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.

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.

• Authors: Loredana Salerno, Valeria Pittalà, Giuseppe Romeo, Maria N Modica, Agostino Marrazzo, Maria A Siracusa, Valeria Sorrenti, Claudia Di Giacomo, Luca Vanella, Neha N Parayath, Khaled Greish
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 96 Pg. 162-72 ( 2015) ISSN: 1768-3254 [Electronic] France
• PMID: 25874340 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cyclooxygenase Inhibitors
• Imidazoles
• HMOX1 protein, human
• Heme Oxygenase (Decyclizing)
• Heme Oxygenase-1
• heme oxygenase-2

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cyclooxygenase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Dogs
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Heme Oxygenase (Decyclizing) (antagonists & inhibitors, metabolism)
• Heme Oxygenase-1 (antagonists & inhibitors, metabolism)
• Humans
• Imidazoles (chemical synthesis, chemistry, pharmacology)
• Madin Darby Canine Kidney Cells (drug effects)
• Molecular Structure
• Structure-Activity Relationship
• Tumor Cells, Cultured