Phenothiazine, anthraquinone and related tricyclic derivatives as inhibitors of monoamine oxidase.

Inhibitors of the monoamine oxidase (MAO) enzymes are important agents for the treatment of central nervous system disorders and have established roles in the therapy of neuropsychiatric diseases such as depression and in the neurodegenerative disorder, Parkinson's disease. A number of good potency MAO inhibitors consist of tricyclic ring systems as exemplified by the structures of harmine and the phenothiazine compound methylene blue. In an attempt to discover novel MAO inhibitors, 30 phenothiazine, anthraquinone and related tricyclic derivatives were selected and evaluated as potential inhibitors of human MAO-A and MAO-B. The results show that, in general, the tricyclic compounds are specific inhibitors of MAO-A over the MAO-B isoform. Quinizarin (IC50 = 0.065 µM), 2-chloro-7-methoxy-10H-phenothiazine (IC50 = 0.576 µM) and xanthone (IC50 = 0.623 µM) proved to be the most potent MAO-A inhibitors, while the most potent MAO-B inhibition was recorded with 2-chloro-7-methoxy-10H-phenothiazine (IC50 = 1.34 µM), 1,2-diaminoanthraquinone (IC50 = 2.41 µM) and emodin (IC50 = 3.24 µM). These compounds may undergo further preclinical evaluation and development, and may also serve as potential lead compounds for the future design of MAO inhibitors.

Antiproliferative, DNA binding, and cleavage properties of dinuclear Co(III) complexes containing the bioactive quinizarin ligand.

The adverse side effects and acquired resistance associated with the clinical application of traditional platinum-based anticancer drugs have forced investigation of alternative transition metal-based compounds and their cytostatic properties. Over the last years, the anticancer potential of cobalt complexes has been extensively studied, and in-depth analyses of their mode of action have been conducted. In this work, we present antiproliferative activity against human cancer cells of the dinuclear Co(III) complexes bearing the quinizarin ligand and tris(2-aminoethyl)amine (tren, compound 1) or tris(2-pyridylmethyl)amine (tpa, compound 2) co-ligands. To contribute the understanding mechanisms of biological action of these compounds, their association with DNA in the cells, DNA binding in cell-free media, and DNA cleavage capability were investigated in detail. The results demonstrate that both complexes interact with DNA in tumor cells. However, their mechanism of antiproliferative action is different, and this difference is mirrored by distinct antiproliferative activity. The antiproliferative effect of 1 is connected with its ability to intercalate into DNA and subsequently to inhibit activities of DNA processing enzymes. In contrast, the total antiproliferative efficiency of 2, thanks to its redox properties, appears to be connected with its ability to form radicals and, consequently, with the ability of 2 to cleave DNA. Hence, the findings presented in this study may significantly contribute to understanding the antitumor potential of cobalt complexes. Dinuclear Co(III) complexes containing the bioactive quinizarin ligand exhibit antiproliferative activity based on distinct mechanism.

Biophysical Characterization and Anticancer Activities of Photosensitive Phytoanthraquinones Represented by Hypericin and Its Model Compounds.

Photosensitive compounds found in herbs have been reported in recent years as having a variety of interesting medicinal and biological activities. In this review, we focus on photosensitizers such as hypericin and its model compounds emodin, quinizarin, and danthron, which have antiviral, antifungal, antineoplastic, and antitumor effects. They can be utilized as potential agents in photodynamic therapy, especially in photodynamic therapy (PDT) for cancer. We aimed to give a comprehensive summary of the physical and chemical properties of these interesting molecules, emphasizing their mechanism of action in relation to their different interactions with biomacromolecules, specifically with DNA.

Design and synthesis of various quinizarin derivatives as potential anticancer agents in acute T lymphoblastic leukemia.

A series of quinizarin derivatives containing quaternary ammonium salts and/or thiourea groups were synthesized and their anticancer activities against leukemia cell lines have been tested. Results showed that most of quinizarin derivatives could inhibit the proliferation of leukemia cells. Among these derivatives, compound 3 showed good inhibition activity against various leukemia cells with IC50 values ranging from 0.90 ±â€¯2.55 µM to 10.90 ±â€¯3.66 µM. At the same time, compound 3 also inhibited the growth of human embryonic kidney-293 cell (HEK-293). Molt-4 and Jurkat cells, acute T lymphoblastic leukemia (T-ALL) cell lines, were selected to reveal potential anticancer mechanism of compound 3. Compound 3 inhibited the proliferation of Molt-4 and Jurkat cells in a dose- and time-dependent manner and led to a marked G0/G1 phase arrest. Analysis of Annexin V-APC and intracellular reactive oxygen species (ROS) level by flow cytometry showed that compound 3 induced significant apoptosis in Molt-4 and Jurkat cells. Western blotting assay showed that compound 3 activated the caspase-dependent apoptosis pathway and induced the degradation of Bcl-2 and c-myc protein.

Monitoring the Activity of Immobilized Lipase with Quinizarin Diester Fluoro-Chromogenic Probe.

Quinizarin diester is used as a fluoro-chromogenic substrate of the activity of lipase supported in poly(methylmetacrylate) beads (CALB, Novozym® 435) dispersed in organic solvents. The monoester and diester of quinizarin are both non-fluorescent species contrasting with the enzymatic product quinizarin that shows optical absorption in the visible region and strong fluorescence signal. The enzymatic conversion is accomplished by spectroscopic measurements and it follows a sigmoid curve from which the mean reaction time of the enzymatic process can be determined. This parameter indicates the enzyme activity of the immobilized lipase. Its dependency with the amount of lipase allowed the determination of the ratio of the catalytic rate and the Michaelis constant (kc/Km) and the experimental value found was (1.0 ± 0.1) × 10-2 mg-1/min in the case of quinizarin diacetate.

Anthraquinones quinizarin and danthron unwind negatively supercoiled DNA and lengthen linear DNA.

The intercalating drugs possess a planar aromatic chromophore unit by which they insert between DNA bases causing the distortion of classical B-DNA form. The planar tricyclic structure of anthraquinones belongs to the group of chromophore units and enables anthraquinones to bind to DNA by intercalating mode. The interactions of simple derivatives of anthraquinone, quinizarin (1,4-dihydroxyanthraquinone) and danthron (1,8-dihydroxyanthraquinone), with negatively supercoiled and linear DNA were investigated using a combination of the electrophoretic methods, fluorescence spectrophotometry and single molecule technique an atomic force microscopy. The detection of the topological change of negatively supercoiled plasmid DNA, unwinding of negatively supercoiled DNA, corresponding to appearance of DNA topoisomers with the low superhelicity and an increase of the contour length of linear DNA in the presence of quinizarin and danthron indicate the binding of both anthraquinones to DNA by intercalating mode.

Digitally enhanced thin layer chromatography: further development and some applications in isotopic chemistry.

Improvements to thin layer chromatography (TLC) analysis can be made easily and cheaply by the application of digital colour photography and image analysis. The combined technique, digitally enhanced TLC (DE-TLC), is applicable to the accurate quantification of analytes in mixtures, to reaction monitoring and to other typical uses of TLC. Examples are given of the application of digitally enhanced TLC to: the deuteromethylations of theophylline to [methyl-(2)H3]caffeine and of umbelliferone to [(2)H3]7-methoxycoumarin; the selection of tertiary amine bases in deuterodechlorination reactions; stoichiometry optimisation in the borodeuteride reduction of quinizarin (1,4-dihydroxyanthraquinone) and to the assessment of xanthophyll yields in Lepidium sativum seedlings grown in deuterated media.

A comprehensive in silico and in vitro studies on quinizarin: a promising phytochemical derived from Rhizophora mucronata Lam.

Mangrove plants are a great source of phytomedicines, since from the beginning of human civilization and the origin of traditional medicines. In the present study, ten different mangrove leaf methanolic extracts were screened for the type of phytochemicals followed by assessing antimicrobial, anti-oxidant and anti-cancer activities. The efficient methanolic crude extract of Rhizospora mucornata was further purified and characterized for the presence of the bioactive compound. Based on UV-visible spectroscopy, FTIR, NMR and HRMS analysis, the bioactive compound was 1,4-dihydroanthraquinone; also termed as Quinizarin. This identified compound was potential in exhibiting antimicrobial, antioxidant, and cytotoxic activity. Quinizarin inhibited the growth of Bacillus cereus and Klebsiella aerogenes with minimum inhibitory concentration (MIC) of 0.78 and 1.5 mg/ml. The DPPH free radical scavenging assay revealed the maximum activity of 99.8% at the concentration of 200 µg/ml with an IC50 value of 12.67 ± 0.41 µg/ml. Cytotoxic assay against HeLa (cervical) and MDA-MB231(breast) cancer cell lines revealed IC50 values to be 4.60 ± 0.26 and 3.89 ± 0.15 µg/ml. Together the results of molecular docking and molecular dynamics simulation studies explained that Quinizarin molecule showed stronger binding affinity (-6.2 kcal/mol) and significant structural stability towards anti-apoptotic Bcl-2 protein. Thus, the study put forth the promising role of the natural molecule - Quinizarin isolated from R. mucornata in the formulation of therapeutic drugs against bacterial infections and cancer. Communicated by Ramaswamy H. Sarma.

Quinizarin suppresses the differentiation of adipocytes and lipogenesis in vitro and in vivo via downregulation of C/EBP-beta/SREBP pathway.

AIMS: Potential anti-obesity effects of quinizarin, a plant anthraquinone, were investigated using 3 T3-L1 preadipocyte cells and high-fat diet (HD)-induced obese mice. MAIN METHOD: Cell viability was determined using the MTT assay. Triglyceride (TG) and lipid accumulation were determined using a TG assay kit and Oil Red O staining, respectively. Adipogenic, lipogenic, and lipolytic gene and protein expression was measured by RT-PCR or Western blot. Serum biochemical indices, including cholesterol and blood glucose, in HD-fed obese mice were determined using corresponding assay kits. Histological analysis was performed with haematoxylin and eosin (H&E) staining. RESULTS: Quinizarin (0-10 µM) significantly reduced intracellular TG and lipid droplets during the differentiation of preadipocytes. Quinizarin significantly suppressed the expression of adipocyte differentiation marker proteins, such as CCAAT/enhancer-binding protein ß (C/EBP-ß), C/EBP-α, PPAR-γ, and aP2, and lipogenic marker proteins, including SREBP1c, SREBP2, fatty acid synthase (FAS), and acetyl-CoA carboxylase 1 (ACC1), reduced ACC2 expression and increased carnitine palmitoyltransferase 1 (CPT1) expression. Oral administration of quinizarin (15-30 mg/kg/day) to HD-fed mice for 6 weeks reduced the body weight gain and size of liver adipocytes and epididymal fat tissues, with significant reductions in liver TG and serum total cholesterol, blood glucose, LDL, and HDL levels. SIGNIFICANCE: The results of this study indicated that quinizarin exerts anti-obesity effects by inhibiting both adipogenesis and lipogenesis and stimulating lipolysis in vitro and in vivo mainly by downregulating the SREBP signalling pathway; thus, it might be a potent candidate as a health-beneficial food or therapeutic agent to prevent or treat obesity.

Probing the intermolecular interactions into serum albumin and anthraquinone systems: a spectroscopic and docking approach.

Intermolecular interaction study of human serum albumin (HSA) with two anthraquinones i.e. danthron and quinizarin has been performed through fluorescence, UV-vis and CD spectroscopy along with docking analysis. The titration of drugs into HSA solution brought about the quenching of fluorescence emission by way of complex formation. The binding constants were found to be 1.51 × 104 L mol-1 and 1.70 × 104 L mol-1 at λexc = 280 nm while at λexc = 295 nm, the values of binding constants were 1.81 × 104 L mol-1 and 1.90 × 104 L mol-1 which hinted toward binding of both the drugs in the vicinity of subdomain IIA. Different temperature study revealed the presence of static quenching mechanism. Moreover, more effective quenching of the fluorescence emission was observed at λexc = 295 nm which also suggested that both the drug molecule bind nearer to Trp-214. Thermodynamic parameters showed that hydrophobic interaction was the major force behind the binding of drugs. The UV-vis spectroscopy testified the formation of complex in both the systems and primary quenching mechanism as static one. The changes in secondary structure and α-helicity in both the systems were observed by circular dichroism spectroscopy. Furthermore, molecular docking analysis predicted the probable binding site of drugs in subdomain IIA of HSA molecule. The types of amino acid residues surrounding the drug molecule advocated that van der Waals forces, hydrophobic forces and electrostatic forces played a vital role in the stabilization of drug-protein complex formed.

Design, synthesis and evaluation of an anthraquinone derivative conjugated to myelin basic protein immunodominant (MBP85-99) epitope: Towards selective immunosuppression.

Anthraquinone type compounds, especially di-substituted amino alkylamino anthraquinones have been widely studied as immunosuppressants. The anthraquinone ring is part of mitoxandrone that has been used for the treatment of multiple sclerosis (MS) and several types of tumors. A desired approach for the treatment of MS would be the immunosuppression and elimination of specific T cells that are responsible for the induction of the disease. Herein, the development of a peptide compound bearing an anthraquinone derivative with the potential to specifically destroy the encephalitogenic T cells responsible for the onset of MS is described. The compound consists of the myelin basic protein (MBP) 85-99 immunodominant epitope (MBP85-99) coupled to an anthraquinone type molecule (AQ) via a disulfide (S-S) and 6 amino hexanoic acid (Ahx) residues (AQ-S-S-(Ahx)6MBP85-99). AQ-S-S-(Ahx)6MBP85-99 could bind to HLA II DRB1*-1501 antigen with reasonable affinity (IC50 of 56 nM) The compound was localized to the nucleus of Jurkat cells (an immortalized line of human T lymphocytes) 10 min after its addition to the medium and resulted in lowered Bcl-2 levels (apoptosis). Entrance of the compound was abolished when cells were pre-treated with cisplatin, an inhibitor of thioredoxin reductase. Accordingly, levels of free thiols were elevated in the culture supernatants of Jurkat cells exposed to N-succinimidyl 3-(2-pyridyldithio) propionate coupled to (Ahx)6MBP85-99 via a disulphide (SPDP-S-S-(Ahx)6MBP85-99) but returned to normal after exposure to cisplatin. These results raise the possibility of AQ-S-S-(Ahx)6MBP85-99 being used as an eliminator of encephalitogenic T cells via implication of the thioredoxin system for the generation of the toxic, thiol-containing moiety (AQ-SH). Future experiments would ideally determine whether SPDP-S-S-(Ahx)6MBP85-99 could incorporate into HLA II DRB1*-1501 tetramers and neutralize encephalitogenic T cell lines sensitized to MBP85-99.

Evaluation of antioxidant, enzyme inhibition, and cytotoxic activity of three anthraquinones (alizarin, purpurin, and quinizarin).

OBJECTIVE: The aim of this work was to investigate the cytotoxic, antioxidative, and enzyme inhibition effects of alizarin, quinizarin, and purpurin, which are anthraquinones (AQ). METHODS: Cytotoxic effects were evaluated with cell inhibition rate by 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide assay. Different chemical assays, including free radical scavenging activity (1,1-diphenyl-2-picrylhydrazyl and 2,2-azino-bis(3-ethylbenzothiazloine-6-sulfonic acid)), phosphomolybdenum and reducing power (ferric reducing antioxidant power and cupric ion reducing activity), were used to evaluate the antioxidant properties. Moreover, enzyme inhibitory activities were analyzed against acetylcholinesterase, butrylcholinesterase, tyrosinase, α-amylase, and α-glucosidase. RESULTS: These components have antioxidant and enzyme inhibition activity. Especially, purpurin showed the strongest antioxidant and good enzyme inhibitory effects. According to our cytotoxicity results, alizarin, purpurin, and quinizarin induced dose- and time-dependent cell proliferation. Furthermore, when we applied AQs with mitomycin C (MC) on L929 cell line, we demonstrated that cell proliferation in MC-AQ groups compared with MC group was increased. The most effective component was alizarin at 100 µM concentration. These AQs showed positive effects on L929 cell lines with high half-maximal inhibitory concentration values. CONCLUSION: Our results demonstrate that AQs may be used as antioxidative compounds in food and medicinal applications.