A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin.
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.
Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia.
Jelica
J
Vucicevic
Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia.
Tatjana
T
Srdic-Rajic
P4T Group, Dipartimento di Farmacia, Università degli Studi di Parma, Viale delle Scienze, 27/A, 43124 Parma, Italy.
Marco
M
Pieroni
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Kiinamyllynkatu 10, FI-20520 Turku, Finland.
Jonne M M
JM
Laurila
Center for Multidisciplinary Research, Institute of Nuclear Sciences Vinca, University of Belgrade, POB 522, Mihaila Petrovica Alasa 14, 11001 Belgrade, Serbia.
Vladimir
V
Perovic
P4T Group, Dipartimento di Farmacia, Università degli Studi di Parma, Viale delle Scienze, 27/A, 43124 Parma, Italy.
Sabrina
S
Tassini
P4T Group, Dipartimento di Farmacia, Università degli Studi di Parma, Viale delle Scienze, 27/A, 43124 Parma, Italy.
Elisa
E
Azzali
P4T Group, Dipartimento di Farmacia, Università degli Studi di Parma, Viale delle Scienze, 27/A, 43124 Parma, Italy.
Gabriele
G
Costantino
Center for Multidisciplinary Research, Institute of Nuclear Sciences Vinca, University of Belgrade, POB 522, Mihaila Petrovica Alasa 14, 11001 Belgrade, Serbia.
Sanja
S
Glisic
Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia.
Danica
D
Agbaba
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Kiinamyllynkatu 10, FI-20520 Turku, Finland; Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland.
Mika
M
Scheinin
Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia. Electronic address: knikolic@pharmacy.bg.ac.rs.
Katarina
K
Nikolic
P4T Group, Dipartimento di Farmacia, Università degli Studi di Parma, Viale delle Scienze, 27/A, 43124 Parma, Italy. Electronic address: marco.radi@unipr.it.
Marco
M
Radi
Center for Multidisciplinary Research, Institute of Nuclear Sciences Vinca, University of Belgrade, POB 522, Mihaila Petrovica Alasa 14, 11001 Belgrade, Serbia. Electronic address: nevenav@vinca.rs.
Nevena
N
Veljkovic
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D020014:K562 Cells; D008024:Ligands; D015394:Molecular Structure; D010080:Oxazoles / Q000494:pharmacology*; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects; D000077769:Rilmenidine
D000316:Adrenergic alpha-Agonists; D000903:Antibiotics, Antineoplastic; D008024:Ligands; D010080:Oxazoles; D018341:Receptors, Adrenergic, alpha-2; D004317:Doxorubicin; D000077769:Rilmenidine
Apoptosis; Cytotoxic activity; Doxorubicin synergism; Drug design; Rilmenidine; Synthesis; α(2)-Adrenoceptors