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.

Structure-activity relationships in 1,4-benzodioxan-related compounds. 8.(1) {2-[2-(4 chlorobenzyloxy)phenoxy]ethyl}-[2-(2,6-dimethoxyphenoxy)ethyl]amine (clopenphendioxan) as a tool to highlight the involvement of alpha1D- and alpha1B-adrenoreceptor subtypes in the regulation of human PC-3 prostate cancer cell apoptosis and proliferation

QUAGLIA, Wilma;SANTONI, Giorgio;PIGINI, Maria;PIERGENTILI, Alessandro;GENTILI, Francesco;BUCCIONI, Michela;MOSCA, Michela;LUCCIARINI, Roberta;AMANTINI, Consuelo;NABISSI, MASSIMO;BALLARINI P;BALLARINI, Patrizia
2005-01-01

Abstract

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.
2005
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/201131
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