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 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.

Figure 1

(A) Cartoon representation of the σ₁R crystal structure (PDB ID: 5HK1); each color outlines a distinguished σ₁R protomer which forms the σ₁R trimer. (B) 2D and 3D representation of protein–ligand interactions of the σ₁R with PD144418 (PDB ID: 5HK1). The ionic bond between the basic nitrogen of PD144418 and the Glu172 amino acid residue is shown as a dashed yellow line.

Figure 2

Selected historic and representative σR ligands.

Figure 3

σRs ligands in clinical trials.

Figure 4

(A) The proposed pharmacophore model by Gilligan et al. (B) Glennon’s pharmacophore model.

Figure 5

3D pharmacophore models for σ₁R: (A) Pharmacophore mapping of compound A in 3D models derived by Vio et al. (B) Pharmacophore mapping of compound B in 3D models derived by Meyer et al. (C) Pharmacophore mapping of PD144418 in 3D models derived by ESTEVE. Color coded as follows: PI (red), HYAr or HYD (light blue), HY (pink), HBA (light green), excluded volumes (gray). Adapted with permission from refs ( and 83). Copyright 2009 and 2012 American Chemical Society.

Figure 6

3D pharmacophore models for σ₂R: (A) Pharmacophore mapping of compound C in 3D models derived by Vio et al. (B) Pharmacophore mapping of compound D in 3D models derived by Iyamu et al. Color coded as follows: PI (red), HYAr or HYD (light blue), HY (pink), HBA (light green), excluded volumes (gray).

Figure 7

Schematized representation of the high-throughput structure-based computational docking approach for the discovery of new σ₁R ligands proposed by Greenfield et al. Adapted with permission from ref (90). Copyright 2020 American Chemical Society.

Figure 8

Representative structures of antiproliferative σ₁R ligands with their σRs binding profile.

Figure 9

N,N-Dialkyl and N-alkyl-N-aralkyl fenpropimorph-derived compounds 1–6 and their σRs binding profile.

Figure 10

Spipethiane and general structure of spipethiane derivatives 7–11 and 12–15 with their σRs binding profile.

Figure 11

Structures of selected spiropiperidines with a thienofuran and thienopyran scaffold (16–21) and their σRs binding profile.

Figure 12

Historically relevant ethylenediamine 22–24 with their σRs binding profile. The ethylenediamine structure is highlighted in light blue.

Figure 13

General structures of piperazine derivatives and structures of compounds 25–28 with σRs binding profile.

Figure 14

General structure of bicyclic piperazines, chemical structures of 6,8-diazabicyclo[3.2.2]nonanes 29 and 30, and 7,9-diazabicyclo[4.2.2]decane derivatives 31–37 with their σRs binding profile.

Figure 15

General structure of 2,5-diazabicyclo[2.2.2]octane derivatives 38–43 and ent-38–43.

Figure 16

(A) 2D schematic representation of the identified interactions between compound 42 and the main amino acid residues. (B) 3D protein–ligand binding interactions of compound 42 with the σ₁R homology model. Color-coded as follows: PI (red), HYAr or HYD (light blue), HY (pink), HBA (light green), π-interactions (Arg119 and Tyr120, cyan), salt bridge (Asp126, red), hydrophobic interactions (Ile128, Phe133, Tyr173, and Leu186, purple), and hydrogen bond (Thr181, green). Adapted with permission from ref (132). Copyright 2016 American Chemical Society.

Figure 17

Representative structures for different chemical classes of σ₂R ligands.

Figure 18

Chemical structure and σRs binding profile of selective N-substituted 9-azabicyclo[3.3.1]nonan-3α-yl phenylcarbamate derivatives and conjugated derivative SW III-123.

Figure 19

Early structural modification of siramesine and its analogs 44–48.

Figure 20

General structure and σRs binding profile of siramesine-related derivatives.

Figure 21

General structure and σRs binding profile of siramesine-related derivatives 51, 52, and 53.

Figure 22

General structure of PB28 analogs with reduced lipophilicity and σRs binding profile of compound 54.

Figure 23

Representative structural modification for PB28 analogs on propylene linker and tetralin scaffold (55 and 56), piperazine ring (PB221), basic N-atom (57), piperazine substitution (58).

Figure 24

Chemical structure and σRs binding profile of N-(4-fluorophenyl)piperazine derivatives.

Figure 25

Chemical structure and σRs binding profile of early 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline analogs 59–64, reported by Mach and co-workers.

Figure 26

Chemical structure and σRs binding profile of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline analogs 65–67.

Figure 27

Chemical structure and σRs binding profile of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline analogs 68–70.

Figure 28

Chemical structure and σRs binding profile of compounds 71–75.

Figure 29

Chemical structure and σRs binding profile of compounds 76–81.

Figure 30

Chemical structures of 3-alkoxyisoxazoles 82–90 and their σRs binding profile.