Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.ejphar.2012.09.021
Title: Pyrrolidinediones reduce the toxicity of thiazolidinediones and modify their anti-diabetic and anti-cancer properties
Authors: Saha, S.
Chan, D.S.Z.
Lee, C.Y.
Wong, W.
New, L.S. 
Chui, W.K. 
Yap, C.W. 
Chan, E.C.Y. 
Ho, H.K. 
Keywords: Anti-cancer
Anti-diabetic
Oxidative stress
PPARγ
Pyrrolidinedione
Thiazolidinedione
Issue Date: 15-Dec-2012
Citation: Saha, S., Chan, D.S.Z., Lee, C.Y., Wong, W., New, L.S., Chui, W.K., Yap, C.W., Chan, E.C.Y., Ho, H.K. (2012-12-15). Pyrrolidinediones reduce the toxicity of thiazolidinediones and modify their anti-diabetic and anti-cancer properties. European Journal of Pharmacology 697 (1-3) : 13-23. ScholarBank@NUS Repository. https://doi.org/10.1016/j.ejphar.2012.09.021
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 PPARγ activities, anti-cancer properties as well as toxicological effects. Of significance, both pyrrolidinedione analogs demonstrated reduced toxicity. Pharmacologically, they also displayed diminished PPARγ 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. © 2012 Elsevier B.V. All rights reserved.
Source Title: European Journal of Pharmacology
URI: http://scholarbank.nus.edu.sg/handle/10635/106268
ISSN: 00142999
DOI: 10.1016/j.ejphar.2012.09.021
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