2. Academic Validation
  3. Discovery of phenylselenoether-hydantoin hybrids as ABCB1 efflux pump modulating agents with cytotoxic and antiproliferative actions in resistant T-lymphoma

Discovery of phenylselenoether-hydantoin hybrids as ABCB1 efflux pump modulating agents with cytotoxic and antiproliferative actions in resistant T-lymphoma

  • Eur J Med Chem. 2020 Aug 15;200:112435. doi: 10.1016/j.ejmech.2020.112435.
Wesam Ali 1,  Gabriella Spengler 2,  Annamária Kincses 2,  Márta Nové 2,  Cecilia Battistelli 3,  Gniewomir Latacz 4,  Małgorzata Starek 5,  Monika Dąbrowska 5,  Ewelina Honkisz-Orzechowska 4,  Annalisa Romanelli 6,  Manuela Monica Rasile 6,  Ewa Szymańska 4,  Claus Jacob 7,  Clemens Zwergel 8,  Jadwiga Handzlik 9
Affiliations

Affiliations

  • 1 Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Kraków, Poland; Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, Campus B 2.1, D-66123, Saarbruecken, Germany.
  • 2 Institute of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Dóm tér 10, H-6720, Szeged, Hungary.
  • 3 Istituto Pasteur Italia, Fondazione Cenci-Bolognetti, Department of Molecular Medicine, "Department of Excellence 2018-2022", Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.
  • 4 Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Kraków, Poland.
  • 5 Department of Inorganic Chemistry, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Cracow, Poland.
  • 6 Department of Drug Chemistry and Technologies, "Department of Excellence 2018-2022", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
  • 7 Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, Campus B 2.1, D-66123, Saarbruecken, Germany. Electronic address: [email protected].
  • 8 Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, Campus B 2.1, D-66123, Saarbruecken, Germany; Department of Drug Chemistry and Technologies, "Department of Excellence 2018-2022", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy; Department of Precision Medicine, "Luigi Vanvitelli" University of Campania, Via L. De Crecchio 7, 80138 Naples, Italy. Electronic address: [email protected].
  • 9 Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Kraków, Poland. Electronic address: [email protected].
PMID: 32505850 DOI: 10.1016/j.ejmech.2020.112435
Abstract

Multidrug resistance (MDR) in Cancer cells is a crucial aspect to consider for a successful Cancer therapy. P-gp/ABCB1, a member of ABC transporters, is involved in the main tumour MDR mechanism, responsible for the efflux of drugs and cytotoxic substances. Herein, we describe a discovery of potent selenium-containing ABCB1 MDR efflux pump modulators with promising Anticancer activity. On three groups of selenoethers comprehensive studies in terms of design, synthesis, and biological assays, including an insight into cellular mechanisms of Anticancer action as well as an ADMET-screening in vitro were performed, followed by in-depth SAR analysis. Among the investigated new phenylselenoether hybrids, four compounds showed significant cytotoxic and anti-proliferative effects, in particular, in resistant Cancer cells. Hydantoin derivatives (5-7) were significantly more effective than the reference inhibitor verapamil (up to 2.6-fold at a 10-fold lower concentration) modulating ABCB1-efflux pump, also possessing a good drug-drug interaction profile. The best compound (6) was further evaluated in human JURKAT T-lymphocytic Cancer cells for its impact on cell proliferation rate. Mechanistically, the expression of cyclin D1, an enhancer of the cell cycle, decreases, while p53, an inhibitor of cell proliferation, was up-regulated upon the treatment with compound 6 alone or in combination with the chemotherapeutic agent doxorubicin. In summary, a new chemical space of highly active selenium-containing Anticancer agents has been discovered, with a new lead compound 6 that warrants more in-depth biological evaluation and further pharmacomodulation.

Keywords

ABCB1; JURKAT; MDR; P-glycoprotein inhibitor; Selenother; T-lymphoma.

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