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 IC <sub>50</sub> values between 10 and 15 μM. Furthermore, nitroimidazole- conjugated NDGA derivatives exhibit better antiproliferative activity under hypoxic conditions. High performance at low O <sub>2</sub> : Nordihydroguaiaretic acid (NDGA) is a natural product that has been used in many medical research fields. A series of novel nitroimidazole-conjugated NDGA compounds were synthesized and shown to possess good activity against hepatocellular carcinoma (HCC) Hep3B cells. The 4′-trimethyl NDGA derivatives are more potent than their unconjugated counterparts in hypoxic cells. These compounds can therefore be regarded as good HCC-targeting agents. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.