Synthesis and structure--activity relationship of new cytotoxic agents targeting human glutathione-S-transferases.

Abstract

The 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (NBDHEX, 1), a "suicide inhibitor" of the glutathione-S-transferase GSTP1-1, showed pro-apoptotic properties in tumor cells, but in vivo studies were limited by poor bioavailability and high affinity towards GSTM2-2, expressed in many non-cancerous tissues. Here we describe the synthesis and biological characterization of new 1 analogs (2-40), in which the hydroxyhexyl portion at the C4-sulfur atom has been replaced with phenyl-containing moieties as well as substituted alkyl chains. Some of the new compounds displayed 10-100 times increased water-solubility (8, 11, 17, 26-28, 34, 35), and most of them showed higher GSTP1-1 selectivity (2-20, 23-26, 31-33, 35) than 1. The presence of a phenyl ring with polar substituents is in general associated, with some exceptions (23, 24) to low cytotoxicity in osteosarcoma U-2OS cells. Differently, some alkyl derivatives possess cytotoxicity comparable (26, 34, 35) or higher (30, 32) than 1. Among the novel compounds, selected ones (26, 27, 34, and 35) deserve further investigation for their anticancer potential.

• Authors: Dante Rotili, Anastasia De Luca, Domenico Tarantino, Silvia Pezzola, Mariantonietta Forgione, Blasco Morozzo Della Rocca, Mattia Falconi, Antonello Mai, Anna Maria Caccuri
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 89 Pg. 156-71 (Jan 07 2015) ISSN: 1768-3254 [Electronic] France
• PMID: 25462236 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Imidazoles
• Naphthalenes
• GSTP1 protein, human
• Glutathione S-Transferase pi
• orteronel

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Glutathione S-Transferase pi (antagonists & inhibitors, metabolism)
• Humans
• Imidazoles (chemical synthesis, chemistry, pharmacology)
• Models, Molecular
• Molecular Structure
• Naphthalenes (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship