obtaining intracellular polarity maps employing potent fluorescence microscopy techniques. Our method is based on the selection of appropriate luminescent probes, in which several emission properties vary with microenvironment polarity, specifically spectral shifts and luminescence lifetime. A multilinear calibration is performed, correlating polarity vs. spectral shift vs. luminescence lifetime, to generate a powerful and error-free 3D space for reliable interpolation of microscopy data. Multidimensional luminescence microscopy is then used to obtain simultaneously spectral shift and luminescence lifetime images, which are then interpolated in the 3D calibration space, resulting in accurate, quantitative polarity maps.

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Seven previously undescribed acridones, named atalantiaphyllines A-G, along with twenty-six known compounds were isolated from the dichloromethane extracts of roots and stems of Atalantia monophylla DC. Their structures were elucidated by analysis of extensive NMR and HRMS data. Aromatase inhibition, cytotoxicity against MOLT-3, HepG2, A549 and HuCCA-1 cell lines and DPPH radical scavenging activity of these compounds were evaluated. Most of the tested acridones exhibited higher potency in inhibiting aromatase than the positive control, ketoconazole, with IC50 values in the range of 0.08-2.0 µM. In the cytotoxicity assay, cycloataphylline A, N-methylbuxifoliadine E and atalantiaphylline G were selectively cytotoxic against MOLT-3 cell line with IC50 values of 8.0, 5.4 and 9.8 µM, respectively, while only atalaphyllidine exhibited highest antioxidant activity as evaluated by DPPH free radical scavenging assay with an IC50 value of 22.4 µM.

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Eleven novel acridone derivatives were synthesized and evaluated for their anticancer activity against 60 human cancer cell lines. Five compounds 8b, 8d, 8g, 8h, and 8k displayed very good in vitro antiproliferative activities well over 95% of the panels. The most active compound is 8k (5, 7-dibromo-3-phenyl-3,4-dihydroacridin-1 (2H)-one). In addition, 8k was the most sensitive agent in all 9 panels starting with prostate (0.075 µm), leukemia (0.116 µm), non-small cell lung cancer (0.164 µm), colon cancer (0.193 µm), CNS cancer (0.264 µm), melanoma (0.317 µm), renal cancer (0.403 µm), ovarian cancer (0.410 µm), and breast cancer (0.608 µm). Virtual screening studies also revealed that nine of the eleven compounds formed good binding interaction with the active site ATPase domain of human topoisomerase IIα (PDB: 1zxm). All nine derivatives exhibited binding affinities that ranged in values from -8.5 to -7.9 kcal/mol, indicating that they could be catalytic inhibitors of the nuclear enzyme, topoisomerase.

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AIM: The increase in the number of fungal infections worldwide, coupled with the limitations of current antifungal chemotherapy, demand the development of safe and effective new antifungals. Here, we presented the synthesis of a novel acridone (M14) and its antifungal properties against Candida and dermatophytes species. METHODS AND RESULTS: A series of 17 acridones was designed, synthesized and tested for its antifungal activity. The minimum inhibitory concentration (MIC) was determined by the broth microdilution method. Only the acridone M14 showed growth-inhibitory activity against reference strains and clinical isolates of Candida and dermatophytes, with MIC range of 7·81-31·25 µg ml-1 . Moreover, M14 exhibited fungicidal activity and prevented biofilm formation by C. albicans as well as reduced the viability of preformed biofilms, even at sub-MICs. The confocal laser scanning microscopy analysis revealed that C. albicans hyphal growth was completely inhibited in the presence of M14. Similarly, there was a severe inhibition on hyphal growth of Trichophyton rubrum. We also found that M14 has relatively low toxicity to human fibroblasts. CONCLUSIONS: The new acridone M14 has antifungal properties against Candida spp. and dermatophytes, and antibiofilm activity against C. albicans. In addition, M14 is relatively selective to fungal cells compared to human normal cells. SIGNIFICANCE AND IMPACT OF THE STUDY: Because of its in vitro antifungal activity, anti-Candida biofilm effect and moderate cytotoxicity towards normal human cell, M14 may serve as a valuable lead compound to develop a new antifungal agent.

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In natural product studies, the purification of metabolites is an important challenge. To accelerate this step, alternatives such as integrated analytical tools should be employed. Based on this, the chemical study of Swinglea glutinosa (Rutaceae) was performed using two rapid dereplication strategies: Target Analysis (Bruker Daltonics®, Bremen, Germany) MS data analysis combined with MS/MS data obtained from the GNPS platform. Through UHPLC-HRMS data, the first approach allowed, from crude fractions, a quick and visual identification of compounds already reported in the Swinglea genus. Aside from this, by grouping compounds according to their fragmentation patterns, the second approach enabled the detection of eight molecular families, which presented matches for acridonic alkaloids, phenylacrylamides, and flavonoids. Unrelated compounds for S. glutinosa have been isolated and characterized by NMR experiments, Lansamide I, Lansiumamide B, Lansiumamide C, and N-(2-phenylethyl)cinnamamide.

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Three new limonoids, limonophyllines A-C (1, 4 and 5), along with two known limonoids (2 and 3) and 11 acridone alkaloids (6-16) were isolated from the stems of Atalantia monophylla. All isolates were evaluated against cholangiocarcinoma, KKU-M156, and HepG2 cancer cell lines. Compounds 12, 14 and 16 displayed cytotoxicity against KKU-M156 cell line with IC50 ranging from 3.39 to 4.1 µg/mL while cytotoxicity against HepG2 cell line with IC50 ranging from 1.43 to 8.4 µg/mL. The structures of all isolated compounds were established by spectroscopic methods including 1D and 2D NMR, IR and mass spectrometry.

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Overexpression of P-glycoprotein (P-gp) leads to the emergence of multidrug resistance (MDR) in cancer treatment. Acridones have the potential to reverse MDR and sensitize cells. In the present study, we aimed to elucidate the chemosensitization potential of acridones by employing various molecular modelling techniques. Pharmacophore modeling was performed for the dataset of chemosensitizing acridones earlier proved for cytotoxic activity against MCF7 breast cancer cell line. Gaussian-based QSAR studies also performed to predict the favored and disfavored region of the acridone molecules. Molecular dynamics simulations were performed for compound 10 and human P-glycoprotein (obtained from Homology modeling). An efficient pharmacophore containing 2 hydrogen bond acceptors and 3 aromatic rings (AARRR.14) was identified. NCI 2012 chemical database was screened against AARRR.14 CPH and identified 25 best-fit molecules. Potential regions of the compound were identified through Field (Gaussian) based QSAR. Regression analysis of atom-based QSAR resulted in r2 of 0.95 and q2 of 0.72, whereas, regression analysis of field-based QSAR resulted in r2 of 0.92 and q2 of 0.87 along with r2cv as 0.71. The fate of the acridone molecule (compound 10) in the P-glycoprotein environment is analyzed through analyzing the conformational changes occurring during the molecular dynamics simulations. Combined data of different in silico techniques provided basis for deeper understanding of structural and mechanistic insights of interaction phenomenon of acridones with P-glycoprotein and also as strategic basis for designing more potent molecules for anti-cancer and multidrug resistance reversal activities.

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Drug resistance in cancer is an unmet medical challenge and a major drawback for the failure of many chemotherapeutic drugs. Search for targeted, effective drug with minimum toxicity is an urgent need. Acridone which is an alkaloid derivative has been attributed as molecule in reversing drug resistance in cancer cells for a long time now. In the present investigation, an attempt has been made to explore the chemosensitizing ability of 2,4-dimethylacridones with alkyl side chain containing terminally substituted tertiary amino groups. Considering the structural features required for the MDR reversal activity, acridone derivatives have been synthesized with propyl and butyl side chain containing morpholinyl, piperidinyl, N-methylpiperazinyl, N,N-diethylamino, N-diethanolamino, N-[(ß-hydroxylethyl)]piperazino at the terminus of the alkyl side chain. cLogP values for the synthesized compounds ranged from 2.96 to 4.72 for the propyl derivatives and 3.41 to 5.15 for the butyl derivatives. All the compounds were screened against breast cancer sensitive MCF7 and resistant MCF7/ADR cell lines. Compounds 12e and 12f have shown better cytotoxicity profiles with IC50 of 4 ± 0.05 and 2 ± 0.03 µM against MCF7 cells, 5.21 ± 0.13 and 2.56 ± 0.05 µM against MCF7/ADR cells. Photolabelling studies with [3H]-azidopine and molecular docking studies have identified that 2,4-dimethylacridones have potential to modulate the P-gp mediated multidrug resistance. Docking studies identified that compounds have shown favorable interactions with P-gp. QSAR equation was derived for cytotoxicity vs molecular descriptors of acridone derivatives. Best models with good predictive ability have been generated with very high square correlation coefficient (R2) values of 0.889, 0.964 and 0.983.

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Sorafenib was the only small-molecule drug approved by FDA for treatment of the advanced hepatocellular carcinoma (HCC). Recent study indicated that YM155 was a promising agent for HCC cells with high survivin expression, however, the antitumor activity needs to be further improved. Based on molecular docking and rational design method, a series of multi-substituted benzyl acridone derivatives were designed and synthesized. MTT assay indicated that some of the synthesized compounds displayed better antiproliferative activity against HepG2 cells than YM155. Later study indicated that the representive compound 8u may directly interact with survivin protein and induce HepG2 cells apoptosis, which is different from YM155. In addition, ADME property was predicted in silico, and it performed well. Moreover, in vivo preliminary experiments showed that 8u may be a good lead compound in the treatment of HCC.

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The main activity of mycophenolic acid 1 (MPA) and its analogs is the inhibition of proliferation of T cells. Here, we hypothesized that MPA and its conjugates inhibits also the activity of antigen-presenting cells (APC) including dendritic cells (DCs). We tested the effect of novel amino acid derivatives of MPA and conjugates of MPA with acridines/acridones on DCs by flow cytometry, ELISA and MLR assay. Both acridines/acridone derivatives could inhibit the maturation of DC, as shown by the decreased expression of B7 family receptors. It was confirmed in the mixed leucocyte reaction (MLR), in which T cells challenged with DCs pretreated with the analogs showed decreased proliferation and reduced cytokine secretion. The most interesting activity in this series of studies, that is, the suppression of CD86 receptor expression, decreased cytokine production and suppressed mixed leucocyte reaction, exhibited (mycophenoyl-N-3-propyl)-9-acridone-4-carboxamide ester 5a and (mycophenoyl-N-5-pentyl)-9-acridone-4-carboxamide ester 5b. These compounds reduced also the secretion of IL-2 and IL-15. In addition, they increased secretion of suppressive IL-10. Equally promising results were obtained for the N-mycophenoyl-D-glutamic acid 4b, which previously gave the highest value of selectivity. Acridone derivatives of MPA are therefore good immunosuppressive drug candidates for further testing.

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Ethylacridone (1 b) and dicyanomethylenated acridones 2 a,b,d showed crystal-jumping activity upon heating. This is the first example of thermosalient behavior in a simple aromatic ketone and its derivatives. A systematic investigation of the jumping behavior of derivatives with different alkyl chains by variable-temperature X-ray crystal-structure analyses revealed the mechanism of this phenomenon. Anisotropic dissociation of π stacking in a dimer was important for inducing crystal jumping in 1 b, whereas the collective fluctuation/flipping motion of a dicyanomethylene unit induced crystal jumping in 2.

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Improved derivatives of mycophenolic acid (MPA) are necessary to reduce the frequency of adverse effects, this drug exerts in treated patients. In this study, MPA was coupled with N-(ω-hydroxyalkyl)-9-acridone-4-carboxamides or N-(ω-hydroxyalkyl)acridine-4-carboxamides to give respective ester conjugates upon Yamaguchi protocol. This esterification required protection of phenol group in MPA. Designed conjugates revealed higher potency in vitro than parent MPA. Acridine derivatives were more active than acridone analogs and length of the alkyl linker between MPA and heterocyclic units influenced the observed cytotoxicity. Derivatives 2b, 2d, 3a, 3b displayed the most promising immunosuppressive activity.

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A palladium-catalyzed regiodivergent C1 insertion multicomponent reaction involving aryne, CO, and 2-iodoaniline is established to construct the scaffolds of phenanthridinone and acridone alkaloids. Regioselective control is achieved under the guidance of selective ligands. The phenanthridinones are solely obtained under ligand-free condition. In comparison, application of the electron-abundant bidentate ligand dppm afforded the acridones with high efficiency. The release rate of the aryne from the precursor assists the regioselectivity of insertion as well, which was revealed through interval NMR tracking. A plausible mechanism was suggested based on the control experiments. Representative natural products and two types of natural product analogues were synthesized divergently through this tunable method.

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