A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin

  • Bioorg Med Chem. 2016 Jul 15;24(14):3174-83. doi: 10.1016/j.bmc.2016.05.043.
Jelica Vucicevic  1 ,  Tatjana Srdic-Rajic  2 ,  Marco Pieroni  3 ,  Jonne M M Laurila  4 ,  Vladimir Perovic  5 ,  Sabrina Tassini  3 ,  Elisa Azzali  3 ,  Gabriele Costantino  3 ,  Sanja Glisic  5 ,  Danica Agbaba  1 ,  Mika Scheinin  6 ,  Katarina Nikolic  7 ,  Marco Radi  8 ,  Nevena Veljkovic  9
Affiliations
  • 1. Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia.
  • 2. Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia.
  • 3. P4T Group, Dipartimento di Farmacia, Università degli Studi di Parma, Viale delle Scienze, 27/A, 43124 Parma, Italy.
  • 4. Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Kiinamyllynkatu 10, FI-20520 Turku, Finland.
  • 5. Center for Multidisciplinary Research, Institute of Nuclear Sciences Vinca, University of Belgrade, POB 522, Mihaila Petrovica Alasa 14, 11001 Belgrade, Serbia.
  • 6. Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Kiinamyllynkatu 10, FI-20520 Turku, Finland; Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland.
  • 7. Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia. Electronic address: [email protected].
  • 8. P4T Group, Dipartimento di Farmacia, Università degli Studi di Parma, Viale delle Scienze, 27/A, 43124 Parma, Italy. Electronic address: [email protected].
  • 9. Center for Multidisciplinary Research, Institute of Nuclear Sciences Vinca, University of Belgrade, POB 522, Mihaila Petrovica Alasa 14, 11001 Belgrade, Serbia. Electronic address: [email protected].
PMID: 27265687 DOI: 10.1016/j.bmc.2016.05.043
Abstract

The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I1-type imidazoline receptors (I1-IR) was recently found to have cytotoxic effects on cultured Cancer cell lines. However, due to its pharmacological effects resulting also from α2-adrenoceptor activation, rilmenidine cannot be considered a suitable Anticancer drug candidate. Here, we report the identification of novel rilmenidine-derived compounds with Anticancer potential and devoid of α2-adrenoceptor effects by means of ligand- and structure-based drug design approaches. Starting from a large virtual library, eleven compounds were selected, synthesized and submitted to biological evaluation. The most active compound 5 exhibited a cytotoxic profile similar to that of rilmenidine, but without appreciable affinity to α2-adrenoceptors. In addition, compound 5 significantly enhanced the apoptotic response to doxorubicin, and may thus represent an important tool for the development of better Adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers.

Keywords
Apoptosis; Cytotoxic activity; Doxorubicin synergism; Drug design; Rilmenidine; Synthesis; α(2)-Adrenoceptors.