Recent Advances in the Development of Sigma Receptor Ligands as Cytotoxic Agents: A Medicinal Chemistry Perspective

Abstract

Since their discovery as distinct receptor proteins, the specific physiopathological role of sigma receptors (σRs) has been deeply investigated. It has been reported that these proteins, classified into two subtypes indicated as σ 1 and σ 2 , might play a pivotal role in cancer growth, cell proliferation, and tumor aggressiveness. As a result, the development of selective σR ligands with potential antitumor properties attracted significant attention as an emerging theme in cancer research. This perspective deals with the recent advances of σR ligands as novel cytotoxic agents, covering articles published between 2010 and 2020. An up-to-date description of the medicinal chemistry of selective σ 1 R and σ 2 R ligands with antiproliferative and cytotoxic activities has been provided, including major pharmacophore models and comprehensive structure–activity relationships for each main class of σR ligands.

Examination of the Novel Sigma-1 Receptor Antagonist, SI 1/28, for Antinociceptive and Anti-allodynic Efficacy against Multiple Types of Nociception with Fewer Liabilities of Use

“…Extending this effort, we recently identified SI 1/13, a selective benzylpiperazine-based S1R antagonist with a S2R/S1R selectivity ratio of 886 that demonstrated efficacy against chronic constrictive nerve injury (CCI)-induced neuropathic pain and formalin-induced inflammatory pain without impairing locomotor activity [ 22 ]. In addition, SI 1/13 demonstrated significant cytotoxic effects towards DU145 and U87MG cancer cells, further corroborating its function profile as a S1R antagonist [ 23 , 24 ].…”

New Pharmacological Strategies against Pancreatic Adenocarcinoma: The Multifunctional Thiosemicarbazone FA4

“…FA4 was obtained according to a polypharmacology strategy, following other σ2 receptor-targeting thiosemicarbazones (e.g., MLP44 and PS3 ) that had shown promising antitumor properties in a panel of immortalized human PDAC cells and in a murine (KP02) tumor model [ 17 , 18 ]. All these thiosemicarbazones were designed with the aim to bind σ-2 receptors, that are overexpressed in a number of cancers [ 19 , 20 ], and chelate metals (in particular iron and copper ions) in order to obtain synergic effects by adding the effects of the alteration of the redox state of cells due to metal chelation to the cytotoxic properties proper of the σ2 agonists [ 21 ].…”

σ2R/TMEM97 in Retinal Ganglion Cell Degeneration

“…σ 2 R/TMEM97 is also known to regulate cellular cholesterol by controlling cholesterol tra cking from lysosomes to the ER and cholesterol uptake [13][14][15] . Furthermore, the high levels of σ 2 R/TMEM97 expression in proliferating cancers have been exploited as a target for cancer therapy and as a biomarker for diagnosis 18,20,22 . σ 2 R/TMEM97 is believed to be associated with a number of neurological disorders, including anxiety, depression, and addiction 23 , although the biological mechanisms are not well understood.…”

“…σ 2 R/TMEM97 is known to regulate intracellular Ca 2+ levels 12 , and to play a role in cholesterol tra cking and uptake [13][14][15] . The high expression of σ 2 R/TMEM97 in proliferating cancer cells makes it a biomarker and target for cancer diagnosis and therapy [16][17][18][19][20][21][22] . σ 2 R/TMEM97 is also involved in various neurological disorders 23 .…”