title: Novel nitric oxide-releasing derivatives of farnesylthiosalicylic acid: synthesis and evaluation of antihepatocellular carcinoma activity.
abstract: Novel furoxan-based nitric oxide (NO) releasing derivatives (8a-p) of farnesylthiosalicylic acid (FTS) were synthesized. Compound 8l displayed the strongest inhibition on the proliferation of human hepatocellular carcinoma (HCC) cells in vitro, superior to FTS, sorafenib, and furoxan moiety, selectively induced high frequency of HCC cell apoptosis, and produced high levels of NO in HCC cells but not in nontumor liver cells. Furthermore, 8l exhibited low acute toxicity to mice and significantly inhibited the growth of HCC tumors in vivo and the Ras-related signaling in the tumors. Therefore, our novel findings may provide a new framework for the design of new NO-releasing furoxan/FTS hybrids for the intervention of human HCC.
authors.affiliation: Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ling
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Ye
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Lai
authors.forename: Hui
authors.initials: H
authors.lastname: Ji
authors.forename: Sixun
authors.initials: S
authors.lastname: Peng
authors.forename: Jide
authors.initials: J
authors.lastname: Tian
mesh_terms: D000818:Animals; 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; D004354:Drug Screening Assays, Antitumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005204:Farnesol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020030:Nitric Oxide Donors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D012459:Salicylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D023382:Toxicity Tests, Acute; D014183:Transplantation, Heterologous
chemical_list: C559860:3-(phenylsulfonyl)-4-(2-(4-(2-(3,7,11-trimethyldodeca-2,6,10-trienylthio)benzoyl)piperazin-1-yl)ethoxy)-1,2,5-oxadiazole-2-oxide; D000970:Antineoplastic Agents; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases