Quaglia, W., Santoni, G., Pigini, M., Piergentili, A., Gentili, F., Buccioni, M., Mosca, M., Lucciarini, R., Amantini, C., Nabissi, M. I., Ballarini, P., Poggesi, E., Leonardi, A., and Giannella, M.
A series of new α1-adrenoreceptor antagonists (5−18) was prepared by introducing various substituents (Topliss approach) into the ortho, meta, and para positions of the benzyloxy function of the phendioxan open analogue 4 (openphendioxan). All the compounds synthesized were potent antagonists and generally displayed, similarly to 4, the highest affinity values at α1D- with respect to α1A- and α1B-AR subtypes and 5-HT1A 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 GI50, TGI, LC50), at low micromolar concentration, with 7 (clopenphendioxan) exhibiting the highest efficacy. Moreover, this study highlighted for the first time α1D- and α1B-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 α1D- and α1B-AR expression in PC3 cells was associated with the apoptosis induced by 7. This depletion was completely reversed by norepinephrine.