New Pharmacological Strategies against Pancreatic Adenocarcinoma: The Multifunctional Thiosemicarbazone FA4

Abstract

A new sigma-2 (σ2) receptor ligand (FA4) was efficiently synthesized and evaluated for cytotoxic, proapoptotic, and antimigratory activity on pancreatic ductal adenocarcinoma (PDAC) primary cell cultures, which restrained the aggressive and chemoresistant behavior of PDAC. This compound showed relevant antiproliferative activity with half maximal inhibitory concentration (IC50) values ranging from 0.701 to 0.825 μM. The cytotoxic activity was associated with induction of apoptosis, resulting in apoptotic indexes higher than those observed after exposure to a clinically relevant concentration of the gemcitabine, the first-line drug used against PDAC. Interestingly, FA4 was also able to significantly inhibit the migration rate of both PDAC-1 and PDAC-2 cells in the scratch wound-healing assay. In conclusion, our results support further studies to improve the library of thiosemicarbazones targeting the σ-2 receptor for a deeper understanding of the relationship between the biological activity of these compounds and the development of more efficient anticancer compounds against PDAC.

Development of Fluorescent 4-[4-(3H-Spiro[isobenzofuran-1,4′-piperidin]-1′-yl)butyl]indolyl Derivatives as High-Affinity Probes to Enable the Study of σ Receptors via Fluorescence-Based Techniques

“…We initially focused our attention on two compounds belonging to our series, namely 17 , the derivative of our panel responsible for the highest σ 2 affinity [ K i = 3.84 nM (Table )], and 23 , the ligand showing the highest σ 2 /σ 1 selectivity [ K i of 5.07 nM vs 296 nM (Table )]. It is noteworthy that the decrease in the σ 1 affinity returned by compound 23 seems to be substantially due to the presence of a butyl-spiropiperidine portion at position N-1 ( 8 -like scaffold) of the indole ring (rather than at position C-3, siramesine-like scaffold) in full agreement with the activity data already published for these reference compounds [i.e., siramesine and 8 (Table )]. , Building on this evidence, we carried out preliminary docking simulations of both reference ligands on the σ receptors. Figure shows the obtained top-scoring docking poses.…”

“…This latter change was made in agreement with previous studies that show how the shift of the butylspiropiperidine portion from the C-3 indole position to the N-1 position leads to a subnanomolar affinity and moderate σ 2 receptor selectivity [compound 8 (Figure 1)]. 33,61 The selected fluorescent tags would enable more confident confocal 57 and the commercially available 4-(1H-indol-3-yl)butanoic acid, upon activation of the latter with 1,1′-carbonyldiimidazole (CDI) (Scheme 1). The indole nitrogen in 9 was alkylated with 3-Br-proprionitrile to provide intermediate 10, whose nitrile and amide functions were reduced in one step with BH 3 •DMS to afford amine derivative 11.…”

“…It is noteworthy that the decrease in the σ 1 affinity returned by compound 23 seems to be substantially due to the presence of a butyl-spiropiperidine portion at position N-1 ( 8 -like scaffold) of the indole ring (rather than at position C-3, siramesine-like scaffold) in full agreement with the activity data already published for these reference compounds [i.e., siramesine and 8 ( Table 1 )]. 33 , 60 Building on this evidence, we carried out preliminary docking simulations of both reference ligands on the σ receptors. Figure 2 shows the obtained top-scoring docking poses.…”

“…This latter change was made in agreement with previous studies that show how the shift of the butyl-spiropiperidine portion from the C-3 indole position to the N-1 position leads to a subnanomolar affinity and moderate σ 2 receptor selectivity [compound 8 ( Figure 1 )]. 33 , 61 The selected fluorescent tags would enable more confident confocal microscopy and live cell microscopy studies, extending their use as imaging tools in vivo , as well.…”

The Sigma Enigma: A Narrative Review of Sigma Receptors

“…* [27,35,36] Note that some of these substances are drugs in development and are not commercially released…”