Pyrrolidinediones reduce the toxicity of thiazolidinediones and modify their anti-diabetic and anti-cancer properties.

Abstract

Thiazolidinediones have been established as a drug class of significant importance in the treatment of Type II diabetes mellitus and have more recently displayed emergent potential as anti-cancer agents. However, their toxicity has hampered clinical development and usage in both therapeutic areas. Studies to date have implicated that the thiazolidinedione ring is responsible for the generation of reactive metabolites after metabolism. As an attempt to improve their safety profiles, we considered the bioisosteric replacement of the thiazolidinedione ring with a chemically conserved pyrrolidinedione heterocyclic system. Using pyrrolidinedione analogs of the thiazolidinedione drugs troglitazone (TGZ), rosiglitazone (RGZ), and pioglitazone (PGZ), we evaluated their PPAR(γ) activities, anti-cancer properties as well as toxicological effects. Of significance, both pyrrolidinedione analogs demonstrated reduced toxicity. Pharmacologically, they also displayed diminished PPAR(γ) binding and ap2 gene expression in a mouse pre-adipocyte cell line 3T3-L1, but enhanced anti-cancer properties based on the suppression of liver cancer cell line (Huh-7) proliferation and the expression of tumor marker, afp. Overall, this study ascertains the general contribution of the thiazolidinedione ring to their cytotoxicity and proposes the applicability of the pyrrolidinedione ring as a selective and safer choice in anti-diabetic and cancer chemotherapeutics for future drug design.

• Authors: Sudipta Saha, Debra Shu Zhen Chan, Chern Yih Lee, Winnie Wong, Lee Sun New, Wai Keung Chui, Chun Wei Yap, Eric Chun Yong Chan, Han Kiat Ho
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 697 Issue 1-3 Pg. 13-23 (Dec 15 2012) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 23041271 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Chromans
• Fabp4 protein, mouse
• Fatty Acid-Binding Proteins
• Hypoglycemic Agents
• PPAR gamma
• Receptors, Peptide
• Succinimides
• Thiazolidinediones
• alpha-fetoprotein receptor, human
• Rosiglitazone
• Receptor Protein-Tyrosine Kinases
• CASP3 protein, human
• Caspase 3
• Glutathione
• Troglitazone
• Pioglitazone

Topics

• 3T3-L1 Cells
• Animals
• Antineoplastic Agents (chemistry, metabolism, toxicity)
• Biotransformation
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Chromans (toxicity)
• Dose-Response Relationship, Drug
• Drug Design
• Fatty Acid-Binding Proteins (genetics, metabolism)
• Gene Expression Regulation
• Glutathione (metabolism)
• Humans
• Hypoglycemic Agents (chemistry, metabolism, toxicity)
• Liver Neoplasms (metabolism, pathology)
• Mice
• Microsomes, Liver (drug effects, metabolism)
• Molecular Structure
• PPAR gamma (agonists, metabolism)
• Phosphorylation
• Pioglitazone
• Protein Carbonylation (drug effects)
• Receptor Protein-Tyrosine Kinases (drug effects, metabolism)
• Receptors, Peptide (metabolism)
• Rosiglitazone
• Structure-Activity Relationship
• Succinimides (chemistry, metabolism, toxicity)
• Thiazolidinediones (chemistry, metabolism, toxicity)
• Troglitazone