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.

A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin / Vucicevic, Jelica; Srdic Rajic, Tatjana; Pieroni, Marco; Laurila, Jonne M. M.; Perovic, Vladimir; Tassini, Sabrina; Azzali, Elisa; Costantino, Gabriele; Glisic, Sanja; Agbaba, Danica; Scheinin, Mika; Nikolic, Katarina; Radi, Marco; Veljkovic, Nevena. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 24:14(2016), pp. 3174-3183. [10.1016/j.bmc.2016.05.043]

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

PIERONI, Marco;TASSINI, Sabrina;AZZALI, ELISA;COSTANTINO, Gabriele;RADI, Marco;
2016-01-01

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.
A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin / Vucicevic, Jelica; Srdic Rajic, Tatjana; Pieroni, Marco; Laurila, Jonne M. M.; Perovic, Vladimir; Tassini, Sabrina; Azzali, Elisa; Costantino, Gabriele; Glisic, Sanja; Agbaba, Danica; Scheinin, Mika; Nikolic, Katarina; Radi, Marco; Veljkovic, Nevena. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 24:14(2016), pp. 3174-3183. [10.1016/j.bmc.2016.05.043]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2809181
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