title: Synthesis and evaluation of nitric oxide-releasing derivatives of farnesylthiosalicylic acid as anti-tumor agents.
abstract: Novel furoxan-based nitric oxide (NO)-releasing derivatives (11a-p) of farnesylthiosalicylic acid (FTA) were synthesized. Compounds 11d, 11f, 11k, and 11m-o displayed anti-tumor activities superior to FTA and sorafenib in most cancer cells tested. Analysis of six compounds revealed that 11d, 11f, 11n, 11o, and 11p, but not 11a that had low anti-tumor activity, produced high levels of NO, associated with their strong anti-tumor activity. Furthermore, the anti-tumor activity of 11f was partially mimicked by the furoxan moiety, but reduced by pre-treatment with hemoglobin. Importantly, treatment with 11f inhibited Ras-related signaling in cancer cells. Apparently, the high anti-tumor activity of 11f was attributed to the synergic effect of high levels of NO production and inhibition of Ras-related signaling in cancer cells. Our findings suggest that the furoxan/FTA hybrids may hold greater promise as therapeutic agents for the intervention of human cancers.
authors.affiliation: Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ling
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Ye
authors.forename: Hui
authors.initials: H
authors.lastname: Ji
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Lai
authors.forename: Sixun
authors.initials: S
authors.lastname: Peng
authors.forename: Jide
authors.initials: J
authors.lastname: Tian
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D005204:Farnesol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011905:Genes, ras / Q000187:drug effects; D006801:Humans; D009569:Nitric Oxide / Q000494:pharmacology*; D010069:Oxadiazoles / Q000378:metabolism / Q000494:pharmacology*; D012459:Salicylates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: C528141:1,2,5-oxadiazole 2-oxide; D000970:Antineoplastic Agents; D010069:Oxadiazoles; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D009569:Nitric Oxide; D005204:Farnesol