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. [Display omitted] •Design, synthesis and binding affinity evaluation of racemic and entiomeric pan-Sigma Receptor (SR) modulators.•S1R agonist/antagonist profile.•Cytotoxic activity toward a panel of cancer cell lines.•Compound 3 (RC-106) highlighted a promising cytotoxic activity on a panel of cancer cell lines of different tumors.