Design, Synthesis, and Structure–Activity Relationship Studies of Novel 3-Alkylindole Derivatives as Selective and Highly Potent Myeloperoxidase Inhibitors

Soubhye, Jalal; Aldib, Iyas; Elfving, Betina; Gelbcke, Michel; Furtmüller, Paul G.; Podrecca, Manuel; Conotte, R.; Colet, Jean‐Marie; Rousseau, Alexandre Fontaine; Reyé, Florence; Sarakbi, Ahmad; Vanhaeverbeek, Michel; Kauffmann, Jean‐Michel; Obinger, Christian; Nève, Jean; Prévost, Martine; Boudjeltia, Karim Zouaoui; Dufrasne, François; Antwerpen, Pierre Van

doi:10.1021/jm4001538

Cited by 36 publications

(39 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Recently a number of direct specific MPO inhibitors have been developed. These include PF-1355 (2-(6-(2,5-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide) (Zheng et al, 2015) and MPOi-II (4-(5-fluoro-1H-indol-3-yl)butanamide) (Soubhye et al, 2013). As expected, both of these inhibitors dramatically reduced MPO activity in NB4 cells (Supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

“…MPO has become a target of interest for novel anti-inflammatory drug development (Malle et al, 2007), and a number of potent specific MPO inhibitors were recently reported (Tidén et al, 2011; Forbes et al, 2013; Soubhye et al, 2013, 2016; Li et al, 2015; Zheng et al, 2015). We have used two such inhibitors, PF1355 and MPOi-II, and show that like SA, they reduce etoposide- and mitoxantrone-induced damage in MPO-expressing cells.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Myeloperoxidase Enhances Etoposide and Mitoxantrone-Mediated DNA Damage: A Target for Myeloprotection in Cancer Chemotherapy

et al. 2016

View full text Add to dashboard Cite

Myeloperoxidase is expressed exclusively in granulocytes and immature myeloid cells and transforms the topoisomerase II (TOP2) poisons etoposide and mitoxantrone to chemical forms that have altered DNA damaging properties. TOP2 poisons are valuable and widely used anticancer drugs, but they are associated with the occurrence of secondary acute myeloid leukemias. These factors have led to the hypothesis that myeloperoxidase inhibition could protect hematopoietic cells from TOP2 poison-mediated genotoxic damage and, therefore, reduce the rate of therapy-related leukemia. We show here that myeloperoxidase activity leads to elevated accumulation of etoposide- and mitoxantrone-induced TOP2A and TOP2B-DNA covalent complexes in cells, which are converted to DNA double-strand breaks. For both drugs, the effect of myeloperoxidase activity was greater for TOP2B than for TOP2A. This is a significant finding because TOP2B has been linked to genetic damage associated with leukemic transformation, including etoposide-induced chromosomal breaks at the MLL and RUNX1 loci. Glutathione depletion, mimicking in vivo conditions experienced during chemotherapy treatment, elicited further MPO-dependent increase in TOP2A and especially TOP2B-DNA complexes and DNA double-strand break formation. Together these results support targeting myeloperoxidase activity to reduce genetic damage leading to therapy-related leukemia, a possibility that is enhanced by the recent development of novel specific myeloperoxidase inhibitors for use in inflammatory diseases involving neutrophil infiltration.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Myeloperoxidase Enhances Etoposide and Mitoxantrone-Mediated DNA Damage: A Target for Myeloprotection in Cancer Chemotherapy

et al. 2016

View full text Add to dashboard Cite

show abstract

“…It should be noted that, in this instance, a direct correlation between IC 50 values and docking scores could not generally be obtained through the use of conventional docking programs. 34 …”

Section: Resultsmentioning

confidence: 99%

Inhibition of myeloperoxidase: Evaluation of 2H-indazoles and 1H-indazolones

Roth

Ott²,

Farber

et al. 2014

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

Myeloperoxidase (MPO) produces hypohalous acids as a key component of the innate immune response; however, release of these acids extracellularly results in inflammatory cell and tissue damage. The two-step, one-pot Davis-Beirut reaction was used to synthesize a library of 2H-indazoles and 1H-indazolones as putative inhibitors of MPO. A structure-activity relationship study was undertaken wherein compounds were evaluated utilizing taurine-chloramine and MPO-mediated H2O2 consumption assays. Docking studies as well as toxicophore and Lipinski analyses were performed. Fourteen compounds were found to be potent inhibitors with IC50 values <1 μM, suggesting these compounds could be considered as potential modulators of pro-oxidative tissue injury pertubated by the inflammatory MPO:H2O2:HOCl/HOBr system.

show abstract

“…Indeed, in important work by Brennan and coworkers in MPO knock out mice, revealed that NT formation in acute inflammation models is largely MPO-dependent [119], consistent with the influx and degranulation of activated neutrophils in the inflammatory sites. MPO-mediated nitration pathways can be further distinguished, by using specific MPO- inhibitors [120] such as alkyl indole derivatives [121]. …”

Section: Peroxynitrite Footprintsmentioning

confidence: 99%

Kinetic and mechanistic considerations to assess the biological fate of peroxynitrite

Carballal

Bartesaghi

Radí

2014

Biochimica et Biophysica Acta (BBA) - General Subjects

137

122

View full text Add to dashboard Cite

Background Peroxynitrite, the product of the reaction between superoxide radicals and nitric oxide, is an elusive oxidant of short half-life and low steady-state concentration in biological systems; it promotes nitroxidative damage. Scope of Review We will consider kinetic and mechanistic aspects that allow rationalizing the biological fate of peroxynitrite from data obtained by a combination of methods that include fast kinetic techniques, electron paramagnetic resonance and kinetic simulations. In addition, we provide a quantitative analysis of peroxynitrite production rates and conceivable state-state levels in living systems. Major Conclusions The preferential reactions of peroxynitrite in vivo include those with carbon dioxide, thiols and metalloproteins; its homolysis represents only < 1 % of its fate. To note, carbon dioxide accounts for a significant fraction of peroxynitrite consumption leading to the formation of strong one-electron oxidants, carbonate radicals and nitrogen dioxide. On the other hand, peroxynitrite is rapidly reduced by peroxiredoxins, which represent efficient thiol-based peroxynitrite detoxification systems. Glutathione, present at mM concentration in cells and frequently considered a direct scavenger of peroxynitrite, does not react sufficiently fast with it in vivo; glutathione mainly inhibits peroxynitrite-dependent processes by reactions with secondary radicals. The detection of protein 3-nitrotyrosine, a molecular footprint, can demonstrate peroxynitrite formation in vivo. Basal peroxynitrite formation rates in cells can be estimated in the order of 0.1 to 0.5 μM s−1 and its steady-state concentration ~ 1 nM. General Significance The analysis provides a handle to predict the preferential fate and steady-state levels of peroxynitrite in living systems. This is useful to understand pathophysiological aspects and pharmacological prospects connected to peroxynitrite.

show abstract

Design, Synthesis, and Structure–Activity Relationship Studies of Novel 3-Alkylindole Derivatives as Selective and Highly Potent Myeloperoxidase Inhibitors

Cited by 36 publications

References 48 publications

Myeloperoxidase Enhances Etoposide and Mitoxantrone-Mediated DNA Damage: A Target for Myeloprotection in Cancer Chemotherapy

Myeloperoxidase Enhances Etoposide and Mitoxantrone-Mediated DNA Damage: A Target for Myeloprotection in Cancer Chemotherapy

Inhibition of myeloperoxidase: Evaluation of 2H-indazoles and 1H-indazolones

Kinetic and mechanistic considerations to assess the biological fate of peroxynitrite

Contact Info

Product

Resources

About