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

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 SRs modulators potentially useful for the treatment of cancer disease. Keywords Sigma Receptor (SR); pan-SR modulators; compound 3 (RC-106); S1R agonist/antagonist profile; potential anticancer property; apoptotic pathway. Recent studies describe how S2R ligands trigger a cell response which inhibit the activity of the P-glycoprotein, responsible for the active extrusion of anticancer drugs, leading to cell death. [17,18]. Moreover, the hypothesis of a correlation between S2R and Progesterone Receptor Membrane Component 1 (PGRMC1) [19,20] supports the idea that S2R may exert a critical role in tumorigenesis [18]. Indeed, the over-expression of PGRMC1 has been associated to tumor stage and to actively proliferating and invasive cancer cells [21]. It is also relevant that proliferating breast carcinoma cells express S2R up to ten times more than quiescent cells, and the degree of S2R expression has been correlated with tumor staging and grading [22-24]. The highest level of S2R has been detected in pancreatic cancer cell lines (Panc-02, Panc-01, CFPAC-1, AsPC-1) [25]. A recent study, carried out on mouse breast cancer (EMT-6) and human melanoma (MDA-MB-435) cell lines, demonstrate that siramesine (Fig. 1), a S2R selective ligand commonly used as reference compound, can induce cell death (with an EC 50 in both cell lines lower than 10 µM) by three different mechanisms: caspase activation, autophagy, and impaired cell-cycle progression [26]. In the same work, it has been also demonstrated that other S2R ligands, i.e. SV119, WC-26 and RHM-138 (Fig. 1), possess a cytotoxic

Sigma Receptors as Endoplasmic Reticulum Stress “Gatekeepers” and their Modulators as Emerging New Weapons in the Fight Against Cancer

“…Over the years, pharmacological, chemical, and biological papers have demonstrated that S2R is a potential therapeutic target for several diseases including neurodegenerative disorders and cancer ( Vilner and Bowen, 1993 ; Vilner et al, 1995 ; Bowen, 2000 ; Wheeler et al, 2000 ; Crawford and Bowen, 2002 ; Kashiwagi et al, 2009 ; Hornick et al, 2010 ; Guo and Zhen, 2015 ). Based on indirect evidence of S2R overexpression in peripheral and cerebral tumors, it has been hypothesized as a potential target for anticancer therapy ( Crawford and Bowen, 2002 ; Crawford et al, 2002 ; Rui et al, 2016 ), and S2R radiotracers have been developed to image tumors ( Tu et al, 2005 , 2007 , 2010 ; Mach and Wheeler, 2009 ; Mach et al, 2009 ). However, despite the numerous studies performed to date in this setting, the unknown molecular identity of the receptor has limited biological investigations and hindered the search for new drugs that act via the S2R pathway.…”

Sigma Receptor (σR) Ligands with Antiproliferative and Anticancer Activity

“…Several reports describe the antiproliferative and anticancer activity of σ2R ligands in variable cell lines and tumors [ 32 , 120 , 121 ] ( Table 1 ). The last years, it has become obvious that σ2R ligands have significant role in anticancer therapy, as they provoke cancer cell death [ 32 , 121 ]. Siramesine was active against all cancer cell lines tested.…”

“…Both σR types are overexpressed in numerous human cancer tissues, such as small- and non-small-cell lung carcinoma [ 24 , 32 ], large-cell carcinoma (NCI-H1299 and NCI-H838) [ 33 ], renal carcinoma [ 24 ], colon carcinoma (HCT-15 and HCT-16) [ 34 ], sarcoma [ 33 ], brain tumors (CNS U51) [ 35 ], breast cancer (MCF-7. T47D and SKBr3) and breast ductal carcinoma (T47D) [ 32 ], melanoma (A375) [ 24 ], glioblastoma [ 24 ], adenocarcinoma (line 66), neuroblastoma (BE(2) and SK-N-SH) [ 24 ], prostate cancer (DU-145, PC3 and LnCap) [ 24 ], pancreas (MiaPaca2 and BX-PC3), liver (SKHep1), ovarian carcinoma (ICROV-1 and OVCAR-5) and leukemia (HL-60) [ 24 ]. Consequently, many pharmaceutical agents acting at the σRs have been used in the treatment of cancer and are receiving considerable attention.…”

PEG 400/Cerium Ammonium Nitrate Combined with Microwave-Assisted Synthesis for Rapid Access to Beta-Amino Ketones. An Easy-to-Use Protocol for Discovering New Hit Compounds

“…In light of these considerations and as part of our ongoing research, we herein focus on the development of an efficient protocol based on the three-component one-pot Mannich reaction for the preparation of a β-amino ketone small library endowed with general formula A ( Figure 2 ), consisting of a tertiary amine bridged to an aromatic ring by a propylenic chain. The final aim is to discover new potential sigma receptor (SR) modulators [ 29 , 30 , 31 , 32 ]. We set up an efficient, clean, quick, and scalable protocol based on microwave-assisted organic synthesis (MAOS), using cerium ammonium nitrate (CAN) as a catalyst and polyethylene glycol 400 (PEG 400) as a solvent, combined with polymer-assisted solid phase synthesis (PASPS).…”