Heme oxygenase inhibition by 2-oxy-substituted 1-(1H-imidazol-1-yl)-4-phenylbutanes: Effect of halogen substitution in the phenyl ring

Roman, Gheorghe; Riley, John G.; Vlahakis, Jason Z.; Kinobe, Robert T.; Brien, James F.; Nakatsu, Kanji; Szarek, Walter A.

doi:10.1016/j.bmc.2007.02.034

Cited by 87 publications

(99 citation statements)

References 28 publications

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“…Determination of the crystal structure of the hHO-1 complex with QC-308 revealed the common elements required for binding the majority of the QC compounds and, further, confirmed the presence of a definitive secondary hydrophobic pocket to accommodate and stabilize the second phenyl moiety in the western region of QC-308 (figure 4e) [88]. Thus, each of the two phenyl moieties of the diphenyl analogue fit into separate hydrophobic pockets, resulting in a 'doubleclamp' binding mode to provide additional stabilization, [75]. Thus, using the 'double-clamp' strategy to increase the potency of an HO-1 isozyme-selective derivative such as this would be an avenue worth pursuing.…”

Section: A Novel Inducible Binding Modementioning

confidence: 61%

“…While this proximal pocket is not involved in binding the northeastern region as previously postulated, there was potential in its exploitation to improve inhibitor potency by creating compounds that could occupy both preformed hydrophobic pockets simultaneously. The synthesis and characterization of 1-(1H-imidazol-1-yl)-4,4-diphenyl-2-butanone (QC-308, IC 50 ¼ 0.27 + 0.07 mM), which contains an additional phenyl moiety in the western region, in contrast to the usual single hydrophobic group in the QC compounds, demonstrated a approximately 15-fold increase in potency relative to its monophenyl analogue, 4-phenyl-1-(1H-imidazol-1-yl)-2-butanone (QC-65; IC 50 ¼ 4.06 + 1.8 mM) [75]. This was quite remarkable given that QC-65 was already quite a potent inhibitor.…”

Section: A Novel Inducible Binding Modementioning

confidence: 99%

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Structural insights into human heme oxygenase-1 inhibition by potent and selective azole-based compounds

Rahman

Vukomanovic

Vlahakis

et al. 2013

J. R. Soc. Interface.

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The development of heme oxygenase (HO) inhibitors, especially those that are isozyme-selective, promises powerful pharmacological tools to elucidate the regulatory characteristics of the HO system. It is already known that HO has cytoprotective properties and may play a role in several disease states, making it an enticing therapeutic target. Traditionally, the metalloporphyrins have been used as competitive HO inhibitors owing to their structural similarity with the substrate, heme. However, given heme's important role in several other proteins (e.g. cytochromes P450, nitric oxide synthase), non-selectivity is an unfortunate side-effect. Reports that azalanstat and other non-porphyrin molecules inhibited HO led to a multi-faceted effort to develop novel compounds as potent, selective inhibitors of HO. This resulted in the creation of non-competitive inhibitors with selectivity for HO, including a subset with isozyme selectivity for HO-1. Using X-ray crystallography, the structures of several complexes of HO-1 with novel inhibitors have been elucidated, which provided insightful information regarding the salient features required for inhibitor binding. This included the structural basis for non-competitive inhibition, flexibility and adaptability of the inhibitor binding pocket, and multiple, potential interaction subsites, all of which can be exploited in future drug-design strategies.

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Section: A Novel Inducible Binding Modementioning

confidence: 61%

Section: A Novel Inducible Binding Modementioning

confidence: 99%

Structural insights into human heme oxygenase-1 inhibition by potent and selective azole-based compounds

Rahman

Vukomanovic

Vlahakis

et al. 2013

J. R. Soc. Interface.

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“…HO-1 and HO-2 antibodies were from StressGene and Santa Cruz Biotechnology, respectively; antibodies against ERK, p38, JNK, phospho-ERK (Tyr 202 /Tyr 204 ), phospho-p38, and phospho-JNK were from Cell Signaling Technology; rabbit polyclonal antibody specific to AKT and phospho-AKT were from Santa Cruz Biotechnology; monoclonal antibody against glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was from Cedarlane Laboratories; Taxol was from the oncology pharmacy of the Jewish General Hospital; and OB-24 was synthesized as described previously (14).…”

Section: Methodsmentioning

confidence: 99%

A Novel Experimental Heme Oxygenase-1–Targeted Therapy for Hormone-Refractory Prostate Cancer

Alaoui‐Jamali

Bismar

Gupta³

et al. 2009

Cancer Research

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112

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Heme oxygenase-1 (HO-1), a member of the heat shock protein family, plays a key role as a sensor and regulator of oxidative stress. Herein, we identify HO-1 as a biomarker and potential therapeutic target for advanced prostate cancer (PCA). Immunohistochemical analysis of prostate tissue using a progression tissue microarray from patients with localized PCA and across several stages of disease progression revealed a significant elevation of HO-1 expression in cancer epithelial cells, but not in surrounding stromal cells, from hormonerefractory PCA (HRPCA) compared with hormone-responsive PCA and benign tissue. Silencing the ho-1 gene in HRPCA cells decreased the HO-1 activity, oxidative stress, and activation of the mitogen-activated protein kinase-extracellular signalregulated kinase/p38 kinase. This coincided with reduced cell proliferation, cell survival, and cell invasion in vitro, as well as inhibition of prostate tumor growth and lymph node and lung metastases in vivo. The effect of ho-1 silencing on these oncogenic features was mimicked by exposure of cells to a novel selective small-molecule HO-1 inhibitor referred to as OB-24. OB-24 selectively inhibited HO-1 activity in PCA cells, which correlated with a reduction of protein carbonylation and reactive oxygen species formation. Moreover, OB-24 significantly inhibited cell proliferation in vitro and tumor growth and lymph node/lung metastases in vivo. A potent synergistic activity was observed when OB-24 was combined with Taxol. Together, these results establish HO-1 as a potential therapeutic target for advanced PCA. [Cancer Res 2009;69(20):8017-24]

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“…Imidazole is a structural unit of constructive histidine, histamine, and it is a part of purines which are molecules showing important biological functions in the human body. Some of the imidazole derivatives possess anti-inflammatory, antituberculotic, antimicrobial, antimycotic, antiviral and even antitumor activity [1][2][3][4][5][6][7]. Tinidazole, ornidazole and metronidazole are known as antimicrobials and antiparasites since the mid-1960s [8].…”

Section: Introductionmentioning

confidence: 99%

Spectroscopic (IR, Raman, UV–Vis) study and thermal analysis of 3d-metal complexes with 4-imidazolecarboxylic acid

Świderski

Wilczewska

Świsłocka

et al. 2018

J Therm Anal Calorim

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In this work, the spectroscopic (IR, Raman, UV-Vis) and thermal properties of 3d metal complexes with 4-imidazolecarboxylic acid were studied in order to determine the effect of 3d metals [i.e., Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II)] on the electronic structure and physicochemical properties of the ligand. The spectroscopic studies showed that the 3d-transition metals stabilize the electronic system of 4-imidazolecarboxylic acid. Similar results were obtained previously for benzoic and pyridinecarboxylic acids. The complexes synthesized in an aqueous medium were hydrated, as determined by the elemental and thermogravimetric analysis. The complexes of 4-imidazolecarboxylic acid have the general formula: M(C 3 N 2 H 3 COO) x ÁnH 2 O where M = Mn, Fe, Co, Ni, Cu, Zn, x = 3 for iron complex, x = 2 for other complex and n = 0-3. Thermogravimetric analysis conducted in oxygen atmosphere showed that the complexes decompose to metal oxides. During the thermal decomposition process carbon monoxide, carbon dioxide and imidazole ring degradation products are released.

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Heme oxygenase inhibition by 2-oxy-substituted 1-(1H-imidazol-1-yl)-4-phenylbutanes: Effect of halogen substitution in the phenyl ring

Cited by 87 publications

References 28 publications

Structural insights into human heme oxygenase-1 inhibition by potent and selective azole-based compounds

Structural insights into human heme oxygenase-1 inhibition by potent and selective azole-based compounds

A Novel Experimental Heme Oxygenase-1–Targeted Therapy for Hormone-Refractory Prostate Cancer

Spectroscopic (IR, Raman, UV–Vis) study and thermal analysis of 3d-metal complexes with 4-imidazolecarboxylic acid

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