title: 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.affiliation: Nuclear Science & Technology Development Center, National Tsing Hua University, Hsinchu, Taiwan 30013 (R.O.C.). mhhsu@mx.nthu.edu.tw.
authors.forename: Ming-Hua
authors.initials: MH
authors.lastname: Hsu
authors.forename: Szu-Chun
authors.initials: SC
authors.lastname: Wu
authors.forename: Kuan-Chuan
authors.initials: KC
authors.lastname: Pao
authors.forename: Irem
authors.initials: I
authors.lastname: Unlu
authors.forename: John N
authors.initials: JN
authors.lastname: Gnabre
authors.forename: David E
authors.initials: DE
authors.lastname: Mold
authors.forename: Ru Chih C
authors.initials: RC
authors.lastname: Huang
authors.forename: Jih Ru
authors.initials: JR
authors.lastname: Hwu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009637:Masoprocol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D009593:Nitroimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009593:Nitroimidazoles; D009637:Masoprocol
keywords: NDGA; anticancer agents; hypoxia; nitroimidazoles; nordihydroguaiaretic acids