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Novel imidazole derivatives as heme oxygenase-1 (HO-1) and heme oxygenase-2 (HO-2) inhibitors and their cytotoxic activity in human-derived cancer cell lines.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2015; Vol. 96, pp. 162-72. Date of Electronic Publication: 2015 Apr 07. - Publication Year :
- 2015
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Abstract
- Heme oxygenase (HO) is a cytoprotective enzyme that can be overexpressed in some pathological conditions, including certain cancers. In this work, novel imidazole derivatives were designed and synthesized as inhibitors of heme oxygenase-1 (HO-1) and heme oxygenase-2 (HO-2). In these compounds the imidazole ring, crucial for the activity, is connected to a hydrophobic group, represented by aryloxy, benzothiazole, or benzoxazole moieties, by means of alkyl or thioalkyl chains of different length. Many of the tested compounds were potent and/or selective against one of the two isoforms of HO. Furthermore, most of the pentyl derivatives showed to be better inhibitors of HO-2 with respect to HO-1, revealing a critical role of the alkyl chain in discriminating between the two isoenzymes. Compounds which showed the better profile of HO inhibition were selected and tested to evaluate their cytotoxic properties in prostate and breast cancer cell lines (DU-145, PC3, LnCap, MDA-MB-231, and MCF-7). In these assays, aryloxyalkyl derivatives resulted more cytotoxic than benzothiazolethioalkyl ones; in particular compound 31 was active against all the cell lines tested, confirming the anti-proliferative properties of HO inhibitors and their potential use in the treatment of specific cancers.<br /> (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Animals
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Cell Proliferation drug effects
Cell Survival drug effects
Cyclooxygenase Inhibitors chemical synthesis
Cyclooxygenase Inhibitors chemistry
Dogs
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Heme Oxygenase (Decyclizing) metabolism
Heme Oxygenase-1 metabolism
Humans
Imidazoles chemical synthesis
Imidazoles chemistry
Madin Darby Canine Kidney Cells drug effects
Molecular Structure
Structure-Activity Relationship
Tumor Cells, Cultured
Antineoplastic Agents pharmacology
Cyclooxygenase Inhibitors pharmacology
Heme Oxygenase (Decyclizing) antagonists & inhibitors
Heme Oxygenase-1 antagonists & inhibitors
Imidazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 96
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25874340
- Full Text :
- https://doi.org/10.1016/j.ejmech.2015.04.003