Anticancer Potential of a Synthetic Quinoline, 9IV-c, by Inducing Apoptosis in A549 Cell and In vivo BALB/c Mice Models.

BACKGROUND: In a previous work from the author of this study, the compound of 9IV-c, ((E)-2-(3,4- dimethoxystyryl)-6,7,8-trimethoxy-N-(3,4,5-trimethoxyphenyl)quinoline-4-amine) was synthesized, and the effects of potent activity on the multiple human tumor cell lines were evaluated considering the spindle formation together with the microtubule network. METHODS: Accordingly, cytotoxic activity, apoptotic effects, and the therapeutic efficiency of compound 9IV-c on A549 and C26 cell lines were investigated in this study. RESULTS: The compound 9IV-c demonstrated high cytotoxicity against A549 and C26 cell lines with IC50 = 1.66 and 1.21 µM, respectively. The flow cytometric analysis of the A549 cancer cell line treated with compound 9IVc showed that This compound induced cell cycle arrest at the G2/M phase and apoptosis. Western blotting analysis displayed that compound 9IV-c also elevated the Bax/Bcl-2 ratio and increased the activation of caspase-9 and -3 but not caspase-8. CONCLUSION: These data presented that the intrinsic pathway was responsible for 9IV-c -induced cell apoptosis. In vivo studies demonstrated that treatment with the compound of 9IV-c at 10 mg/kg dose led to a decrease in tumor growth compared to the control group. It was found that there was not any apparent body weight loss in the period of treatment. Also, in the vital organs of the BALB/c mice, observable pathologic changes were not detected.

In Silico Evaluation of NO-Sartans against SARS-CoV-2.

INTRODUCTION: Numerous clinical trials are currently investigating the potential of nitric oxide (NO) as an antiviral agent against coronaviruses, including SARS-CoV-2. Additionally, some researchers have reported positive effects of certain Sartans against SARS-CoV-2. METHOD: Considering the impact of NO-Sartans on the cardiovascular system, we have compiled information on the general structure, synthesis methods, and biological studies of synthesized NOSartans. In silico evaluation of all NO-Sartans and approved sartans against three key SARS-CoV- -2 targets, namely Mpro (PDB ID: 6LU7), NSP16 (PDB ID: 6WKQ), and ACE-2 (PDB ID: 1R4L), was performed using MOE. RESULTS: Almost all NO-Sartans and approved sartans demonstrated promising results in inhibiting these SARS-CoV-2 targets. Compound 36 (CLC-1280) showed the best docking scores against the three evaluated targets and was further evaluated using molecular dynamics (MD) simulations. CONCLUSION: Based on our in silico studies, CLC-1280 (a Valsartan dinitrate) has the potential to be considered as an inhibitor of the SARS-CoV-2 virus. However, further in vitro and in vivo evaluations are necessary for the drug development process.

Ultra selective and high-capacity dummy template molecular imprinted polymer to control quorum sensing and biofilm formation of Pseudomonas aeruginosa.

Here a highly selective molecular imprinting polymer was developed to attenuate biofilm formation of the multidrug-resistant pathogen Pseudomonas aeruginosa by disrupting the intermolecular signaling system. Firstly, a dummy template molecular imprinting polymer (MIP) was rationally designed through molecular modeling to capture 2-heptyl-3-hydroxy-4-quinolone (Pseudomonas quinolone signal). This multifunctional signaling molecule interferes with the pathogenicity of P. aeruginosa as an auto-inducer. Then, the synthesized MIP and the non-imprinted polymer (NIP) as reference polymer were evaluated for their binding capacity and biofilm inhibition. The results indicated a significant difference in biofilm inhibition (∼56%) between imprinted (∼67%) and non-imprinted (∼11%) polymer, which is an impressive level, especially for the treatment of various surfaces affected by P. aeruginosa. These results open a new window in the special biological application of MIPs as a promising candidate to reduce concerns in clinical or industrial issues by preventing microbial infections.

In Silico Exploration of Novel Tubulin Inhibitors: A Combination of Docking and Molecular Dynamics Simulations, Pharmacophore Modeling, and Virtual Screening.

Microtubules play a critical role in mitosis and cell division and are regarded as an excellent target for anticancer therapy. Although microtubule-targeting agents have been widely used in the clinical treatment of different human cancers, their clinical application in cancer therapy is limited by both intrinsic and acquired drug resistance and adverse toxicities. In a previous work, we synthesized compound 9IV-c, ((E)-2-(3,4-dimethoxystyryl)-6,7,8-trimethoxy-N-(3,4,5-trimethoxyphenyl)quinoline-4-amine) that showed potent activity against multiple human tumor cell lines, by targeting spindle formation and/or the microtubule network. Accordingly, in this study, to identify potent tubulin inhibitors, at first, molecular docking and molecular dynamics studies of compound 9IV-c were performed into the colchicine binding site of tubulin; then, a pharmacophore model of the 9IV-c-tubulin complex was generated. The pharmacophore model was then validated by Güner-Henry (GH) scoring methods and receiver operating characteristic (ROC) analysis. The IBScreen database was searched by using this pharmacophore model as a screening query. Finally, five retrieved compounds were selected for molecular docking studies. These efforts identified two compounds (b and c) as potent tubulin inhibitors. Investigation of pharmacokinetic properties of these compounds (b and c) and compound 9IV-c displayed that ligand b has better drug characteristics compared to the other two ligands.

Corrigendum to "3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies for Identification of Tubulin Inhibitors with Potential Anticancer Activity".

[This corrects the article DOI: 10.1155/2021/6480804.].

NO-HDAC dual inhibitors.

HDAC inhibitors and NO donors have both demonstrated independently broad therapeutic potential in a variety of diseases. Borretto et al. presented the topic of NO-HDAC dual inhibitors for the first time in 2013 as an attractive new topic. Here we collected the general structure of all synthesized NO-HDAC dual inhibitors, lead compounds, synthesis methods and biological features of the most potent dual NO-HDAC inhibitor in each category with the intention of assisting in the synthesis and optimization of new drug-like compounds for diverse diseases. Based on studies done so far, NO-HDAC dual inhibitors have displayed satisfactory results against wound healing (3), heart hypertrophy (3), inflammatory, cardiovascular, neuromuscular illnesses (11a-11e) and cancer (6a-6o, 9a-9d, 10a-10d, 16 and 17). NO-HDAC dual inhibitors can have high therapeutic potential for various diseases due to their new properties, NO properties, HDAC inhibitor properties and also due to the effects of NO on HDAC enzymes.

Coumarins and Quinolones as Effective Multiple Targeted Agents Versus Covid-19: An In Silico Study.

BACKGROUND: The Covid-19 virus emerged a few months ago in China, and infections rapidly escalated into a pandemic. OBJECTIVE: To date, there is no selective antiviral agent for the management of pathologies associated with covid-19 and the need for an effective agent against it is essential. METHODS: In this work, two home-made databases from synthetic quinolines and coumarins were virtually docked against viral proteases (3CL and PL), human cell surface proteases (TMPRSS2 and furin) and spike proteins (S1 and S2). Chloroquine, a reference drug without a clear mechanism against coronavirus was also docked on mentioned targets and the binding affinities compared with title compounds. RESULTS: The best compounds of synthetic coumarins and quinolines for each target were determined. All compounds against all targets showed binding affinity between -5.80 to -8.99 kcal/mol in comparison with the FDA-approved drug, Chloroquine, with binding affinity of -5.7 to -7.98 kcal/mol. Two compounds, quinoline-1 and coumarin-24, were found to be effective on three targets - S2, TMPRSS2 and furin - simultaneously, with good predicted affinity between -7.54 to -8.85 kcal/mol. In silico ADME studies also confirmed good oral absorption for them. Furthermore, PASS prediction was calculated and coumarin-24 had higher probable activity (Pa) than probable inactivity (Pi) with acceptable protease inhibitory as well as good antiviral activity against Hepatitis C virus (HCV), Human immunodeficiency virus (HIV) and influenza. CONCLUSION: Quinoline-1 and Coumarin-24 have the potential to be used against Covid-19. Hence these agents could be useful in combating covid-19 infection after further in vitro and in vivo studies.

Synthesis and biological evaluation of novel quinoline analogs of ketoprofen as multidrug resistance protein 2 (MRP2) inhibitors.

OBJECTIVES: A new series of quinoline analogs of ketoprofen was designed and synthesized as multidrug resistance protein 2 (MRP2) inhibitors using ketoprofen as the lead compounds. MATERIALS AND METHODS: The cytotoxic activity of the compounds was evaluated againt two cancer cell lines including A2780/RCIS (MRP2-overexpressing ovarian carcinoma), A2780, drug-sensitive ovarian carcinoma using MTT assay. Compounds showing low toxicity in MTT test were selected to investigate their MRP inhibition activity. MRP2 inhibitory potency was evaluated by determination of the uptake amount of fluorescent 5-carboxy fluorescein diacetate (5-CFDA) substrate, by A2780/RCIS in the presence of the selected compounds. Mode of interaction between synthesized ligands and homology modeled MRP2 was investigated by MOE software. RESULTS: Compound 6d, a 4-carboxy quinoline possessing dimethoxy phenyl in position 2 of quinoline ring, showed the most MRP2 inhibition activity among all the quinolines and more than the reference drug ketoprofen. MRP2 inhibition activity of compound 7d was less in comparison to that of compound 6d, indicating that carboxyl group in position 4 of quinoline may interact with MRP2. Docking studies showed that compound 7d methyl ester of 6d, interacted less compared to its parent 6d, which is consistent with biological results. CONCLUSION: This study indicates that 6- or 8-benzoyl-2-arylquinoline is a suitable scaffold to design MRP2 inhibitors. The position of benzoyl in quinoline ring is important in inhibition of MRP2. Generally, MRP2 inhibition activity of compound 7d was less in comparison to that of 6d, indicating that carboxyl group in position 4 of quinoline may interact with MRP2.

3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies for Identification of Tubulin Inhibitors with Potential Anticancer Activity.

In this study, we aimed to develop a pharmacophore-based three-dimensional quantitative structure activity relationship (3D-QSAR) for a set including sixty-two cytotoxic quinolines (1-62) as anticancer agents with tubulin inhibitory activity. A total of 279 pharmacophore hypotheses were generated based on the survival score to build QSAR models. A six-point pharmacophore model (AAARRR.1061) was identified as the best model which consisted of three hydrogen bond acceptors (A) and three aromatic ring (R) features. The model showed a high correlation coefficient (R 2 = 0.865), cross-validation coefficient (Q 2 = 0.718), and F value (72.3). The best pharmacophore model was then validated by the Y-Randomization test and ROC-AUC analysis. The generated 3D contour maps were used to reveal the structure activity relationship of the compounds. The IBScreen database was screened against AAARRR.1061, and after calculating ADMET properties, 10 compounds were selected for further docking study. Molecular docking analysis showed that compound STOCK2S-23597 with the highest docking score (-10.948 kcal/mol) had hydrophobic interactions and can form four hydrogen bonds with active site residues.

Anti-quorum sensing potential of ketoprofen and its derivatives against Pseudomonas aeruginosa: insights to in silico and in vitro studies.

Antibiotics are usually used for the treatment of bacterial infections, but multidrug-resistant strains are a phenomenon that has been growing at an increasing rate worldwide. Thus, there is an increasing need for novel strategies for combatting infectious diseases. Many pathogenic bacteria apply quorum sensing (QS) to regulate their pathogenicity and virulence factors production. This circuit makes the QS system an attractive target for antibacterial therapy. In the present study, an important member of non-steroidal anti-inflammatory drugs (NSAIDs), by reducing the biofilm and producing QS-regulated virulence factors, ketoprofen and its synthetic derivatives were screened against the Pseudomonas aeruginosa PAO1. All compounds showed anti-biofilm activity (16-79%) and most of them presented anti-virulence activity. In the co-treatment of ketoprofen, G20, G21, or G77 with tobramycin, biofilm is significantly reduced (potentiated to > 50%) in the number of cells protected inside the impermeable matrix. The in silico studies in addition to the similarities between the chemical structures of PqsR natural ligands and ketoprofen derivatives reinforce the possibility that the mechanism of action is through PqsR inhibition. Based on the results, the anti-pathogenic effect was more appreciable in ketoprofen, G77, and G20.

Design, synthesis and biological evaluation of novel 5-(imidazolyl-methyl) thiazolidinediones as antidiabetic agents.

A newly designed series of imidazolyl-methyl- l-2,4-thiazolidinediones 9 (a-m) were synthesized and In Silico studies were carried out to rationalize their anti-diabetic activity. Generally, all newly synthesized thiazolidinediones had anti-hyperglycemic activity compared with a diabetic-control group, without toxicity in 3T3 cells (viability ≥ 90%). These studies revealed that the compounds 9e and 9b (11∗10-6mol/kg) lowered blood glucose more effectively when compared to pioglitazone at the same dose. Following the administration of compound 9e, no weight gains or any serious side effects on liver and pancreas were observed. Moreover, the glucose consumption assay results showed a significant glucose-lowering effect (p < 0.001) in HepG2 cells, which were exposed to 11 mM of glucose at concentrations of 1.25-10 mM of compound 9e. Also, the PPAR-γ gene expression study revealed that pioglitazone and 9e showed similar behavior relative to the control group.

Design, synthesis and biological evaluation of novel imidazole-chalcone derivatives as potential anticancer agents and tubulin polymerization inhibitors.

Novel imidazole-chalcone derivatives were designed and synthesized as tubulin polymerization inhibitors and anticancer agents. The antiproliferative activity of the imidazole-chalcone was assessed on some human cancer cell lines including A549 (adenocarcinoma human alveolar basal epithelial cells), MCF-7 (human breast cancer cells), MCF-7/MX (mitoxantrone resistant human breast cancer cells), and HEPG2 (human hepatocellular carcinoma cells). Generally, the imidazole-chalcone derivatives exhibited more cytotoxicity on A549 cancer cells in comparison to the other three cell lines, among them compounds 9j' and 9g showed significant cytotoxicity with IC50 values ranging from 7.05 to 63.43 µM against all the four human cancer cells. The flow cytometry analysis of A549 cancer cells treated with 9g and 9j' displayed that these compounds induced cell cycle arrest at the G2/M phase at low concentrations and increased the number of apoptotic cells (cells in subG1 phase) at higher concentrations. They have also inhibited tubulin polymerization similar to combretastatin A-4 (CA-4). Annexin V binding staining assay in A549 cancer cells revealed that compound 9j' induced apoptosis (early and late). Finally, molecular docking studies of 9j' into the colchicine-binding site of tubulin presented the probable interactions of these compounds with tubulin.

Design and synthesis of new carbamates as inhibitors for fatty acid amide hydrolase and cholinesterases: Molecular dynamic, in vitro and in vivo studies.

As anandamide (N-arachidonoylethanolamine, AEA) shows neuroprotective effects, the inhibition of its degradative enzyme, fatty acid amide hydrolase (FAAH) has been considered as a hopeful avenue for the treatment of neurodegenerative diseases, like Alzheimer's disease (AD). Memory loss, cognitive impairment and diminution of the cholinergic tone, due to the dying cholinergic neurons in the basal forebrain, are common hallmarks in patients with AD. By taking advantage of cholinesterase inhibitors (ChEIs), the degradation of acetylcholine (ACh) is decreased leading to enhanced cholinergic neurotransmission in the aforementioned region and ultimately improves the clinical condition of AD patients. In this work, new carbamates were designed as inhibitors of FAAH and cholinestrases (ChEs) (acetylcholinestrase (AChE), butyrylcholinestrase (BuChE)) inspired by the structure of the native substrates, structure of active sites and the SARs of the well-known inhibitors of these enzymes. All the designed compounds were synthesized using different reactions. All the target compounds were tested for their inhibitory activity against FAAH and ChEs by employing the Cayman assay kit and Elman method respectively. Generally, compounds possessing aminomethyl phenyl linker was more potent compared to their corresponding compounds possessing piperazinyl ethyl linker. The inhibitory potential of the compounds 3a-q extended from 0.83 ± 0.03 µM (3i) to ˃100 µM (3a) for FAAH, 0.39 ± 0.02 µM (3i) to 24% inhibition in 113 ± 4.8 µM (3b) for AChE, and 1.8 ± 3.2 µM (3i) to 23.2 ± 0.2 µM (3b) for BuChE. Compound 3i a heptyl carbamate analog possessing 2-oxo-1,2-dihydroquinolin ring and aminomethyl phenyl linker showed the most inhibitory activity against three enzymes. Also, compound 3i was investigated for memory improvement using the Morris water maze test in which the compound showed better memory improvement at 10 mg/kg compared to reference drug rivastigmine at 2.5 mg/kg. Molecular docking and molecular dynamic studies of compound 3i into the enzymes displayed the possible interactions of key residues of the active sites with compound 3i. Finally, kinetic study indicated that 3i inhibits AChE through the mixed- mode mechanism and non-competitive inhibition mechanism was revealed for BuChE.

Anti-oxidant and anti-inflammatory effects of auraptene on phytohemagglutinin (PHA)-induced inflammation in human lymphocytes.

BACKGROUND: Inflammation is characterized as a defensive response of our body against endogenous or exogenous stimuli. Chronic inflammation and oxidative stress play an important role in the pathogenesis of various disorders such as asthma, cancers, and multiple sclerosis. Recently, diverse pharmacological activities of auraptene, a natural prenyloxycoumarin, were reported. In the present study, we aimed to evaluate the anti-oxidative and anti-inflammatory effects of auraptene on human isolated lymphocytes. METHOD: The effects of auraptene (10, 30 and 90 µM) and dexamethasone (0.1 mM) were evaluated on cell viability, reactive oxygen species (ROS), and malondialdehyde (MDA) levels, superoxide dismutase (SOD) and catalase (CAT) activities, and total glutathione content (GSH) as well as the secretion of interleukin 6 (IL-6) and tumor necrosis factor (TNF)-α in phytohemagglutinin (PHA)-stimulated human lymphocytes. RESULTS: Auraptene (10-90 µM) did not affect lymphocytes' viability after 48 h incubation. PHA markedly elevated ROS, MDA, IL-6, and TNF-α levels, while diminished the GSH content, and CAT and SOD activities in human lymphocytes (p < 0.001 for all cases). Treatment with auraptene (10-90 µM) significantly ameliorated ROS, MDA, IL-6, and TNF-α levels, and markedly increased GSH content, and CAT and SOD activities (p < 0.5-0.001). CONCLUSION: Auraptene may possess promising healing effects in the different inflammatory disorders associated with activation of the acquired immune system such as multiple sclerosis and asthma.

Synthesis and biological evaluation of oxazinonaphthalene-3-one derivatives as potential anticancer agents and tubulin inhibitors.

OBJECTIVES: In the present study, a new series of oxazinonaphthalene-3-one analogs was designed and synthesized as novel tubulin inhibitors. MATERIALS AND METHODS: The cytotoxic activity of the synthesized compounds was evaluated against four human cancer cell lines including A2780 (human ovarian carcinoma), A2780/RCIS (cisplatin resistant human ovarian carcinoma), MCF-7 (human breast cancer cells), and MCF-7/MX (mitoxantrone resistant human breast cancer cells), those compounds which demonstrated the most antiproliferative activity in the MTT test were selected to investigate their tubulin inhibition activity and their effects on cell cycle arrest (at the G2/M phase). Moreover, molecular docking studies of the selected compounds in the catalytic site of tubulin (PDB ID: 4O2B) were carried out to describe the results of biological experiments. RESULTS: Most of our compounds exhibited significant to moderate cytotoxic activity against four human cancer cell lines. Among them, Compounds 4d, 5c, and 5g, possessing trimethoxy phenyl, showed the most antiproliferative activity with IC50 values ranging from 4.47 to 52.8 µM. CONCLUSION: The flow cytometric analysis of A2780 cancer cell line treated with compounds 4d, 5c, and 5g showed that these compounds induced cell cycle arrest at the G2/M phase. Compound 5g, the most antiproliferative compound, inhibited tubulin polymerization in a dose-dependent manner. Molecular docking studies of 5g into the colchicine-binding site of tubulin displayed a possible mode of interaction between this compound and tubulin.

Structure-activity relationship studies of indolin-2-one derivatives as vascular endothelial growth factor receptor inhibitors and anticancer agents.

Angiogenesis is a requirement for the growth of cancer cells. The family of vascular endothelial growth factor receptors (VEGFRs) is the main target in metastasis. Indolin-2-one is proved to be an essential scaffold of antiangiogenic drugs. Sunitinib is the first oral indolin-2-one derivative marketed as a VEGFR inhibitor in the treatment of renal cell carcinoma and gastrointestinal stromal tumors. Therefore, novel compounds possessing the scaffold of sunitinib were designed and synthesized by different researchers to improve the anticancer activity, bioavailability, and solubility, and to decrease the toxicity of sunitinib. In this comprehensive review, the structure-activity relationship of different indolin-2-one analogs as VEGFR inhibitors is discussed. It has been observed that the indolin-2-one core is necessary for the inhibition of VEGFRs. It was determined that substitutions at C-3 of the oxindole ring play an important role in their antiangiogenic and anticancer activities.

Design, synthesis and biological evaluation of novel 5,6,7-trimethoxy-N-aryl-2-styrylquinolin-4-amines as potential anticancer agents and tubulin polymerization inhibitors.

A new series of styrylquinolines was designed and synthesized as anticancer agents and tubulin polymerization inhibitors. The in vitro anticancer activity of the synthesized quinolines was evaluated against four human cancer cell lines including A-2780 (human ovarian carcinoma), A-2780/RCIS (cisplatin resistant human ovarian carcinoma), MCF-7 (human breast cancer cells), MCF-7/MX (mitoxantrone resistant human breast cancer cells) and normal Huvec cells. Generally, among the forty-eight newly synthesized quinolines, compounds possessing N-trimethoxy phenyl showed stronger cytotoxic activity with IC50 values ranging from 0.38 to 5.01 µM against all four cancer cell lines. Compounds 9VII-c and 9IV-c showed significant cytotoxic activity on A-2780 cancer cells, stronger than the other compounds and comparable to reference drug CA-4. Compound 9IV-c possessing 3,4-dimethoxystyryl and N-trimethoxy phenyl groups demonstrated potent cytotoxic effects with IC50 values ranging from 0.5 to 1.66 µM on resistant cancer cells as well as their parental cells. Annexin V binding staining assay in A-2780 and MCF-7/MX cancer cells, revealed that compound 9IV-c induced early and late apoptosis. Compounds 9IV-c and 9VII-b, inhibited tubulin polymerization similar to CA4. Finally, molecular docking studies of 9IV-c and 9VII-b into the colchicine-binding site of tubulin displayed the possible interactions of these compounds with tubulin.

Design, synthesis, and biological evaluation of novel 5,6,7-trimethoxy quinolines as potential anticancer agents and tubulin polymerization inhibitors.

OBJECTIVES: Microtubules have key roles in essential cellular processes such as mitosis, cell motion, and intracellular organelle transport. Increasing interest has been given to tubulin binding compounds after the introduction of taxanes into clinical oncology. The object of this study was synthesis and biological evaluation of novel 5,6,7-trimethoxy quinolines as tubulin inhibitors. MATERIALS AND METHODS: The cytotoxicity of the newly synthesized compounds was assessed against different human cancer cell lines including MCF-7, A2780, MCF-7/MX, A2780/RCIS, and normal cells. Compounds demonstrating the most antiproliferative activity, were chosen to examine their tubulin inhibition activity and their ability to arrest the cell cycle and induce apoptosis. Molecular docking studies and molecular dynamics simulation of compound 7e in the catalytic site of tubulin were performed. RESULTS: Most of the synthesized quinolines showed moderate to significant cytotoxic activity against human cancer cells. Compounds 7e and 7f, possessing N-(4-benzoyl phenyl) and N-(4-phenoxy phenyl), respectively, exhibited the most antiproliferative activity more potent than the other compounds and exhibited similar antiproliferative activity on both resistant and parental cancer cells. CONCLUSION: Flow cytometry analysis of A2780, A2780/RCIS, MCF-7, and MCF-7/MX cancer cells treated with 7e and 7f exhibited that these compounds arrested the cell cycle (at the G2/M phase) and induced cellular apoptosis in A2780 cancer cells. These quinolines inhibited tubulin polymerization in a way resembling that of CA-4. Molecular dynamics simulation and molecular docking studies of compound 7e into the binding site of tubulin displayed the probable interactions of 7e with the binding site of tubulin.

Synthesis, Characterization and In-vitro Evaluation of Novel Naphthoquinone Derivatives and Related Imines: Identification of New Anticancer Leads.

Quinones such as 1,4-naphthoquinones are abundant in nature and naphthoquinone based natural products are known to possess anticancer activity. This pharmacophore is known to convey anticancer activity to some drugs such as streptonigrin, mitomycin A, etc. We synthesized and characterized different classes of naphthoquinone derivatives including bis naphthoquinone, 2-arylaminonaphthoquinone, benzoxantene-6,11-dione and benzoacridine-5,6-dione derivatives instead of the expected 2-hydroxy-3-(substituted phenyl(aryl amino)methyl)naphthalene-1,4-dione derivatives from the reaction of 2-hydroxy1,4-naphthoquinone (lawson) with different benzaldehydes and aryl amines. Benzoacridine-5,6-dione derivatives and related imines showed potent anti-breast cancer activity in MCF-7 cancer cells. The in-vitro results revealed that five compounds benzoacridinedione derivatives (6b and 7b) and imines (13, 14 and 15) by the IC50 range of 5.4-47.99 µM are the most potent anti-breast cancer structures.

Synthesis and biological evaluation of novel benzo[c]acridine-diones as potential anticancer agents and tubulin polymerization inhibitors.

A new series of novel benzo[c]acridine-diones possessing pharmacophoric elements of antitubulins with central dihydropyridine bridge were designed and synthesized as potential anticancer agents and tubulin polymerization inhibitors. The cytotoxic activity of the synthesized compounds was evaluated against eight cancer cell lines including MCF-7, A2780, HeLa, HepG2, DU145, A549, PC3, and LNCAP cancer cells and normal cells human umbilical vein endothelial cell (HUVEC) through 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, wherein ß-lapachone and combretastatin A-4 were used as positive controls. Some of our compounds (4c and 4g) showed significant cytotoxic activity on cancer cells with IC50 values in the range of 5.23-24.32 µM. None of the synthesized compounds showed significant cytotoxicity on normal HUVEC cells. Among all investigated derivatives, compound 4g showed promising greater antiproliferative activity against all tested cancer cells with the highest sensitivity observed for the PC3 cell line. Results from the flow cytometry analysis of PC3 and MCF-7 cancer cells treated with 4g showed an induced cell-cycle arrest at G2/M, and therefore induced apoptosis which occurred at low concentration of test compound, whereas annexin V-FITC/propidium iodide staining assay in the aforementioned cancer cell lines treated with 4g showed that 4g can cause necrosis in PC3 and MCF-7 cancer cells at higher concentration. Compound 4g proved to be an inhibitor of tubulin polymerization in a mode similar to that of colchicine and in a dose-dependent manner. Molecular docking studies of 4g into the colchicine-binding site of tubulin exhibited a possible mode of interaction between this compound and tubulin.