A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin
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2016
Authors
Vučićević, JelicaSrdić-Rajić, Tatjana
Pieroni, Marco
Laurila, Jonne M. M.
Perović, Vladimir R.
Tassini, Sabrina
Azzali, Elisa
Costantino, Gabriele
Glišić, Sanja
Agbaba, Danica
Scheinin, Mika
Nikolić, Katarina M.
Radi, Marco
Veljković, Nevena V.
Article (Published version)
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© 2016 Elsevier Ltd
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Show full item recordAbstract
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 developme...nt of better adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers. (C) 2016 Elsevier Ltd. All rights reserved.
Keywords:
Drug design / Synthesis / Rilmenidine / Doxorubicin synergism / alpha(2)-Adrenoceptors / Cytotoxic activity / ApoptosisSource:
Bioorganic and Medicinal Chemistry, 2016, 24, 14, 3174-3183Funding / projects:
- Application of the EIIP/ISM bioinformatics platform in discovery of novel therapeutic targets and potential therapeutic molecules (RS-MESTD-Basic Research (BR or ON)-173001)
- Synthesis, Quantitative Structure and Activity Relationship, Physico-Chemical Characterisation and Analysis of Pharmacologically Active Substances (RS-MESTD-Basic Research (BR or ON)-172033)
- University of Parma, Italy, Turku University Hospital, Finland, Chiesi Foundation
DOI: 10.1016/j.bmc.2016.05.043
ISSN: 0968-0896
PubMed: 27265687
WoS: 000377469800011
Scopus: 2-s2.0-84975807224
Institution/Community
VinčaTY - JOUR AU - Vučićević, Jelica AU - Srdić-Rajić, Tatjana AU - Pieroni, Marco AU - Laurila, Jonne M. M. AU - Perović, Vladimir R. AU - Tassini, Sabrina AU - Azzali, Elisa AU - Costantino, Gabriele AU - Glišić, Sanja AU - Agbaba, Danica AU - Scheinin, Mika AU - Nikolić, Katarina M. AU - Radi, Marco AU - Veljković, Nevena V. PY - 2016 UR - https://vinar.vin.bg.ac.rs/handle/123456789/1110 AB - 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. T2 - Bioorganic and Medicinal Chemistry T1 - A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin VL - 24 IS - 14 SP - 3174 EP - 3183 DO - 10.1016/j.bmc.2016.05.043 ER -
@article{ author = "Vučićević, Jelica and Srdić-Rajić, Tatjana and Pieroni, Marco and Laurila, Jonne M. M. and Perović, Vladimir R. and Tassini, Sabrina and Azzali, Elisa and Costantino, Gabriele and Glišić, Sanja and Agbaba, Danica and Scheinin, Mika and Nikolić, Katarina M. and Radi, Marco and Veljković, Nevena V.", year = "2016", abstract = "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.", journal = "Bioorganic and Medicinal Chemistry", title = "A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin", volume = "24", number = "14", pages = "3174-3183", doi = "10.1016/j.bmc.2016.05.043" }
Vučićević, J., Srdić-Rajić, T., Pieroni, M., Laurila, J. M. M., Perović, V. R., Tassini, S., Azzali, E., Costantino, G., Glišić, S., Agbaba, D., Scheinin, M., Nikolić, K. M., Radi, M.,& Veljković, N. V.. (2016). A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin. in Bioorganic and Medicinal Chemistry, 24(14), 3174-3183. https://doi.org/10.1016/j.bmc.2016.05.043
Vučićević J, Srdić-Rajić T, Pieroni M, Laurila JMM, Perović VR, Tassini S, Azzali E, Costantino G, Glišić S, Agbaba D, Scheinin M, Nikolić KM, Radi M, Veljković NV. A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin. in Bioorganic and Medicinal Chemistry. 2016;24(14):3174-3183. doi:10.1016/j.bmc.2016.05.043 .
Vučićević, Jelica, Srdić-Rajić, Tatjana, Pieroni, Marco, Laurila, Jonne M. M., Perović, Vladimir R., Tassini, Sabrina, Azzali, Elisa, Costantino, Gabriele, Glišić, Sanja, Agbaba, Danica, Scheinin, Mika, Nikolić, Katarina M., Radi, Marco, Veljković, Nevena V., "A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin" in Bioorganic and Medicinal Chemistry, 24, no. 14 (2016):3174-3183, https://doi.org/10.1016/j.bmc.2016.05.043 . .