Evaluation of novel aryloxyalkyl derivatives of imidazole and 1,2,4-triazole as heme oxygenase-1 (HO-1) inhibitors and their antitumor properties

Salerno, Loredana; Pittalà, Valeria; Romeo, Giuseppe; Modica, Maria; Siracusa, M. A.; Giacomo, Claudia Di; Acquaviva, Rosaria; Barbagallo, Ignazio; Tibullo, Daniele; Sorrenti, Valeria

doi:10.1016/j.bmc.2013.06.040

Cited by 70 publications

(43 citation statements)

References 54 publications

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“…The synergistic effect was observed when OB-24 was combined with Taxol [109]. Similarly to porphyrin inhibitors, imidazolebased compounds have been shown to exert synergistic effects with imatinib in LAMA-84-R cell line overexpressing HO-1 and resistant to imatinib mesylate [129]. Such sensitizing activities of imidazole-based HO-1 inhibitors represent a very powerful activity so those compounds can be the prototypic molecules for the development of a new class of inhibitors.…”

Section: Accepted Manuscriptmentioning

confidence: 95%

HO-1/CO system in tumor growth, angiogenesis and metabolism — Targeting HO-1 as an anti-tumor therapy

Łoboda

Józkowicz

Dulak

2015

Vascular Pharmacology

154

156

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Section: Accepted Manuscriptmentioning

confidence: 95%

HO-1/CO system in tumor growth, angiogenesis and metabolism — Targeting HO-1 as an anti-tumor therapy

Łoboda

Józkowicz

Dulak

2015

Vascular Pharmacology

154

156

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“…Such upregulation represents an intrinsic defense mechanism to maintain cellular homeostasis and enhance cell survival [31-34]. In particular, HO-1 is considered to play a major role as an essential survival factor, protecting against chemotherapy-induced reactive oxygen species (ROS) increase [27, 35-39]. Most of the studies so far were directed at evaluating the protective effect of these enzymes because of their ability to generate antioxidant and antiapoptotic molecules such as CO and bilirubin [40-47].…”

Section: Introductionmentioning

confidence: 99%

The non-canonical functions of the heme oxygenases

et al. 2016

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Heme oxygenase (HO) isoforms catalyze the conversion of heme to carbon monoxide (CO) and biliverdin with a concurrent release of iron, which can drive the synthesis of ferritin for iron sequestration. Most of the studies so far were directed at evaluating the protective effect of these enzymes because of their ability to generate antioxidant and antiapoptotic molecules such as CO and bilirubin. Recent evidences are suggesting that HO may possess other important physiological functions, which are not related to its enzymatic activity and for which we would like to introduce for the first time the term “non canonical functions”. Recent evidence suggest that both HO isoforms may form protein-protein interactions (i.e. cytochrome P450, adiponectin, CD91) thus serving as chaperone-like protein. In addition, truncated HO-1 isoform was localized in the nuclear compartment under certain experimental conditions (i.e. excitotoxicity, hypoxia) regulating the activity of important nuclear transcription factors (i.e. Nrf2) and DNA repair. In the present review, we discuss three potential signaling mechanisms that we refer to as the non-canonical functions of the HO isoforms: protein-protein interaction, intracellular compartmentalization, and extracellular secretion. The aim of the present review is to describe each of this mechanism and all the aspects warranting additional studies in order to unravel all the functions of the HO system.

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“…In vitro results indicated that inhibition activity was maximum for A549 cell line, compared to MG 63 and MCF7. This suggests that each cancer line responds differently to inhibition treatment, i. e., differential expression of HO‐1 and distinct role of the enzyme . Degese et al., reported the upregulation of HO‐1 during lung carcinogenesis, where it is localized in cytoplasm and the expression of HO‐1 correlates with higher stages of the disease and with lymph node metastasis in NSCLC (non‐small cell lung cancer) …”

Section: Resultsmentioning

confidence: 99%

Quinoline‐Based Imidazole Derivative as Heme Oxygenase‐1 Inhibitor: A Strategy for Cancer Treatment

et al. 2018

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Heme oxygenase (HO) is a cytoprotective enzyme that gets overexpressed under some pathological conditions, like cancer where it provides growth advantage and protection against radiotherapy, chemotheraphy and photodynamic therapy. Earlier studies on HO inhibition were carried out with metalloporphyrins, which not only inhibit HO‐1 but also other constitutively expressed HOs and other heme‐dependent enzymes. Hence, the present study was aimed at synthesizing highly‐substituted imidazole heterocycles as inhibitors of heme oxygenase‐1 (HO‐1). The synthesized compounds were structurally characterized by IR, 1H, 13C NMR, CHN and single crystal XRD analysis. Among the synthesized compounds, compound 6(3‐(4,5‐diphenyl‐1H‐imidazol‐2‐yl)‐6‐methoxy‐1H‐quinoline‐2‐one) showed > 50% HO‐1 inhibitory activity at a least concentration of 9.2 μM and like many pharmaceutically important drugs, it showed competitive inhibition which was confirmed by Lineweaver‐Burk plot. Compound 6 was also tested for cytotoxicity against cancer (A549, MG63, MCF7) and normal cell (HEK293). The compound showed maximum efficacy against A549 cell line and moderate activity against other cell lines. In order to determine the molecular interactions of compound 6 with HO, the molecular docking study was carried out using Schrodinger software, which was in good agreement with experimental observations.

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Evaluation of novel aryloxyalkyl derivatives of imidazole and 1,2,4-triazole as heme oxygenase-1 (HO-1) inhibitors and their antitumor properties

Cited by 70 publications

References 54 publications

HO-1/CO system in tumor growth, angiogenesis and metabolism — Targeting HO-1 as an anti-tumor therapy

HO-1/CO system in tumor growth, angiogenesis and metabolism — Targeting HO-1 as an anti-tumor therapy

The non-canonical functions of the heme oxygenases

Quinoline‐Based Imidazole Derivative as Heme Oxygenase‐1 Inhibitor: A Strategy for Cancer Treatment

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