Design, Synthesis, and Cytotoxic Assessment of New Haloperidol Analogues as Potential Anticancer Compounds Targeting Sigma Receptors
Sigma receptors (SRs), comprising SR1 and SR2 subtypes, have gained significant attention in recent years due to their involvement in various physiological processes, such as the modulation of opioid analgesia, neuroprotection, and potential anticancer effects. Among SR ligands, haloperidol (HAL), a widely used antipsychotic drug, has demonstrated activity at SRs and exhibits cytotoxic properties. In this study, we report the discovery of novel SR ligands developed through a chemical hybridization strategy. These ligands displayed broad affinity for both SR subtypes and were evaluated for their anticancer activity against SH-SY5Y and HUH-7 cancer cell lines.
Through this chemical hybridization approach, we identified several new compounds (4d, 4e, 4g, and 4j) with dual affinity for SR1 and SR2 receptors. These compounds underwent cytotoxicity evaluation using a resazurin assay, revealing significant cytotoxic effects against both cell lines, with IC50 values comparable to those of HAL. Notably, the cytotoxic potency of these novel compounds was more akin to that of the SR1 antagonist HAL than the SR2 agonist siramesine (SRM), suggesting that SR1 antagonism may play a crucial role in their mechanism of action. Further investigation into their structure-activity relationships and assessment in additional cancer cell lines will help clarify their therapeutic potential, potentially leading to the development of new anticancer agents targeting SRs.