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 σ1 and σ2, 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 σ1R and σ2R 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.
Highlights
Cancer is a severe health concern, and it is the second leading cause of death globally.[1]
Several factors may affect the effectiveness of the chemotherapy regimen, including early intracellular drug inactivation, overexpression of drug efflux pumps, low drug uptake, or dysregulation of specific intracellular signaling pathways targeted by the therapeutic drugs
These studies highlighted the binding determinants of bicyclic piperazine derivatives as follows: (i) the cyclohexyl methyl moiety is buried in a hydrophobic pocket of the receptor; (ii) the aromatic portion of the molecule is involved in the formation of π−π and π-cation interactions; (iii) the nitrogen atom linked to the aryl methyl moiety establishes a salt bridge bond with the carboxylic residue of Asp[126]; and (iv) the hydroxy group assumes the role of a hydrogen-bond-acceptor group (HBA) (Figure 16)
Summary
Cancer is a severe health concern, and it is the second leading cause of death globally.[1]. A reliable in vitro protocol useful to distinguish between the agonist or antagonist properties of σ1R and σ2R ligands has not been established yet, mostly due to a lack of known endogenous ligands which does not allow to compare the molecular effect of a tested compound at the level of the receptor A comprehensive medicinal chemistry perspective on the past, present, and future of σR ligands as a new potential generation of cytotoxic agents will be provided
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