Recent Developments of Free-Radical Substitutions of Heteroaromatic Bases

Minisci, Francesco; Vismara, Elena; Fontana, Francesca

doi:10.3987/rev-88-sr1

Cited by 439 publications

(162 citation statements)

References 1 publication

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“…Much of the literature related to the activation of INH by KatG has focused on the fate of INH and possible intermediates involved in the process (6 -8). With NAD ϩ included in the mix, the generation of the isonicotinoyl-NAD adduct was observed both with and without KatG present (7)(8)(9), leading to the suggestions that the role of KatG is limited to the hydrazinolysis of INH and that the subsequent reaction of the isonicotinoyl radical with NAD ϩ is a nonenzymatic event involving a homolytic aromatic substitution (7,10). Reactive oxygen species have been implicated in INH activation both in vivo (11,12) and in vitro (6), and an elevated level of superoxide (13) was identified as a possible reason for the high sensitivity of M. tuberculosis to INH (1).…”

Section: Isonicotinic Acid Hydrazide (Isoniazid or Inh)mentioning

confidence: 99%

Catalase-peroxidases (KatG) Exhibit NADH Oxidase Activity

Singh

Wiseman

Deemagarn

et al. 2004

Journal of Biological Chemistry

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Catalase-peroxidases (KatG) produced by Burkholderia pseudomallei, Escherichia coli, and Mycobacterium tuberculosis catalyze the oxidation of NADH to form NAD ؉ and either H 2 O 2 or superoxide radical depending on pH. The NADH oxidase reaction requires molecular oxygen, does not require hydrogen peroxide, is not inhibited by superoxide dismutase or catalase, and has a pH optimum of 8.75, clearly differentiating it from the peroxidase and catalase reactions with pH optima of 5.5 and 6.5, respectively, and from the NADH peroxidase-oxidase reaction of horseradish peroxidase. B. pseudomallei KatG has a relatively high affinity for NADH (K m ‫؍‬ 12 M), but the oxidase reaction is slow (k cat ‫؍‬ 0.54 min ؊1 ) compared with the peroxidase and catalase reactions. The catalase-peroxidases also catalyze the hydrazinolysis of isonicotinic acid hydrazide (INH) in an oxygen-and H 2 O 2 -independent reaction, and KatG-dependent radical generation from a mixture of NADH and INH is two to three times faster than the combined rates of separate reactions with NADH and INH alone. The major products from the coupled reaction, identified by high pressure liquid chromatography fractionation and mass spectrometry, are NAD ؉ and isonicotinoyl-NAD, the activated form of isoniazid that inhibits mycolic acid synthesis in M. tuberculosis. Isonicotinoyl-NAD synthesis from a mixture of NAD ؉ and INH is KatG-dependent and is activated by manganese ion. M. tuberculosis KatG catalyzes isonicotinoyl-NAD formation from NAD ؉ and INH more efficiently than B. pseudomallei KatG.

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Section: Isonicotinic Acid Hydrazide (Isoniazid or Inh)mentioning

confidence: 99%

Catalase-peroxidases (KatG) Exhibit NADH Oxidase Activity

Singh

Wiseman

Deemagarn

et al. 2004

Journal of Biological Chemistry

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“…[8] Accordingly, the selective formation of 2 might be explained by the intrinsic affinity of acyl radicals for electron-deficient heterocycles such as NAD and would not depend on specific interactions within the active site of InhA. To test this hypothesis, we first examined if 2 is formed via NADH or NAD and if in both cases actually the same inhibitor is formed.…”

mentioning

confidence: 99%

Spontaneous Formation of the Bioactive Form of the Tuberculosis Drug Isoniazid

Wilming

Johnsson

1999

Angew. Chem. Int. Ed.

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“…[31][32][33][34][35][36] The title compound 2 was achieved from 2f by the method analogus with 1f prepared from 1d mentioned above.…”

Section: -Aminosulfonyl-1-carbamoyl-3-(1h-benzo[d]imidazol-2-yl)-β-cmentioning

confidence: 99%

Synthesis and Structure of the β-Carboline Derivatives and Their Binding Intensity with Cyclin-Dependent Kinase 2

Wang

Jin

Lin

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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Series of 3-substituted of 6-aminosulfonyl-β-carbolines were designed and synthesized. In addition, the binding mode of these β-carboline derivatives with cyclin-dependent kinase 2 (CDK2) was studied by means of fluorescence measurements and molecular docking calculation. The results showed that replacement of 3-cyclohexylmethoxy group will increase the hydrophobic binding interaction with the deep hydrophobic pocket of CDK2 correlate to the higher binding intensity.Key words cyclin-dependent kinase 2; β-carboline; synthesis; molecular docking; fluorescence It is well known that the phases of the cell cycle are driven by cyclin-dependent kinases (CDKs). Upon complexation with its activating proteins, cyclin E or cyclin A, cyclin-dependent kinase 2 (CDK2) modulates the activity of many cellular substrates via phosphorylation on serine (Ser) and/or threonine (Thr) residues.1-4) Abnormal CDK control of the cell cycle has been strongly linked to the molecular pathology of cancer. 5)The importance of CDK2 for cell cycle progression has led to an active pursuit of small molecule inhibitors of this enzyme as a possible treatment against cancer and other hyper-proliferative disorders.6-9) All CDK inhibitors, identified so far, function by competing with ATP for binding to the catalytic site. Actually several CDK inhibitors have entered clinical evaluation for the treatment of cancer, including flavopiridol, amino-thiazole compound.10) In our program to develop CDK2 inhibitors, we recently investigate the β-carboline alkaloids containing a planar tricyclic system as a large group of naturally-occurring and synthetic alkaloids, [11][12][13][14] which has a broad spectrum of biochemical effects and pharmaceutical properties. These compounds have been shown to intercalate into DNA, to inhibit CDK, topisomerase and monoamine oxidase, and to interact with benzodiazepine receptors (BZ), 5-hydroxy serotonin receptors (5-HT), dopamine (DA) and imidazoline receptors. [15][16][17][18][19][20][21][22][23] Inspired by these results, our research group recently focused on first of all, using a structure-guided strategy based on CDK2 as appropriate means to generate potent CDK2 inhibitors; then to synthesize disubstituted β-carbolines and to complete their biological evaluation study. As a part of our systematic work, in this paper, structure modification of β-carboline based on increasing its hydrophobic nature has been adopted. Herein we reported the design and synthesis of series of 3-substituted of 6-aminosulfonyl-β-carbolines. Series of 3-substituted compounds with different hydrophobic groups (Chart 1) were synthesized and one of their structures was elucidated with X-ray crystal analysis. The new derivatives were prepared following the reaction sequences depicted in Charts 2-4. Their binding intensity with CDK2 was measured by fluorescence spectroscopy. ExperimentalSynthesis The target compounds were prepared using the reaction sequence. All the chemical structures of the synthesized compounds were confirmed by spectroscopic me...

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Recent Developments of Free-Radical Substitutions of Heteroaromatic Bases

Cited by 439 publications

References 1 publication

Catalase-peroxidases (KatG) Exhibit NADH Oxidase Activity

Catalase-peroxidases (KatG) Exhibit NADH Oxidase Activity

Spontaneous Formation of the Bioactive Form of the Tuberculosis Drug Isoniazid

Synthesis and Structure of the β-Carboline Derivatives and Their Binding Intensity with Cyclin-Dependent Kinase 2

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