Structure‐Activity Relationship of Novel Compounds Based on Tamoxifen with Proposed Sigma‐2 Receptor Activity

Abstract

Sigma‐2 receptors are overexpressed in several different types of human cancer cells and are regarded as potential therapeutic targets. Ligands for sigma‐2 receptors have been shown to elicit anticancer properties including growth arrest and apoptosis. While much research has been devoted to designing sigma‐2 receptor ligands for therapeutic benefits, none have stood up to rigorous testing and clinical trials needed for approval in human patients. In an attempt to provide more literature on the potential usefulness of sigma‐2 receptor ligands for anticancer activity, we synthesized a series of analogs based upon the known sigma‐2 receptor ligand tamoxifen that lack estrogen receptor binding properties.We previously reported on the first molecule in this series, SP‐1, with IC50 activity ranging from 30–60 μM against several dissimilar cell lines. To further elucidate structurally important regions of the molecule and ascertain a structure‐activity relationship (SAR) for anticancer activity, six additional molecules were synthesized and tested. These molecules included modifications to both the terminal phenyl and nitrogen moieties of SP‐1 (N,N‐dimethyl‐2‐(4‐(1‐(p‐tolyl) vinyl)phenoxy)ethan‐1‐amine). The XTT cell viability assay was then used to screen these compounds for anticancer activity in four diverse human cancer cell lines including A‐172 human glioblastoma, A375 human malignant melanoma, HT‐29 human colorectal adenocarcinoma, and MCF7 human breast adenocarcinoma. Interestingly, hydration of the ethylene moiety attached to the carbon linker between the two phenyl rings markedly reduced anticancer activity of SP‐2, SP‐3, SP‐7 and SP‐8. Substantial anticancer activity was not observed at concentrations less than 90 μM regardless of structural modifications made to the periphery of these molecules. However, SP‐5 and SP‐6, which conserved the nonpolar central linker present in SP‐1, demonstrated moderately potent anticancer activity against the four cancer cell lines. SP‐5, which only differs from SP‐1 by the addition of one carbon to the peripheral phenyl ring, was found to have nearly the same potency as SP‐1. However, SP‐6, which includes the addition of a morpholine ring to the periphery of the molecule, demonstrated slightly less potent activity than that of SP‐1 and SP‐5. However IC50 values were still found to range from 45–90 μM in all four cells lines. While the changes made to these analogs failed to improve the efficacy of our parent molecule SP‐1, the information regarding the SAR will help guide the synthesis of further analogs. Additional studies investigating the mechanisms of death and putative targets are ongoing for these lead molecules.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.