51. Synthesis and biological evaluation of new aryl-alkyl(alkenyl)-4-benzylpiperidines, novel Sigma Receptor (SR) modulators, as potential anticancer-agents
- Author
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Marta Rui, Sabrina Pricl, Daniela Curti, Erik Laurini, Vittorio Pace, Daniela Rossi, Bernhard Wűnsch, Mayra Paolillo, Alice Zamagni, Michela Cortesi, Sergio Schinelli, Simona Collina, Dirk Schepmann, Annamaria Marra, Ernst Urban, Anna Tesei, Rui, Marta, Rossi, Daniela, Marra, Annamaria, Paolillo, Mayra, Schinelli, Sergio, Curti, Daniela, Tesei, Anna, Cortesi, Michela, Zamagni, Alice, Laurini, Erik, Pricl, Sabrina, Schepmann, Dirk, Wűnsch, Bernhard, Urban, Ernst, Pace, Vittorio, and Collina, Simona
- Subjects
0301 basic medicine ,Cell Survival ,Blotting, Western ,Sigma receptor ,Apoptotic pathway ,Druggability ,Antineoplastic Agents ,Apoptosis ,Pharmacology ,PC12 Cells ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,Piperidines ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,Receptors, sigma ,Cell Proliferation ,Pan-SR modulator ,Molecular Structure ,Potential anticancer property ,Drug Discovery3003 Pharmaceutical Science ,Aryl ,Organic Chemistry ,Cancer ,Sigma Receptor (SR) ,General Medicine ,medicine.disease ,Small molecule ,Compound 3 (RC-106) ,Pan-SR modulators ,S1R agonist/antagonist profile ,Rats ,030104 developmental biology ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,Cancer cell - 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.
- Published
- 2016