2. Academic Validation
  3. Synthesis and biological evaluation of new aryl-alkyl(alkenyl)-4-benzylpiperidines, novel Sigma Receptor (SR) modulators, as potential anticancer-agents

Synthesis and biological evaluation of new aryl-alkyl(alkenyl)-4-benzylpiperidines, novel Sigma Receptor (SR) modulators, as potential anticancer-agents

  • Eur J Med Chem. 2016 Nov 29:124:649-665. doi: 10.1016/j.ejmech.2016.08.067.
Marta Rui 1,  Daniela Rossi 2,  Annamaria Marra 2,  Mayra Paolillo 3,  Sergio Schinelli 3,  Daniela Curti 4,  Anna Tesei 5,  Michela Cortesi 5,  Alice Zamagni 5,  Erik Laurini 6,  Sabrina Pricl 7,  Dirk Schepmann 8,  Bernhard Wűnsch 8,  Ernst Urban 9,  Vittorio Pace 9,  Simona Collina 10
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Viale Taramelli 6 and 12, 27100, Pavia, Italy.
  • 3 Department of Drug Sciences, Pharmacology Section, University of Pavia, Viale Taramelli 6 and 12, 27100, Pavia, Italy.
  • 4 Department of Biology and Biotechnology "L. Spallanzani", Lab. of Cellular and Molecular Neuropharmacology, University of Pavia, Via Ferrata 9, 27100, Pavia, Italy.
  • 5 Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, 47014, Meldola (FC), Italy.
  • 6 MOSE - DEA, University of Trieste, Piazzale Europa 1, 34127, Trieste, Italy.
  • 7 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.
  • 8 Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Correnstrasse 48, 48149, Muenster, Germany.
  • 9 Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090, Vienna, Austria.
  • 10 Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Viale Taramelli 6 and 12, 27100, Pavia, Italy. Electronic address: [email protected].
PMID: 27614411 DOI: 10.1016/j.ejmech.2016.08.067
Abstract

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.

Keywords

Apoptotic pathway; Compound 3 (RC-106); Pan-SR modulators; Potential anticancer property; S1R agonist/antagonist profile; Sigma Receptor (SR).

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