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ID: ALA3813687
Journal: Bioorg Med Chem
Title: A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin.
Authors: Vucicevic J, Srdic-Rajic T, Pieroni M, Laurila JM, Perovic V, Tassini S, Azzali E, Costantino G, Glisic S, Agbaba D, Scheinin M, Nikolic K, Radi M, Veljkovic N.
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.
CiteXplore: 27265687