Synthesis and biological evaluation of new aryl-alkyl(alkenyl)-4-benzylpiperidines, novel Sigma Receptor (SR) modulators, as potential anticancer-agents.
In the early 2000s, the Sigma Receptor (SR) family was identified as potential "druggable" target in cancer treatment. Indeed, high density of SRs was found in breast, lung, and prostate cancer cells, supporting the idea that SRs could play a role in tumor growth and progression. Moreover, a link between the degree of SR expression and tumor aggressiveness has been postulated, justified by the presence of SRs in high metastatic-potential cancer cells. As a consequence, considerable efforts have been devoted to the development of small molecules endowed with good affinity towards the two SR subtypes (S1R and S2R) with potential anticancer activity. Herein, we report the synthesis and biological profile of aryl-alkyl(alkenyl)-4-benzylpiperidine derivatives - as novel potential anticancer drugs targeting SR. Among them, 3 (RC-106) exhibited a preclinical profile of antitumor efficacy on a panel of cell lines representative of different cancer types (i.e. Paca3, MDA-MB 231) expressing both SRs, and emerged as a hit compound of a new class of SR modulators potentially useful for the treatment of cancer disease.
Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Viale Taramelli 6 and 12, 27100, Pavia, Italy; Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090, Vienna, Austria.
Marta
M
Rui
Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Viale Taramelli 6 and 12, 27100, Pavia, Italy.
Daniela
D
Rossi
Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Viale Taramelli 6 and 12, 27100, Pavia, Italy.
Annamaria
A
Marra
Department of Drug Sciences, Pharmacology Section, University of Pavia, Viale Taramelli 6 and 12, 27100, Pavia, Italy.
Mayra
M
Paolillo
Department of Drug Sciences, Pharmacology Section, University of Pavia, Viale Taramelli 6 and 12, 27100, Pavia, Italy.
Sergio
S
Schinelli
Department of Biology and Biotechnology "L. Spallanzani", Lab. of Cellular and Molecular Neuropharmacology, University of Pavia, Via Ferrata 9, 27100, Pavia, Italy.
Daniela
D
Curti
Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, 47014, Meldola (FC), Italy.
Anna
A
Tesei
Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, 47014, Meldola (FC), Italy.
Michela
M
Cortesi
Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, 47014, Meldola (FC), Italy.
Alice
A
Zamagni
MOSE - DEA, University of Trieste, Piazzale Europa 1, 34127, Trieste, Italy.
Erik
E
Laurini
MOSE - DEA, University of Trieste, Piazzale Europa 1, 34127, Trieste, Italy; National Interuniversity Consortium for Material Science and Technology (INSTM), Research Unit MOSE-DEA, University of Trieste, Trieste, Italy.
Sabrina
S
Pricl
Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Correnstrasse 48, 48149, Muenster, Germany.
Dirk
D
Schepmann
Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Correnstrasse 48, 48149, Muenster, Germany.
Bernhard
B
Wűnsch
Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090, Vienna, Austria.
Ernst
E
Urban
Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090, Vienna, Austria.
Vittorio
V
Pace
Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Viale Taramelli 6 and 12, 27100, Pavia, Italy. Electronic address: simona.collina@unipv.it.
Simona
S
Collina
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D016716:PC12 Cells; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017480:Receptors, sigma / Q000819:agonists / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D010880:Piperidines; D017480:Receptors, sigma
Apoptotic pathway; Compound 3 (RC-106); Pan-SR modulators; Potential anticancer property; S1R agonist/antagonist profile; Sigma Receptor (SR)