期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 697, 期 1-3, 页码 13-23出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2012.09.021
关键词
Thiazolidinedione; Pyrrolidinedione; PPAR gamma; Oxidative stress; Anti-cancer; Anti-diabetic
资金
- NUS Start-up Grant [R-148-000-117-133]
- MOE AcRF Tier I [R-148-000-135-112, R-148-000-136-112]
- NUS Graduate Scholarship
- Department of Pharmacy Final Year Project Grant [R-148-000-003-001]
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 gamma activities, anti-cancer properties as well as toxicological effects. Of significance, both pyrrolidinedione analogs demonstrated reduced toxicity. Pharmacologically, they also displayed diminished PPAR gamma 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. (C) 2012 Elsevier B.V. All rights reserved.
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