title: Hybrids of phenylsulfonylfuroxan and coumarin as potent antitumor agents.
abstract: Sixteen furoxan-based nitric oxide (NO) releasing coumarin derivatives (6a-c, 8a-g, 10a, 13a,b, 15, and 17a,b) were designed, synthesized, and evaluated against the A549, HeLa, A2780, A2780/CDDP, and HUVEC cell lines. Most derivatives displayed potent antiproliferation activities. Among them, 8b exhibited the strongest antiproliferation activity on the four sensitive cell lines mentioned above and three drug resistant tumor cell lines A2780/CDDP, MDA-MB-231/Gem, and SKOV3/CDDP with IC50 values from 14 to 53 nM and from 62 to 140 nM, respectively. Furthermore, 8b inhibited the growth of A2780 in vivo and displayed lower toxicity on nontumorigenesis T29, showing good selectivity against malignant cells in vitro. Preliminary pharmacological studies showed that 8b induces apoptosis, arrests the cell cycle at the G2/M phase in the A2780 cell line, and disrupts the phosphorylation of MEK1 and ERK1. Overall, the NO-releasing capacity and the inhibition of ERK/MAPK pathway signaling may explain the potent antineoplastic activity of these compounds.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai, 201203, China.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Liu
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Chen
authors.forename: Yao-Qing
authors.initials: YQ
authors.lastname: Huang
authors.forename: Pan
authors.initials: P
authors.lastname: Feng
authors.forename: Ya-Lan
authors.initials: YL
authors.lastname: Guo
authors.forename: Gong
authors.initials: G
authors.lastname: Yang
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D063646:Carcinogenesis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003374:Coumarins / Q000008:administration & dosage* / Q000737:chemistry*; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy*; D009569:Nitric Oxide / Q000737:chemistry; D010069:Oxadiazoles / Q000008:administration & dosage* / Q000737:chemistry*; D015398:Signal Transduction
chemical_list: C000594747:4-(2-(4-methyl-2-oxo-2H-chromen-7-yloxy)ethanoxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole 2-oxide; D003374:Coumarins; D004338:Drug Combinations; D010069:Oxadiazoles; C010166:furoxans; D009569:Nitric Oxide; C030123:coumarin; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1