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

: Jelica Vucicevic, Tatjana Srdic-Rajic, Marco Pieroni, Jonne M. M. Laurila, Vladimir Perovic, Sabrina Tassini, Elisa Azzali, Gabriele Costantino, Sanja Glisic, Danica Agbaba, Mika Scheinin, Katarina Nikolic, Marco Radi, Nevena Veljkovic

Publisher: PERGAMON-ELSEVIER SCIENCE LTD

: 2016

: Bioorganic and Medicinal Chemistry

: BIOORGANIC & MEDICINAL CHEMISTRY

: BIOORGAN MED CHEM

: 24

: 14

: 3174

: 3183

: 10

: 0968-0896

DOI: https://doi.org/10.1016/j.bmc.2016.05.043

The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I-1-type imidazoline receptors (I-1-IR) was recently found to have cytotoxic effects on cultured cancer cell lines. However, due to its pharmacological effects resulting also from alpha(2)-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 alpha(2)-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 alpha(2)-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. (C) 2016 Elsevier Ltd. All rights reserved.