ABSTRACT
Newly prepared tetracyclic imidazo[4,5-b]pyridine derivatives were synthesized to study their antiproliferative activity against human cancer cells. Additionally, the structure-activity was studied to confirm the impact of the N atom position in pyridine nuclei as well as the chosen amino side chains on antiproliferative activity. Targeted amino substituted regioisomers were prepared by using uncatalyzed amination from corresponding chloro substituted precursors. The most active compounds 6 a, 8 and 10 showed improved activity in comparison to standard drug etoposide with IC50 values in a nanomolar range of concentration (0.2-0.9â µM). NMR-based metabolomics is a powerful instrument to elucidate activity mechanism of new chemotherapeutics. Multivariate and univariate statistical analysis of metabolic profiles of non-small cell lung cancer cells before and after exposure to 6 a revealed significant changes in metabolism of essential amino acids, glycerophospholipids and oxidative defense. Insight into the changes of metabolic pathways that are heavily involved in cell proliferation and survival provide valuable guidelines for more detailed analysis of activity metabolism and possible targets of this class of bioactive compounds.
ABSTRACT
Newly designed pentacyclic benzimidazole derivatives featuring amino or amido side chains were synthesized to assess their in vitro antiproliferative activity. Additionally, we investigated their direct interaction with nucleic acids, aiming to uncover potential mechanisms of biological action. These compounds were prepared using conventional organic synthesis methodologies alongside photochemical and microwave-assisted reactions. Upon synthesis, the newly derived compounds underwent in vitro testing for their antiproliferative effects on various human cancer cell lines. Notably, derivatives 6 and 9 exhibited significant antiproliferative activity within the submicromolar concentration range. The biological activity was strongly influenced by the N atom's position on the quinoline moiety and the position and nature of the side chain on the pentacyclic skeleton. Findings from fluorescence, circular dichroism spectroscopy, and thermal melting assays pointed toward a mixed binding mode-comprising intercalation and the binding of aggregated compounds along the polynucleotide backbone-of these pentacyclic benzimidazoles with DNA and RNA.
Subject(s)
Antineoplastic Agents , Humans , Structure-Activity Relationship , Cell Line, Tumor , Drug Screening Assays, Antitumor , Antineoplastic Agents/chemistry , Benzimidazoles/chemistry , Cell Proliferation , Molecular StructureABSTRACT
Newly designed and synthesized cyano, amidino and acrylonitrile 2,5-disubstituted furane derivatives with either benzimidazole/benzothiazole nuclei have been evaluated for antitumor and antimicrobial activity. For potential antitumor activity, the compounds were tested in 2D and 3D cell culture methods on three human lung cancer cell lines, A549, HCC827 and NCI-H358, with MTS cytotoxicity and BrdU proliferation assays in vitro. Compounds 5, 6, 8, 9 and 15 have been proven to be compounds with potential antitumor activity with high potential to stop the proliferation of cells. In general, benzothiazole derivatives were more active in comparison to benzimidazole derivatives. Antimicrobial activity was evaluated with Broth microdilution testing (according to CLSI (Clinical Laboratory Standards Institute) guidelines) on Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus. Additionally, Saccharomyces cerevisiae was included in testing as a eukaryotic model organism. Compounds 5, 6, 8, 9 and 15 showed the most promising antibacterial activity. In general, the compounds showed antitumor activity, higher in 2D assays in comparison with 3D assays, on all three cell lines in both assays. In natural conditions, compounds with such an activity profile (less toxic but still effective against tumor growth) could be promising new antitumor drugs. Some of the tested compounds showed antimicrobial activity. In contrast to ctDNA, the presence of nitro group or chlorine in selected furane-benzothiazole structures did not influence the binding mode with AT-DNA. All compounds dominantly bound inside the minor groove of AT-DNA either in form of monomers or dimer and higher-order aggregates.
Subject(s)
Anti-Infective Agents/pharmacology , Benzimidazoles/pharmacology , Benzothiazoles/pharmacology , Neoplasms/drug therapy , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Benzothiazoles/chemical synthesis , Benzothiazoles/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Staphylococcus aureus/drug effects , Staphylococcus aureus/pathogenicity , Structure-Activity RelationshipABSTRACT
A novel series of tetracyclic imidazo[4,5-b]pyridine derivatives was designed and synthesized as potential antiproliferative agents. Their antiproliferative activity against human cancer cells was influenced by the introduction of chosen amino side chains on the different positions on the tetracyclic skeleton and particularly, by the position of N atom in the pyridine nuclei. Thus, the majority of compounds showed improved activity in comparison to standard drug etoposide. Several compounds showed pronounced cytostatic effect in the submicromolar range, especially on HCT116 and MCF-7 cancer cells. The obtained results have confirmed the significant impact of the position of N nitrogen in the pyridine ring on the enhancement of antiproliferative activity, especially for derivatives bearing amino side chains on position 2. Thus, regioisomers 6, 7 and 9 showed noticeable enhancement of activity in comparison to their counterparts 10, 11 and 13 with IC50 values in a nanomolar range of concentration (0.3-0.9 µM). Interactions with DNA (including G-quadruplex structure) and RNA were influenced by the position of amino side chains on the tetracyclic core of imidazo[4,5-b]pyridine derivatives and the ligand charge. Moderate to high binding affinities (logKs = 5-7) obtained for selected imidazo[4,5-b]pyridine derivatives suggest that DNA/RNA are potential cell targets.
Subject(s)
Antineoplastic Agents/pharmacology , DNA, Neoplasm/drug effects , Drug Design , Imidazoles/pharmacology , Pyridines/pharmacology , RNA, Neoplasm/drug effects , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Binding Sites/drug effects , Cell Proliferation/drug effects , Cells, Cultured , DNA, Neoplasm/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , RNA, Neoplasm/chemistry , Structure-Activity RelationshipABSTRACT
BACKGROUND: Benzazole and coumarin derivatives are one of the most privileged heterocyclic substructures in the medicinal chemistry with well-known biological features, which include a wide range of versatile biological activities as well as excellent spectroscopic characteristics thus offering their potential application in many research fields. OBJECTIVE: The prepared iminocoumarins were synthesized to evaluate their antioxidative potential by using ABTS and FRAP assays and in vitro antiproliferative activity. METHODS: A series of coumarin derivatives containing a 2-benzazole motif were synthesized and evaluated for their antioxidative capacity and antiproliferative activity. Their molecular structure incorporates a push-pull functionality: an electron donor donating group at the 7-position with an electron-withdrawing group, such as benzimidazole, benzothiazole and imidazopyridine fragment at the 3-position. RESULTS: The iminocoumarins bearing different substituents on 7-position were evaluated for their antiproliferative activity on tree cancer cells with only 4 compounds showing the antiproliferative activity. The most active derivative was N,N-diethylamino substituted benzimidazole derivative 4d and imidazo[4,5-b]pyridine analogue 6b, both also displayed selective activity toward CEM with submicromolar inhibitory concentration (0.059 µM; 0.17 ± 0.09, respectively). The inhibitory effect of 4d and 6b derivatives on the cell-cycle progression of HeLa cells was studied. A flow cytometric analysis of the HeLa cells indicated an appreciable cell-cycle arrest in a dose-dependent manner. Antioxidant properties were studied by ABTS and FRAP assays and obtained results revealed that the most promising antioxidant has proven to be compound 3b while other compounds, in general, showed moderate to very low antioxidative capacity in both assays. CONCLUSION: Unsubstituted benzimidazole derivatives bearing hydroxyl group on iminocoumarin nuclei exhibited the most prominent antioxidant potential in ABTS assay (3b; 40.5 ± 0.01). The most significant and selective antiproliferative activity was displayed by compounds 4d and 6b (0.059 µM; 0.17 ± 0.09, respectively), which were chosen as lead compounds for further optimization and rational design to obtain more active and selective antiproliferative agents.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antioxidants/chemistry , Antioxidants/pharmacology , Benzothiazoles/chemistry , Coumarins/chemistry , Coumarins/pharmacology , Cell Cycle/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HeLa Cells , HumansABSTRACT
The three series of 5-mono- and 2,5-bis-1,2,3-triazolyl-substituted benzimidazo[1,2-a]quinolines as potential antitumor agents were synthesized. Their growth-inhibitory activity is influenced by the introduction of fluorine at C-2 and the mono-triazolyl nuclei at C-5 of the tetracyclic skeleton, particularly if the 1,2,3-triazole moiety contains a short aliphatic side-chain. Thus, the chloropropyl side-chain in all three series had the highest impact on the inhibitory effect. 1,2,3-Triazolyl-2-fluorobenzimidazo[1,2-a]quinoline conjugates 8a and 8b with 3-chloropropyl and 2-hydroxyethyl substituents, respectively, exhibited the most pronounced cytostatic effect on colon cancer (HCT116) cells in the submicromolar range. The compound 8a emerged as the most promising candidate because of its higher potency and some selectivity in the non-tumor aneuploid immortal keratinocyte (HaCaT) cells. Fluorescence and CD spectroscopy, as well as the thermal denaturation assays, revealed moderate to high DNA/RNA binding affinities of the selected compounds and identified intercalation as a dominant binding mode to both polynucleotides. However, results of intracellular distribution assay in human lung carcinoma (H460) cells suggest that both 8a and 8b do not target nuclear DNA and that their non-specific cytotoxic effect may be attributed to the damage of intercellular membranes.
Subject(s)
Antineoplastic Agents/pharmacology , Benzimidazoles/pharmacology , DNA/chemistry , Quinolones/pharmacology , RNA/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Binding Sites/drug effects , Cattle , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Quinolones/chemical synthesis , Quinolones/chemistry , Structure-Activity RelationshipABSTRACT
Herein we present and describe the design and synthesis of novel phenantrene derivatives substituted with either amino or amido side chains and their biological activity. Antiproliferative activities were assessed in vitro on a panel of human cancer cell lines. Tested compounds showed moderate activity against cancer cells in comparison with 5-fluorouracile. Among all tested compounds, some compounds substituted with cyano groups showed a pronounced and selective activity in the nanomolar range of inhibitory concentrations against HeLa and HepG2. The strongest selective activity against HeLa cells was observed for acrylonitriles 8 and 11 and their cyclic analogues 15 and 17 substituted with two cyano groups with a corresponding IC50â¯=â¯0.33, 0.21, 0.65 and 0.45⯵M, respectively. Compounds 11 showed the most pronounced selectivity being almost non cytotoxic to normal fibroblasts. Additionally, mode of biological action analysis was performed in silico and in vitro by Western blot analysis of HIF-1-α relative expression for compounds 8 and 11.
Subject(s)
Antineoplastic Agents/pharmacology , Phenanthrenes/pharmacology , Thiophenes/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HeLa Cells , Hep G2 Cells , Humans , Molecular Structure , Phenanthrenes/chemical synthesis , Phenanthrenes/chemistry , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistry , Tumor Cells, CulturedABSTRACT
This work presents a systematic evaluation of 2-amino, 5-amino and 2,5-diamino substituted benzimidazo[1,2-a]quinoline-6-carbonitriles as novel pH probes with a potential application in pH sensing materials or as H+ fluoroionophores in bulk optode membranes. The study was carried out by varying the length, type and position of amino substituents in ten fluorescent dyes with the same benzimidazo[1,2-a]quinoline-6-carbonitrile core. The photophysical and acid-base properties of the dyes were investigated by the UV/Vis absorption and fluorescence spectroscopies, and interpreted by the electronic structure DFT calculations. pH sensing mechanisms and structure-property relations affecting the fluorescence response were discussed through a detailed analysis of the piperidine substituted derivatives 1-4. Push-pull donor-acceptor interactions stimulate strong fluorescence in the visible spectral range (up to Φâ¯=â¯0.65 for 7) and induce significant changes in the photophysical properties associated with the acid-base equilibria (up to a 50-fold increase in the fluorescence intensity). pKa values in aqueous and mixed solutions (v/v H2O:EtOH 99:1, 50:50), appear suitable for monitoring acidic pH in solution. The most promising candidates were immobilised in thin polymer matrices by the spin coating technique to form fluorescent sensing materials - optodes, and examined as novel pH-sensitive fluoroionophores. In the liquid membrane environment, dyes exhibited significant increase of the apparent pKas by almost 4 units. Bright and blue emissive thin films showed pH response and dynamic range around pKaâ¯=â¯5, making them suitable for a wide range of optical sensing applications.
ABSTRACT
This paper discusses antioxidative and biological activities of 25 novel amidino substituted benzamides with a variety of heteroaromatic nuclei attached to the benzamide moiety and with a variable number of methoxy or hydroxy substituents. Targeted compounds, bearing either amidino or 2-imidazolinyl substituent, were obtained in the Pinner reaction from cyano precursors. 3D-QSAR models were generated to predict antioxidative activity of the 25 novel aromatic and heteroaromatic benzamide derivatives. The compounds were tested for antioxidative activity using in vitro spectrophotometric assays. Direct validation of 3D-QSAR approach for predicting activities of novel benzamide derivatives was carried out by comparing experimental and computationally predicted antioxidative activity. Experimentally determined activities for all novel compounds were found to be within a standard deviation of error of the models. Following this, structure-activity relationships among the synthesized compounds are discussed. Furthermore, antiproliferative activity in vitro against HeLa cells as well as antibacterial and antifungal activity was tested to confirm the other biological activities of the prepared compounds.
Subject(s)
Anti-Infective Agents/pharmacology , Antineoplastic Agents/pharmacology , Antioxidants/pharmacology , Benzamides/pharmacology , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antioxidants/chemical synthesis , Antioxidants/chemistry , Aspergillus/drug effects , Bacteria/drug effects , Benzamides/chemical synthesis , Benzamides/chemistry , Candida albicans/drug effects , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Microbial Sensitivity Tests , Molecular Structure , Principal Component Analysis , Quantitative Structure-Activity Relationship , Saccharomyces cerevisiae/drug effectsABSTRACT
We prepared a range of N-arylbenzamides with a variable number of methoxy and hydroxy groups, bearing either amino or amino-protonated moieties, and used DPPH and FRAP assays to evaluate their antioxidant capacity. Most of the systems exhibit improved antioxidative properties relative to the reference BHT molecule in both assays. Combining results from both sets of experiments, the most promising antioxidative potential was displayed by the trihydroxy derivative 26, which we propose as a lead compound for a further optimization of the benzamide scaffold. Computational analysis helped in interpreting the observed trends and demonstrated that protonated systems are better antioxidants than their neutral counterparts, while underlying the positive influence of the electron-donating methoxy group on the antioxidant properties, thus confirming the experiments. It also revealed that the introduction of the hydroxy groups shifts the reactivity from both amide and amine groups toward this moiety and additionally enhances antioxidative features. This is particularly evident in 26Hâ¢+, which owes its pronounced reactivity to the stabilizing [O⢷··H-O] hydrogen bonding between the created phenoxyl radical and the two neighboring hydroxy groups. We demonstrated that its antioxidative activities are more favorable than those for analogous trihydroxy derivatives without the N-phenyl group or without the amide moiety, which strongly justifies the employed strategy in utilizing bisphenylamides in designing potent antioxidants.
Subject(s)
Amines/chemistry , Antioxidants/pharmacology , Benzamides/pharmacology , Computer Simulation , Antioxidants/chemistry , Benzamides/chemistry , Free Radicals/chemistry , Hydrogen Bonding , Structure-Activity RelationshipABSTRACT
An experimental search for new benzimidazole derivatives with enhanced antiproliferative activity was successfully guided by QSAR modelling. Robust 3D-QSAR models were derived on an available database of compounds with previously measured activities. Our QSAR analysis revealed that an increase of the antiproliferative activities towards H460, HCT 116, MCF-7 and SW 620 cells will be obtained if new compounds are charged at a pH range from 5 to 7 and if their hydrophobicity is increased compared to the dataset compounds. Novel benzimidazo[1,2-a]quinolines bearing quarternary amino groups with corresponding aliphatic chains were designed, and their antiproliferative activities were computationally predicted. Using uncatalysed microwave-assisted amination reactions, 14 novel compounds were obtained to assess their antiproliferative activities towards H460, HCT 116, MCF-7, and SW 620 tumour cell lines in vitro. Novel compounds showed antiproliferative activities at micromolar and submicromolar inhibition concentrations. Experimental measurements of antiproliferative activities validation the QSAR models showing very good agreement between experimentally measured activities and computational predictions. In an attempt to elucidate the mode of action through which benzimidazole derivatives accomplish their antiproliferative activities, thermal denaturation experiments were performed to test their DNA-binding properties.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzimidazoles/chemistry , Quinolines/chemical synthesis , Quinolines/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Screening Assays, Antitumor , HCT116 Cells , Humans , MCF-7 Cells , Mesylates/chemistry , Models, Molecular , Molecular Structure , Quantitative Structure-Activity Relationship , Quinolines/chemistryABSTRACT
Benzimidazo[1,2-a]quinolines and benzo[b]thieno[2,3-b]pyrido[1,2-a]benzimidazoles with amino chains on the different positions have been evaluated by 2D and 3D assays on the human breast cancer cells. Pentacyclic derivatives were synthesized by microwave assisted amination to study the influence of the thiophene substructure on antitumor activity in comparison to tetracyclic analogues. The results obtained from 2D assay reveals that the antitumor activity is strongly dependent on the nature and position of amino chains. Tetracyclic derivatives displayed selective activity on SK-BR-3 with the 2-amino substituted derivatives as the most active ones while pentacyclic derivatives 6-16 and 21-25 showed more pronounced activity on T-47D. The evaluation of antitumor activity in the 3D assay pointed out that some of the tetracyclic and pentacyclic amino substituted derivatives showed selective activity on the MDA-MB-231 cell line. Influence of physico-chemical properties of the compounds on antiproliferative activity have been investigated by multivariate statistical methods. As a measure of lipophilicity, experimental Chrom LogD values have been determined and number of structural parameters have been calculated for investigated compounds. Main factors contributing to the antiproliferative effect for both 2D and 3D cell cultures are found to be basicity, lipophilicity, molecular weight and number of H-bond donors.
Subject(s)
Benzimidazoles/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Carboxylic Acids/chemistry , Cell Culture Techniques , Cell Line, Tumor , Cell Proliferation/drug effects , Computer Simulation , Doxorubicin/chemistry , Doxorubicin/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Structure , Multivariate Analysis , Pyridones/chemistry , Structure-Activity RelationshipABSTRACT
Biofilms provide an ideal environment for protecting the microbial cells from damage caused by humoral and cellular immune system components, promoting resistance, infections and increasing mortality and morbidity of patients in health facilities. In an attempt to provide an innovative solution for preventing contamination in hospital environments, this study evaluated nine structural complementary fluorescent benzimidazo[1,2-α]quinolines as bifunctional agents that both detect and have biocidal activity against yeast biofilms on stainless steel surfaces. The benzimidazoles' staining capability was determined by a fluorescence microscopy study and spraying the substance on yeast biofilm contaminated stainless steel surfaces. Furthermore, their in vitro human leukocyte cytotoxicity was evaluated with trypan blue and their biocidal activity was determined as the minimum inhibitory concentration against Candida tropicalis, C. albicans and C. parapsilosis strains. Moreover, scanning electron micrographs were recorded to study the biocidal activity. This resulted in the identification of 7, which presents all the desired characteristics (such as solubility) and capabilities (staining and biocide activity against all tested biofilm forming yeast strains) at the same time. As such, benzimidazole 7 has the potential to guarantee the use of disinfected medical and surgical instruments in clinical and surgical procedures, consequently, contributing to an increased safety for patients.
Subject(s)
Biofilms , Candida albicans/drug effects , Candida albicans/physiology , Fluorescent Dyes/chemistry , Fluorescent Dyes/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Biofilms/drug effects , Candida albicans/isolation & purification , Drug Resistance, Fungal/drug effects , Microbial Sensitivity TestsABSTRACT
We describe the synthesis, 3D-derived quantitative structure-activity relationship (QSAR), antiproliferative activity and DNA binding properties of a series of 2-amino, 5-amino and 2,5-diamino substituted benzimidazo[1,2-a]quinolines prepared by environmentally friendly uncatalyzed microwave assisted amination. The antiproliferative activities were assessed in vitro against colon, lung and breast carcinoma cell lines; activities ranged from submicromolar to micromolar. The strongest antiproliferative activity was demonstrated by 2-amino-substituted analogues, whereas 5-amino and or 2,5-diamino substituted derivatives resulted in much less activity. Derivatives bearing 4-methyl- or 3,5-dimethyl-1-piperazinyl substituents emerged as the most active. DNA binding properties and the mode of interaction of chosen substituted benzimidazo[1,2-a]quinolines prepared herein were studied using melting temperature studies, a series of spectroscopic studies (UV/Visible, fluorescence, and circular dichroism), and biochemical experiments (topoisomerase I-mediated DNA relaxation and DNase I footprinting experiments). Both compound 36 and its bis-quaternary iodide salt 37 intercalate between adjacent base pairs of the DNA helix while compound 33 presented a very weak topoisomerase I poisoning activity. A 3D-QSAR analysis was performed to identify hydrogen bonding properties, hydrophobicity, molecular flexibility and distribution of hydrophobic regions as these molecular properties had the highest impact on the antiproliferative activity against the three cell lines.
Subject(s)
Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Benzimidazoles/chemistry , DNA/metabolism , Quantitative Structure-Activity Relationship , Quinolines/metabolism , Quinolines/pharmacology , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Quinolines/chemistryABSTRACT
The synthesis of 5-amino substituted benzimidazo[1,2-a]quinolines prepared by microwave assisted amination from halogeno substituted precursor was described. The majority of compounds were active at micromolar concentrations against colon, lung and breast carcinoma cell lines in vitro. The N,N-dimethylaminopropyl 9 and piperazinyl substituted derivative 19 showed the most pronounced activity towards all of the three tested tumor cell lines, which could be correlated to the presence of another N heteroatom and its potential interactions with biological targets. The DNA binding studies, consisting of UV/Visible absorbency, melting temperature studies, and fluorescence and circular dichroism titrations, revealed that compounds 9, 19 and 20 bind to DNA as strong intercalators. The cellular distribution analysis, based on compounds' intrinsic fluorescence, showed that compound 20 does not enter the cell, while compounds 9 and 19 do, which is in agreement with their cytotoxic effects. Compound 9 efficiently targets the nucleus whereas 19, which also showed DNA intercalating properties in vitro, was mostly localised in the cytoplasm suggesting that the antitumor mechanism of action is DNA-independent.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Intercalating Agents/chemical synthesis , Intercalating Agents/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Benzimidazoles/chemistry , Benzimidazoles/metabolism , Cattle , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , Humans , Intercalating Agents/chemistry , Intercalating Agents/metabolismABSTRACT
This manuscript described the synthesis and biological activity of novel nitro substituted E-2-styryl-benzimidazoles and E-2-(2-benzimidazolyl)-3-phenylacrylonitriles and nitro and amino substituted benzimidazo[1,2-a]quinolines (4-5, 6-11, 17-20, and 21-32). All of the compounds showed significant growth inhibitory effect towards five tumor cell lines, whereby the IC(50) concentrations of 11, 20, 28, 29, 30, 32 are in the low micromolar range (IC(50)=2-19 µM). The DNA binding experiments did not show significant affinity of two selected compounds towards ct-DNA. The flow cytometry analysis of potential cell cycle perturbations after the treatment with compounds 9, 11, 25, and 29 demonstrated that all of the compounds (5 µM ≈ IC(50)) significantly delayed the progression through G1 phase, as demonstrated by the accumulation of cells in G1 phase, accompanied with the reduction of the cell number in the cells in S phase, which does not point to DNA damage as the main mechanism of action. Also, fluorescence microscopy study showed cytoplasmic distribution of the compounds, demonstrating that DNA is not the primary target of compounds. Thus, considerable antiproliferative effects of studied compounds are due to interactions with other biological targets within cells.