Structure−Activity Relationships in 1,4-Benzodioxan-Related Compounds. 8.<SUP>1</SUP> {2-[2-(4-Chlorobenzyloxy)phenoxy]ethyl}-[2-(2,6-dimethoxyphenoxy)ethyl]amine (Clopenphendioxan) as a Tool to Highlight the Involvement of α<INF>1D</INF>- and α<INF>1B</INF>-Adrenoreceptor Subtypes in the Regulation of Human PC-3 Prostate Cancer Cell Apoptosis and Proliferation

A series of new α<INF>1</INF>-adrenoreceptor antagonists (<BO>5</BO><BO>−</BO><BO>18</BO>) was prepared by introducing various substituents (Topliss approach) into the ortho, meta, and para positions of the benzyloxy function of the phendioxan open analogue <BO>4</BO> (“openphendioxan”). All the compounds synthesized were potent antagonists and generally displayed, similarly to <BO>4</BO>, the highest affinity values at α<INF>1D</INF>- with respect to α<INF>1A</INF>- and α<INF>1B</INF>-AR subtypes and 5-HT<INF>1A</INF> subtype. By sulforhodamine B (SRB) assay on human PC-3 prostate cancer cells, the new compounds showed antitumor activity (estimated on the basis of three parameters GI<INF>50</INF>, TGI, LC<INF>50</INF>), at low micromolar concentration, with <BO>7</BO> (“clopenphendioxan”) exhibiting the highest efficacy. Moreover, this study highlighted for the first time α<INF>1D</INF>- and α<INF>1B</INF>-AR expression in PC3 cells and also demonstrated the involvement of these subtypes in the modulation of apoptosis and cell proliferation. A significant reduction of α<INF>1D</INF>- and α<INF>1B</INF>-AR expression in PC3 cells was associated with the apoptosis induced by <BO>7</BO>. This depletion was completely reversed by norepinephrine.