Acridinone Derivatives Research Articles

Iron-Catalyzed Annulation of 2-Aminobenzaldehydes with Iodonium Ylides: A Mild and General Route for the Synthesis of Acridinone Derivatives

Iron-Catalyzed Annulation of 2-Aminobenzaldehydes with Iodonium Ylides: A Mild and General Route for the Synthesis of Acridinone Derivatives

Anti-amoebic effects of synthetic acridine-9(10H)-one against brain-eating amoebae

Pathogenic A. castellanii and N. fowleri are opportunistic free-living amoebae. Acanthamoeba spp. are the causative agents of granulomatous amebic encephalitis (GAE) and amebic keratitis (AK), whereas Naegleria fowleri causes a very rare but severe brain infection called primary amebic meningoencephalitis (PAM). Acridinone is an important heterocyclic scaffold and both synthetic and naturally occurring derivatives have shown various valuable biological properties. In the present study, ten synthetic Acridinone derivatives (I-X) were synthesized and assessed against both amoebae for anti-amoebic and cysticidal activities in vitro. In addition, excystation, encystation, cytotoxicity, host cell pathogenicity was also performed in-vitro. Furthermore, molecular docking studies of these compounds with three cathepsin B paralogous enzymes of N. fowleri were performed in order to predict the possible docking mode with pathogen. Compound VII showed potent anti-amoebic activity against A. castellanii with IC50 53.46 µg/mL, while compound IX showed strong activity against N. fowleri in vitro with IC50 72.41 µg/mL. Compounds II and VII showed a significant inhibition of phenotypic alteration of A. castellanii, while compound VIII significantly inhibited N. fowleri cysts. Cytotoxicity assessment showed that these compounds caused minimum damage to human keratinocyte cells (HaCaT cells) at 100 µg/mL, while also effectively reduced the cytopathogenicity of Acanthamoeba to HaCaT cells. Moreover, Cathepsin B protease was investigated in-silico as a new molecular therapeutic target for these compounds. All compounds showed potential interactions with the catalytic residues. These results showed that acridine-9(10H)-one derivatives, in particular compounds II, VII, VIII and IX hold promise in the development of therapeutic agents against these free-living amoebae.

Acridine as an Anti-Tumour Agent: A Critical Review

This review summarized the current breakthroughs in the chemistry of acridines as anti-cancer agents, including new structural and biologically active acridine attributes. Acridine derivatives are a class of compounds that are being extensively researched as potential anti-cancer drugs. Acridines are well-known for their high cytotoxic activity; however, their clinical application is restricted or even excluded as a result of side effects. The photocytotoxicity of propyl acridine acts against leukaemia cell lines, with C1748 being a promising anti-tumour drug against UDP-UGT's. CK0403 is reported in breast cancer treatment and is more potent than CK0402 against estrogen receptor-negative HER2. Acridine platinum (Pt) complexes have shown specificity on the evaluated DNA sequences; 9-anilinoacridine core, which intercalates DNA, and a methyl triazene DNA-methylating moiety were also studied. Acridine thiourea gold and acridinone derivatives act against cell lines such as MDA-MB-231, SK-BR-3, and MCF-7. Benzimidazole acridine compounds demonstrated cytotoxic activity against Dual Topo and PARP-1. Quinacrine, thiazacridine, and azacridine are reported as anti-cancer agents, which have been reported in the previous decade and were addressed in this review article.

Enhanced Activity of P4503A4 and UGT1A10 Induced by Acridinone Derivatives C-1305 and C-1311 in MCF-7 and HCT116 Cancer Cells: Consequences for the Drugs' Cytotoxicity, Metabolism and Cellular Response.

Activity modulation of drug metabolism enzymes can change the biotransformation of chemotherapeutics and cellular responses induced by them. As a result, drug-drug interactions can be modified. Acridinone derivatives, represented here by C-1305 and C-1311, are potent anticancer drugs. Previous studies in non-cellular systems showed that they are mechanism-based inhibitors of cytochrome P4503A4 and undergo glucuronidation via UDP-glucuronosyltranspherase 1A10 isoenzyme (UGT1A10). Therefore, we investigated the potency of these compounds to modulate P4503A4 and UGT1A10 activity in breast MCF-7 and colon HCT116 cancer cells and their influence on cytotoxicity and cellular response in cells with different expression levels of studied isoenzymes. We show that C-1305 and C-1311 are inducers of not only P4503A4 but also UGT1A10 activity. MCF-7 and HCT116 cells with high P4503A4 activity are more sensitive to acridinone derivatives and undergo apoptosis/necrosis to a greater extent. UGT1A10 was demonstrated to be responsible for C-1305 and C-1311 glucuronidation in cancer cells and glucuronide products were excreted outside the cell very fast. Finally, we show that glucuronidation of C-1305 antitumor agent enhances its pro-apoptotic properties in HCT116 cells, while the cytotoxicity and cellular response induced by C-1311 did not change after drug glucuronidation in both cell lines.

SYNTHESIS OF NEW PYRROLO[3,2- l ]ACRIDINONES AND PYRROLO[3,2- c ][1,8]NAPHTHYRIDINONES BY CONDENSATION OF METHOXYBENZENES OR PHENOLS WITH ISOBUTYRIC ALDEHYDE AND o -AMINONITRILES

A reaction of methoxybenzenes or phenols with isobutyric aldehyde and 2-amino-5-nitro- or 2-amino-4-chlorobenzonitriles in concentrated H 2 SO 4 medium was used for the preparation of new pyrrolo[3,2-l]acridinone derivatives. Analogous reactions using 2amino-3-pyridinecarbonitrile enabled the synthesis of previously unknown benzo[b]pyrrolo[3,2c][1,8]naphthyridinones.

Modulation of UDP-glucuronidation by acridinone antitumor agents C-1305 and C-1311 in HepG2 and HT29 cell lines, despite slight impact in noncellular systems.

Among the studied antitumor acridinone derivatives developed in our laboratory, 5-dimethylaminopropylamino-8-hydroxytriazoloacridinone (C-1305) and 5-diethylaminoethylamino-8-hydroxyimidazoacridinone (C-1311) exhibited cytotoxic and antitumor properties against several cancer types and were selected to be evaluated in preclinical and early-phase clinical trials. In the present work, we investigated the impact of C-1305 and C-1311 on UDP-glucuronosyltransferase (UGT) activity. Enzyme activity modulation was studied using HPLC by analyzing standard UGT substrate metabolism in the presence and absence of antitumor drugs. The investigations were performed in two model systems: (i) under noncellular conditions, including human liver microsomes (HLM) and recombinant UGT1A1, 1A9 and 1A10 isoenzymes and (ii) in tumor cells. There was observed a slight impact of studied drugs on enzyme activity. Only UGT1A1 action was altered by both compounds. The modulatory effects of UGT activity in cellular systems depended on the tumor cell type. In the case of HepG2, C-1305 and C-1311 strongly induced UGT activity, particularly for C-1311, at concentrations significantly lower than the EC50. This effect contradicted irinotecan mediated UGT inhibition. HT29 colon tumor cells were less sensitive than HepG2 to enzyme modulation in the presence of the studied compounds, particularly C-1305, where enzymatic inhibition similar to that of irinotecan was observed. The results demonstrated that UGT activity modulation should be expected in the case of antitumor therapy with C-1305 or/and C-1311. Analysis of the results indicated that these modulations would occur via cellular regulatory pathways not by direct drug-enzyme interactions.

Synthesis of new pyrrolo[3,2-l]acridinones and pyrrolo[3,2-c][1,8]naphthyridinones by condensation of methoxybenzenes or phenols with isobutyric aldehyde and o-aminonitriles

A reaction of methoxybenzenes or phenols with isobutyric aldehyde and 2-amino-5-nitro- or 2-amino-4-chlorobenzonitriles in concentrated H2SO4 medium was used for the preparation of new pyrrolo[3,2-l]acridinone derivatives. Analogous reactions using 2-amino-3-pyridinecarbonitrile enabled the synthesis of previously unknown benzo[b]pyrrolo[3,2-c][1,8]naphthyridinones.

Cascade synthesis of selective dihydro pyridazino fused acridinone derivatives via MCM-41 catalyzed ring-opening/ring-closure reaction

An enhanced one-pot synthesis of new functionalized 5,6-dihydro-5,5-dimethyl-2-phenyl-2H-pyridazino[3,4,5-kl]acridin-1(4H)-one derivatives with different substituted patterns by using mesoporous MCM-41 catalyst via a ring opening/ring closure reaction process has been established. This MCM-41 silica catalyst has been synthesized and characterized using an array of sophisticated analytical techniques like BET, XRD, UHRTEM, etc. This reaction could be conducted from inexpensive substrates within short period under neat reflux conditions. Compared with the usual methods, the remarkable advantages of this method are milder reaction conditions, operational simplicity, higher yields, short reaction times and an environmentally friendly procedure.

Prediction of Acridinones’ Ability to Interstrand DNA Crosslinks Formation Using Connected QSRR and QSAR Analysis

QSAR studies to predict acridinones’ ability to interstrand DNA crosslinks formation were performed. The study is based on experimental, as well as predicted retention data (log k) and was conducted by connected QSRR and QSAR strategy. For this purpose, chromatography analysis of acridinone derivatives was utilized. Moreover, computer modeling of the above-mentioned compounds was performed. Afterwards, statistical analysis of the obtained results was performed by two different HPLC stationary phases: phosphatidylcholine (IAM) and α1-glycoprotein (AGP). This approach allowed determining retention parameter log k, which characterizes binding affinity of acridinones to phospholipids or proteins. Moreover, molecular modeling was performed based on the chemical structure of considered acridinones using HyperChem 8.0 program (HyperCube Inc., Gainesville, FL, USA). Structural descriptors were obtained from Dragon 6.0 software (Talete, Italy). Those data were used to create general QSAR equations. Derived QSAR models described acridinones’ ability to interstrand DNA crosslinks formation (C0) depending on HPLC retention parameters, whereas log k parameter obtained by HPLC analysis was mostly dependent on molecular descriptors calculated. Additionally, the predictive performance of obtained QSARs and QSRRs models allowed us to predict the ability to interstrand DNA crosslinks formation by acridinones derivatives. It also enabled us to predict their chromatographic retention parameters. Proposed connected QSRR and QSAR approach could be a useful tool for in silico experiments, which verifies acridinones’ activity, without any in vivo biological test. Keywords: Quantitative structure-activity relationships (QSAR), quantitative structure-retention relationships (QSRR), multiple linear regression (MLR), high-Performance Liquid Chromatography (HPLC), acridinones, interstrand DNA crosslinks, molecular modeling descriptors.

The application of connected QSRR and QSAR strategies to predict the physicochemical interaction of acridinone derivatives with DNA.

Acridinone derivatives as imidazoacridinones and triazoloacridinones are the new potent antitumor agents characterized by different mechanisms of action related to their ability to interact with DNA. The analysis undertaken in this study involves searching of QSAR (Quantitative Structure-Activity Relationship) and QSRR (Quantitative Structure- Retention Relationship) models, which would allow to predict the biological activity of acridinones expressed as the ability to stabilize the secondary structure of DNA (ΔT), based on their structural parameters and chromatographic retention data. For this purpose, 20 acridinone derivatives were subjected to chromatographic analyses and molecular modeling, followed by statistical analyses using multiple linear regression method (MLR). As a novelty aspect, except for RP-HPLC approach, hydrophilic interaction chromatography (HILIC) columns were tested. As a result of performed analysis, appropriate QSAR and QSRR models were obtained, and each model was analyzed in terms of prediction of acridinones' ability to interact with DNA. Derived QSAR and QSRR models were characterized as one, with good prediction performance. Conclusively, the proposed connected QSAR and QSRR strategies allow to predict in silico the ability of acridinones to interact with DNA without the necessity of performing any biological experiments under in vitro and in vivo conditions.

The Evaluation of Multivariate Adaptive Regression Splines for the Prediction of Antitumor Activity of Acridinone Derivatives

Multivariate adaptive regression splines (MARSplines) have been applied for the quantitative structure-activity relationships (QSAR) studies of antitumor activity of acridinone derivatives. Molecular modeling studies were performed with the use of HyperChem and Dragon software. The structures of the compounds were firstly pre-optimized with the MM+ mechanics and semi-empirical AM1 method procedure included in the HyperChem and resulting geometrical structures were studied with the use of Dragon software, and several molecular descriptors of acridinones were calculated and used as predictor (independent) variables in the MARS model building. Principal component analysis (PCA) was used to select the training and test sets. The optimal MARS model uses 28 basis functions to describe acridinones' antitumor activity and characterized high correlation between predicted antitumor activity and that one from biological experiments for the data used in the training and testing sets of acridinones with correlation coefficients on the level of 0.9477 and 0.9660, respectively. Generally, results showed that MARS model provided powerful capacity of prediction of antitumor activity of acridinone derivatives. Moreover, a physicochemical explanation of the descriptors selected by MARSplines analysis is also given, and indicated that molecular parameters describing 3-D properties as well as lipophilicity of acridinone derivative molecule are important for acridinones antitumor activity.

TiO2 Nanoparticles as an Efficient Catalyst for the One-pot Preparation of Tetrahydrobenzo[c]acridines in Aqueous Media

A series of tetrahydrobenzo[c]acridinone derivatives have been prepared by a one-pot fourcomponent reaction of 1-naphthol, aromatic aldehydes, dimedone, and ammonium acetate in aqueous media using a catalytic amount of titanium dioxide nanoparticles (TiO2 NPs). The advantages of this novel protocol include the excellent yields, operational simplicity, short reaction time, easy work-up, reusability of the catalyst and an environmentally friendly procedure.

Influence of LC Retention Data on Antitumor Acridinones’ Classification Evaluated by Factor Analysis Method

The application of factor analysis (FA) method in classification of the antitumor acridinones based on high-performance liquid chromatography (HPLC) retention data and calculated parameters of lipophilicity as well as some nonempirical structural parameters was studied. First, a group of 19 acridinone (imidazoacridinone and triazoloacridinone) derivatives was chromatographed in six RP-HPLC systems, and the values of their HPLC retention data as retention' times determined in both 10 min and 30 min gradient times were obtained as well as log kw (retention factor log k extrapolated to 0% organic modifier) parameters using DryLab program were calculated. Additionally, molecular modeling studies were performed based on the structural formula of considered acridinones and structural descriptors were derived as well as log P parameters using some commonly available software were calculated and subsequently used. A matrix of 19 x 32 HPLC data together with log P data and molecular properties parameters was subjected to factor analysis and led to extract three main factors with eigenvalues higher than 1. The first principal component (factor 1) accounted for, by 80.87% of the variance in data, the second principal component (factor 2) explained 7.77% and the third principal component (factor 3) was responsible by 4.46% of data variance. The total data variance was at the level 93.09% and was explained by the first three principal components. Moreover, one of the most significant influences on the values of factor 1 and factor 2 possessed HPLC retention data and calculated parameters describing lipophilicity, respectively. More importantly, distribution of individual drugs on the plane determined by two principal components produced patterns in good agreement with their chemical structures as well as with their antitumor activity.

Application of Artificial Neural Networks for the Prediction of Antitumor Activity of a Series of Acridinone Derivatives

Artificial neural networks (ANNs) have been applied for the quantitative structure-activity relationships (QSAR) studies of antitumor activity of acridinone derivatives. Molecular modeling studies were performed with the use of HyperChem and Dragon computer programs and molecular geometry optimization using MM+ molecular mechanics and semi-empirical AM1 method, and several molecular descriptors of agents were obtained. A high correlation resulted between the ANN predicted antitumor activity and that one from biological experiments for the data used in the testing set of acridinones was obtained with correlation coefficient on the level of 0.9484. Moreover, the sensitivity analysis indicated that molecular parameters describing geometrical properties as well as lipophilicity of acridinone derivative molecule are important for acridinones antitumor activity.

The Influence of Lipophilicity on the Classification of Antitumor Acridinones Evaluated by Principal Component Analysis

Principal component analysis (PCA) has been performed for some acridinone derivatives with antitumor activity to model relationships between structural descriptors and lipophilicity and their antileukemia activity. Principal component analysis obtained with the use of parameters of lipophilicity led to extract two main factors with eigenvalue higher than 1. The first principal component (factor 1) accounted for, by 84.3% of the variance in data and the second principal component (factor 2) explained 10.0% of data variance indicating that total data variance at the level 94.5% can be explained by the first two principal components. On the other hand, principal component analysis obtained with the use of parameters of lipophilicity together with some other molecular descriptors led to extract five main factors with eigenvalue higher than 1. In this case, the first principal component (factor 1) accounted for, by 62.64% of the variance in data, the second principal component (factor 2) explained 19.04% and the third principal component (factor 3) explained 8.49% of data variance indicating that total data variance at the level 90.17% can be explained by the first three principal components. Moreover, one of the most significant influences on the value of factors possessed parameters describing lipophilicity. However, some other descriptors considered in the study (some of constitutional, topological, molecular and geometrical one) could play an important role in the reflection of acridinone properties, too. More importantly, distribution of individual drugs on the plane determined by two and three principal components produced patterns in good agreement with their chemical structures as well as with their antitumor activity. Keywords: Acridinones, Antitumor activity, Compounds classification, Data variance, Lipophilicity, Molecular modeling, Principal component analysis (PCA), Statistical analysis, Structural descriptors, Varimax rotation

Determination of lipophilicity for antitumor acridinone derivatives supported by gradient high-performance liquid chromatography method

Abstract The lipophilicity values of selected acridinone (imidazoacridinone and triazoloacridinone) derivatives were measured by gradient reversed-phase high-performance liquid chromatography (RP-HPLC) using a C18 stationary phase with a water/acetonitrile mixture as a mobile phase. The retention times obtained served as input data and appropriate log kw values (i.e., the retention factor log kw extrapolated to 0% organic modifier) as an alternative to log P were calculated using the DryLab program. The relationships between the lipophilicity (log kw) and the chemical structure of the studied compounds, as well as correlation between experimentally determined lipophilicities (log kw) and log P data calculated using some commonly available software, are discussed.

Antimalarial activity of new acridinone derivatives

Malaria is one of the major threats concerning world public health. Resistance to the current antimalarial drugs has led to searches for new antimalarial compounds. Acridinone derivatives have recently demonstrated to be active against malaria parasite. We focused our attention on synthesized new acridinone derivatives, some of them resulting with high antiviral and trypanocidal activity. In this study new derivatives of 10-alyl-, 10-(3-methyl-2-butenyl)- and 10-(1,2-propadienyl)-9(10 H)-acridinone were evaluated for their antimalarial activity against Plasmodium falciparum. To assess the selectivity, cytotoxicity was assessed in parallel against human MRC-5 cells. Inhibition of β-hematin formation was determined using a spectrophotometric assay. Mitochondrial bc 1 complexes were isolated from yeast and bovine heart cells to test acridinone inhibitory activity. This study resulted in the identification of three compounds with submicromolar efficacy against P. falciparum and without cytotoxic effects on human cellular line. One compound, IIa (1-fluoro-10-(3-methyl-2-butenyl)-9(10 H)-acridinone), can be classified as hit for antimalarial drug development exhibiting IC 50 less than 0.2 μg/mL with SI greater than 100. In molecular tests, no relevant inhibitory activity was obtained for our compounds. The mechanism of acridinones antimalarial action remains unclear.

Physicochemical interaction of antitumor acridinone derivatives with DNA in view of QSAR studies

The acridinone derivatives with antitumor activity and ability with respect to noncovalent DNA binding were investigated for their quantitative structure–activity relationships (QSAR). Multiple regression analysis was used to model relationships between molecular descriptors and antileukemia activity, or between molecular descriptors and DNA-duplexes stabilization. Studies were performed on molecular modeling using HyperChem and Dragon computer programs, and molecular geometry optimization using MM+ molecular mechanics and semi-empirical AM1 method. Two multiple regression equations were derived and characterized as good and with statistically significant correlations, R = 0.9384 and R = 0.8388, for quantitative structure–antitumor activity relationships and quantitative structure–ability to DNA-duplexes stabilization relationships, respectively. Moreover, hydrophobic and total molecular symmetry properties are important for antitumor activity of acridinone derivatives, and electronic and topological properties are important for physicochemical (noncovalent) DNA-duplexes stabilization of these compounds. The obtained equations can be used for prediction of acridinone derivatives’ activity and their ability to noncovalent interaction with DNA which, as it was shown earlier, play important role in the antitumor mechanism of action of these compounds.

Novel synthetic 2-amino-10-(3,5-dimethoxy)benzyl-9(10 H)-acridinone derivatives as potent DNA-binding antiproliferative agents

A series of novel 9(10 H)-acridinone derivatives with terminal amino substituents at C2 position on the acridinone ring were synthesized and studied for their antiproliferative activity and underlying mechanisms. These compounds demonstrated promising cytotoxicity to leukemia cells CCRF-CEM, displaying IC 50 values in the low micromolar range. Structure–activity relationships (SAR) indicated that the compound 6d bearing a pyrrolidine substituent and 8a with a methyl ammonium side chain displayed higher cytotoxicity to CCRF-CEM cells and also solid tumor cells A549, HepG2, and MCF7. Furthermore, the compounds 6d and 8a had strong binding activity to calf thymus DNA (ct DNA), as detected by UV absorption and fluorescence quenching assays, but limited inhibitory activity to human topoisomerase 1 (topo 1). Taken together, this study discovered a series of new synthetic 9(10 H)-acridinone derivatives with potent DNA binding and anticancer activity.

Chemometric Evaluation of the Significance of Molecular Structural Descriptors on Binding of Acridinone Derivatives to DNA

The acridinones represented by imidazo- and triazoloacridinones are a group of potential antitumor agents. The most active derivative, the antitumor imidazoacridone C-1311 expected to be used as a topoisomerase II poison, has been recently selected for extended preclinical and clinical trials. In the current study, one of the chemometric techniques, namely factor analysis was performed to model the relationships between several molecular structural descriptors and the ability of the selected acridinone derivatives to the noncovalent binding to DNA. The noncovalent binding to DNA was measured and expressed as DNA-duplexes stabilization. Factor analysis led to extract four main factors with eigenvalues higher than 1 and the total variance explanation was on the level of 84.5% (by the first three principal component). Among the molecular structural descriptors studied, the most significant influence was recognized for lipophilicity parameters, quantum-chemical parameters and electron affinity specifying parameters. Importantly, distribution of individual compounds on the plane determined by two principal components produced patterns in good agreement with their ability to noncovalent binding to DNA as well as with their chemical structures. Finally, the proposed FA-based strategy enabled to classify the tested acridinone derivatives in view of their ability to noncovalent interaction with DNA. Keywords: Acridinones, Noncovalent binding to DNA, Factor analysis (FA), Lipophilicity, Structural descriptors