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@ARTICLE{Sachs:862492,
      author       = {Sachs, Julia and Döhl, Katja and Weber, Anja and Bonus,
                      Michele and Ehlers, Ferdinand and Fleischer, Edmond and
                      Klinger, Anette and Gohlke, Holger and Pietruszka, Jörg and
                      Schmitt, Lutz and Teusch, Nicole},
      title        = {{N}ovel 3,4-{D}ihydroisocoumarins {I}nhibit {H}uman {P}-gp
                      and {BCRP} in {M}ultidrug {R}esistant {T}umors and
                      {D}emonstrate {S}ubstrate {I}nhibition of {Y}east {P}dr5},
      journal      = {Frontiers in pharmacology},
      volume       = {10},
      issn         = {1663-9812},
      address      = {Lausanne},
      publisher    = {Frontiers Media},
      reportid     = {FZJ-2019-02798},
      pages        = {400},
      year         = {2019},
      abstract     = {Multidrug resistance (MDR) in tumors and pathogens remains
                      a major problem in the efficacious treatment of patients by
                      reduction of therapy options and subsequent treatment
                      failure. Various mechanisms are described to be involved in
                      the development of MDR with overexpression of ATP-binding
                      cassette (ABC) transporters reflecting the most extensively
                      studied. These membrane transporters translocate a wide
                      variety of substrates utilizing energy from ATP hydrolysis
                      leading to decreased intracellular drug accumulation and
                      impaired drug efficacy. One treatment strategy might be
                      inhibition of transporter-mediated efflux by small
                      molecules. Isocoumarins and 3,4-dihydroisocoumarins are a
                      large group of natural products derived from various sources
                      with great structural and functional variety, but have so
                      far not been in the focus as potential MDR reversing agents.
                      Thus, three natural products and nine novel
                      3,4-dihydroisocoumarins were designed and analyzed regarding
                      cytotoxicity induction and inhibition of human ABC
                      transporters P-glycoprotein (P-gp), multidrug
                      resistance-associated protein 1 (MRP1) and breast cancer
                      resistance protein (BCRP) in a variety of human cancer cell
                      lines as well as the yeast ABC transporter Pdr5 in
                      Saccharomyces cerevisiae. Dual inhibitors of P-gp and BCRP
                      and inhibitors of Pdr5 were identified, and distinct
                      structure-activity relationships for transporter inhibition
                      were revealed. The strongest inhibitor of P-gp and BCRP,
                      which inhibited the transporters up to 80 to $90\%$ compared
                      to the respective positive controls, demonstrated the
                      ability to reverse chemotherapy resistance in resistant
                      cancer cell lines up to 5.6-fold. In the case of Pdr5,
                      inhibitors were identified that prevented substrate
                      transport and/or ATPase activity with IC50 values in the low
                      micromolar range. However, cell toxicity was not observed.
                      Molecular docking of the test compounds to P-gp revealed
                      that differences in inhibition capacity were based on
                      different binding affinities to the transporter. Thus, these
                      small molecules provide novel lead structures for further
                      optimization.},
      cin          = {JSC / ICS-6 / NIC / IBOC / IBG-1},
      ddc          = {610},
      cid          = {I:(DE-Juel1)JSC-20090406 / I:(DE-Juel1)ICS-6-20110106 /
                      I:(DE-Juel1)NIC-20090406 / I:(DE-Juel1)IBOC-20090406 /
                      I:(DE-Juel1)IBG-1-20101118},
      pnm          = {511 - Computational Science and Mathematical Methods
                      (POF3-511) / Forschergruppe Gohlke $(hkf7_20170501)$ / 581 -
                      Biotechnology (POF3-581)},
      pid          = {G:(DE-HGF)POF3-511 / $G:(DE-Juel1)hkf7_20170501$ /
                      G:(DE-HGF)POF3-581},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31040786},
      UT           = {WOS:000464599600001},
      doi          = {10.3389/fphar.2019.00400},
      url          = {https://juser.fz-juelich.de/record/862492},
}