Hepatocellular carcinoma targeting agents: conjugates of nitroimidazoles with trimethyl nordihydroguaiaretic acid.

Abstract

Cancer has been a primary global health issue for decades, with hepatocellular carcinoma (HCC) resulting in more than half a million new cases annually. With survival rates as low as <5% after five years, it remains a poorly treated cancer. Nordihydroguaiaretic acid (NDGA), an antioxidant, was previously proven effective against cancer cells. Nitroimidazole derivatives convert into reactive compounds under hypoxic conditions. In this study, eight methylated NDGAs containing a 2- or 4-nitroimidazole moiety were synthesized as leads against HCC. Four of these conjugates, possessing a poly(ethylene glycol) tether, had superior aqueous solubility. These four NDGA-nitroimidazole conjugates were found to inhibit the proliferation HCC Hep3B cells with IC50 values between 10 and 15 μM. Furthermore, nitroimidazole-conjugated NDGA derivatives exhibit better antiproliferative activity under hypoxic conditions.

• Authors: Ming-Hua Hsu, Szu-Chun Wu, Kuan-Chuan Pao, Irem Unlu, John N Gnabre, David E Mold, Ru Chih C Huang, Jih Ru Hwu
• Journal: ChemMedChem (ChemMedChem) Vol. 9 Issue 5 Pg. 1030-7 (May 2014) ISSN: 1860-7187 [Electronic] Germany
• PMID: 24648164 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antineoplastic Agents
• Nitroimidazoles
• Masoprocol

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Carcinoma, Hepatocellular (drug therapy, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Humans
• Liver Neoplasms (drug therapy, pathology)
• Masoprocol (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Models, Molecular
• Molecular Conformation
• Nitroimidazoles (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship