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Inhibitory effects of drugs on the metabolic activity of mouse and human aldehyde oxidases and influence on drug?drug interactions

As aldehyde oxidase (AOX) plays an emerging role in drug metabolism, understanding its significance for drug?drug interactions (DDI) is important. Therefore, we tested 10 compounds for species-specific and substrate-dependent differences in the inhibitory effect of AOX activity using genetically engineered HEK293 cells over-expressing human AOX1, mouse AOX1 or mouse AOX3. The IC50 values of 10 potential inhibitors of the three AOX enzymes were determined using phthalazine and O6-benzylguanine as substrates. 17beta-Estradiol, menadione, norharmane and raloxifene exhibited marked differences in inhibitory effects between the human and mouse AOX isoforms when the phthalazine substrate was used. Some of the compounds tested exhibited substrate-dependent differences in their inhibitory effects. Docking simulations with human AOX1 and mouse AOX3 were conducted for six representative inhibitors. The rank order of the minimum binding energy reflected the order of the corresponding IC50 values. We also evaluated the potential DDI between an AOX substrate (O6-benzylguanine) and an inhibitor (hydralazine) using chimeric mice with humanized livers. Pretreatment of hydralazine increased the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC0?24) of O6-benzylguanine compared to single administration. Our in vitro data indicate species-specific and substrate-dependent differences in the inhibitory effects on AOX activity. Our in vivo data demonstrate the existence of a DDI which may be of relevance in the clinical context.

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Reference£º
Phthalazine – Wikipedia,
Phthalazine | C8H6N432 – PubChem

The important role of 2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid

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Discovery of Novel Dual Poly(ADP-ribose)polymerase and Phosphoinositide 3-Kinase Inhibitors as a Promising Strategy for Cancer Therapy

Concomitant inhibition of PARP and PI3K pathways has been recognized as a promising strategy for cancer therapy, which may expand the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/PI3K inhibitors that merge the pharmacophores of PARP and PI3K inhibitors. Among them, compound 15 stands out as the most promising candidate with potent inhibitory activities against both PARP-1/2 and PI3Kalpha/deltawith pIC50 values greater than 8. Compound 15 displayed superior antiproliferative profiles against both BRCA-deficient and BRCA-proficient cancer cells in cellular assays. The prominent synergistic effects produced by the concomitant inhibition of the two targets were elucidated by comprehensive biochemical and cellular mechanistic studies. In vivo, 15 showed more efficacious antitumor activity than the corresponding drug combination (Olaparib + BKM120) in the MDA-MB-468 xenograft model with a tumor growth inhibitory rate of 73.4% without causing observable toxic effects. All of the results indicate that 15, a first potent dual PARP/PI3K inhibitor, is a highly effective anticancer compound.

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Reference£º
Phthalazine – Wikipedia,
Phthalazine | C8H6N786 – PubChem

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1,2,3,?Triazole-Based Catalysts: From Metal- to Supramolecular Organic Catalysis

1,2,3-Triazoles are unique heterocycles with intriguing physical properties that allow not only the coordination to metals, but also the establishment of supramolecular interactions based on their polarized C?H bonds. In this account, an extensive work of our group on the design and application of 1,2,3-triazole catalysts is covered. Initially, a family of BINOL triazoles (Click-BINOLs) was synthesized and employed in model test reactions in asymmetric metal catalysis such as the Ti-catalyzed addition of alkylzinc reagents to aldehydes. The evolution from the Click-BINOLs to a novel class of triazole-based anion-binding organocatalysts is further discussed. Consequently, these catalysts were successfully applied in alkylation reactions, as well as asymmetric dearomatizations of diverse N-heteroarenes.

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Reference£º
Phthalazine – Wikipedia,
Phthalazine | C8H6N516 – PubChem

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A novel chemiluminescent immunoassay based on original acridinium ester labels as better solution for diagnosis of human toxoplasmosis than conventional ELISA test

Toxoplasma gondii infection is one of the most common human zoonosis. Laboratory diagnosis of this disease is mainly based on the results of serological methods detecting specific antibodies in the patient’s sera. In this study we aimed to evaluate the performance of a chemiluminescence immunoassay (CLIA) based on the use of a novel immunochemical reagent in the form of the conjugate of original acridinium label (AL) attached to secondary antibody (IgG-AL) and SAG2-GRA1-ROP1L chimeric antigen for T. gondii specific antibodies detection. The CLIA test was compared with conventional ELISA, which was based on the same recombinant antigen and differed only in terms of the detection methodology of immune complexes. The new CLIA assay proved to be more sensitive and better differentiated sera of patients with T. gondii infection from sera of healthy individuals, being a promising alternative to more labor, cost-demanding and less versatile ELISA as screening test in toxoplasmosis diagnostics.

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Phthalazine – Wikipedia,
Phthalazine | C8H6N570 – PubChem

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Synthesis, structural and magnetic characterization of oxalate copper(II) complexes of phthalazine, 3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine and 6,7-dimethyl-2,3-di(2-pyridyl)quinoxaline. Supramolecular architectures stabilized by hydrogen bonding

The paper presents a combined experimental and computational study for three oxalate copper(II) complexes [Cu(ptz)2(C2O 4)(H2O)]1.5H2O (1), [Cu(dppt)(C 2O4)(H2O)]H2OMeOH (2) and [Cu(dmdpq)(C2O4)(-H2O)]¡¤5H2O (3) (ptz = phthalazine, dppt = 3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine and dmdpq=6,7-dimethyl-2,3-di(2-pyridyl)quinoxaline). The compounds have been studied by IR, UV-Vis spectroscopy and single crystal X-ray analysis. Due to the presence of coordinated water molecules and oxalate groups together with the lattice solvent molecules (water and methanol) their crystal structures are dominated by the hydrogen-bonding interactions that give rise to the supramolecular architectures. To elucidate the structural and spectroscopic properties of[Cu(ptz)2(C2O4)(H2O)], [Cu(dppt)(C2O4)(H2O)] and [Cu(dmdpq)(C 2O4)(H2O)], calculations at DFT, TDDFT level were undertaken. Magnetic studies of all complexes under study showed paramagnetic behavior with large orbital magnetic contribution.

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Phthalazine – Wikipedia,
Phthalazine | C8H6N273 – PubChem

Properties and Exciting Facts About 2-(3-(4-Bromo-2-fluorobenzyl)-4-oxo-3,4-dihydrophthalazin-1-yl)acetic acid

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Inhibition of hexonate dehydrogenase and aldose reductase from bovine retina by sorbinil, statil, M79175 and valproate.

Aldose reductase inhibitors (A.R.I.s), developed as potentially therapeutic agents for the treatment of complications of long-term diabetes, were found to be potent inhibitors of aldose reductase (ALR2) partially purified from bovine retina (IC50 values: Statil 0.89 microM, Sorbinil 2 microM, M79175 greater than 1 microM). These compounds varied, however, in their ability to inhibit hexonate dehydrogenase (ALR1), a closely related enzyme isolated from the same source (IC50 values: Statil greater than 1 microM, Sorbinil 3.9 microM, M79175 0.18 microM). Statil and Sorbinil were active against ALR2 at very low concentrations (approx. 5% inhibition at 100 pM), but did not inhibit ALR1 at less than or equal to 10 nM. In contrast, M79175 (structurally very similar to Sorbinil) and M7HEQ (a flavonoid) were preferential inhibitors of ALR1. Valproate, a compound of value in the treatment of epilepsies, was a poor inhibitor of ALR2 (18% at 1 mM). Furthermore, valproate was found to be a relatively poor inhibitor of ALR1, particularly in comparison with M79175.

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Reference£º
Phthalazine – Wikipedia,
Phthalazine | C8H6N907 – PubChem

Extended knowledge of Phthalazine

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Enzymes of the Xanthine Oxidase Family

Enzymes from the xanthine oxidase (XO) family of molybdenum enzymes are generally, with some exceptions, molybdenum iron-sulfur flavin hydroxylases. Mammalian xanthine oxidoreductase and aldehyde oxidase were among the first enzymes to be studied in detail more than 100 years ago and, surprisingly, they continue to be thoroughly studied in molecular detail with many open and unresolved questions remaining. Enzymes of the XO family are characterized by a molybdenum cofactor (Moco) active site with a MoVIOS(OH) ligand sphere where substrate hydroxylation of either aromatic or aliphatic carbon centers is catalyzed. During the reaction, electrons are transferred to the oxidizing substrate, most commonly O2 or NAD+, which react at the FAD site.

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Reference£º
Phthalazine – Wikipedia,
Phthalazine | C8H6N321 – PubChem

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763114-26-7, Name is 2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid, belongs to phthalazine compound, is a common compound. Quality Control of 2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acidIn an article, once mentioned the new application about 763114-26-7.

Benzene and [4, 5] imidazo [1, 2 – a] pyrazine ketone derivative and its preparation and use (by machine translation)

The invention provides a benzene and [4, 5] imidazo [1, 2 – a] pyrazine ketone derivatives and their pharmaceutically acceptable salt, its structure is shown as formula I. The invention also discloses containing benzo [4, 5] imidazo [1, 2 – a] pyrazine ketone derivatives preparation method and its in the preparation of antineoplastic drug in the preparation and application of PARP inhibitors. (by machine translation)

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Phthalazine – Wikipedia,
Phthalazine | C8H6N774 – PubChem

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PHTHALAZINONE DERIVATIVES

This review tries to shed light on the early history of different methods for the generation of N-heterocyclic carbenes (NHCs), i.e., the extrusion of heterocumulenes (decarboxylations) from suitable mesomeric betaines, deprotonations of hetarenium salts, alpha-eliminations, tautomerizations of mesomeric betaines, and reductive desulfurizations of cyclic thioureas. Selected examples of acyclic and three- to eight-membered NHCs are presented, as well the generation of selected five- and six-membered anionic NHCs.

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Reference£º
Phthalazine – Wikipedia,
Phthalazine | C8H6N814 – PubChem

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N-Heterocyclic Carbenes

This review tries to shed light on the early history of different methods for the generation of N-heterocyclic carbenes (NHCs), i.e., the extrusion of heterocumulenes (decarboxylations) from suitable mesomeric betaines, deprotonations of hetarenium salts, alpha-eliminations, tautomerizations of mesomeric betaines, and reductive desulfurizations of cyclic thioureas. Selected examples of acyclic and three- to eight-membered NHCs are presented, as well the generation of selected five- and six-membered anionic NHCs.

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Reference£º
Phthalazine – Wikipedia,
Phthalazine | C8H6N391 – PubChem