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: knikolic@pharmacy.bg.ac.rs.
8 P4T Group, Dipartimento di Farmacia, Università degli Studi di Parma, Viale delle Scienze, 27/A, 43124 Parma, Italy. Electronic address: marco.radi@unipr.it.
9 Center for Multidisciplinary Research, Institute of Nuclear Sciences Vinca, University of Belgrade, POB 522, Mihaila Petrovica Alasa 14, 11001 Belgrade, Serbia. Electronic address: nevenav@vinca.rs.

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.

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