Modulation of MRP-1-mediated multidrug resistance by indomethacin analogues
Multidrug resistance (MDR) is a major limiting factor in the development and application of drug candidates. MDR caused by MRP-1 is known to be modulated by the nonsteroidal antiinflammatory drug indomethacin. We have synthesized and biologically evaluated a library of indomethacin analogues. The indomethacin-derived compound library was synthesized employing the Fischer-indole synthesis as the key transformation and making use of a resin-capture-release strategy. Sixty representative members of the library were evaluated in a cell biological cytotoxicity assay employing the MRP-1 expressing human glioblastoma cell line T98G as a model system. Nine of the 60 tested derivatives increased the doxorubicin-mediated cytotoxicity at a comparable or higher level than indomethacin itself. Analysis of these derivatives revealed an interesting structure-function relationship. Most remarkably, two substances increased the toxicity, when doxorubicin was used at clinically relevant low concentrations, at a higher degree than indomethacin.
Rosenbaum, Claudia,R?hrs, Sonja,Müller, Oliver,Waldmann, Herbert
p. 1179 - 1187
(2007/10/03)
Synthesis and Biological Evaluation of an Indomethacin Library Reveals a New Class of Angiogenesis-Related Kinase Inhibitors
Capture and release: Indomethacin has served as a lead compound for the synthesis of a library that revealed a new class of kinase inhibitors. A synthetic approach termed "resin-capture-release" was developed (see scheme) that allowed a large library to be synthesized easily. Six of the library compounds were found to be inhibitors of angiogenesis-related receptor tyrosine kinases.
Rosenbaum, Claudia,Baumhof, Patrick,Mazitschek, Ralf,Mueller, Oliver,Giannis, Athanassios,Waldmann, Herbert
p. 224 - 228
(2007/10/03)
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