A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin
Copyright © 2016 Elsevier Ltd. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2016 |
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| Erschienen: |
2016 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
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| Enthalten in: |
Bioorganic & medicinal chemistry - 24(2016), 14 vom: 15. Juli, Seite 3174-83 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Vucicevic, Jelica [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 02.08.2017 Date Revised 02.12.2018 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bmc.2016.05.043 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM261091301 |
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| 100 | 1 | |a Vucicevic, Jelica |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a 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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| 500 | |a Date Revised 02.12.2018 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2016 Elsevier Ltd. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Apoptosis | |
| 650 | 4 | |a Cytotoxic activity | |
| 650 | 4 | |a Doxorubicin synergism | |
| 650 | 4 | |a Drug design | |
| 650 | 4 | |a Rilmenidine | |
| 650 | 4 | |a Synthesis | |
| 650 | 4 | |a α(2)-Adrenoceptors | |
| 650 | 7 | |a Adrenergic alpha-Agonists |2 NLM | |
| 650 | 7 | |a Antibiotics, Antineoplastic |2 NLM | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Oxazoles |2 NLM | |
| 650 | 7 | |a Receptors, Adrenergic, alpha-2 |2 NLM | |
| 650 | 7 | |a Doxorubicin |2 NLM | |
| 650 | 7 | |a 80168379AG |2 NLM | |
| 650 | 7 | |a Rilmenidine |2 NLM | |
| 650 | 7 | |a P67IM25ID8 |2 NLM | |
| 700 | 1 | |a Srdic-Rajic, Tatjana |e verfasserin |4 aut | |
| 700 | 1 | |a Pieroni, Marco |e verfasserin |4 aut | |
| 700 | 1 | |a Laurila, Jonne M M |e verfasserin |4 aut | |
| 700 | 1 | |a Perovic, Vladimir |e verfasserin |4 aut | |
| 700 | 1 | |a Tassini, Sabrina |e verfasserin |4 aut | |
| 700 | 1 | |a Azzali, Elisa |e verfasserin |4 aut | |
| 700 | 1 | |a Costantino, Gabriele |e verfasserin |4 aut | |
| 700 | 1 | |a Glisic, Sanja |e verfasserin |4 aut | |
| 700 | 1 | |a Agbaba, Danica |e verfasserin |4 aut | |
| 700 | 1 | |a Scheinin, Mika |e verfasserin |4 aut | |
| 700 | 1 | |a Nikolic, Katarina |e verfasserin |4 aut | |
| 700 | 1 | |a Radi, Marco |e verfasserin |4 aut | |
| 700 | 1 | |a Veljkovic, Nevena |e verfasserin |4 aut | |
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