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.
A series of new alpha1-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 alpha1D- with respect to alpha1A- and alpha1B-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 alpha1D- and alpha1B-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 alpha1D- and alpha1B-AR expression in PC3 cells was associated with the apoptosis induced by 7. This depletion was completely reversed by norepinephrine.
Quaglia
Wilma
W
Dipartimento di Scienze Chimiche, Università degli Studi di Camerino, via S. Agostino 1, 62032 Camerino, Italy.
Santoni
Giorgio
G
Pigini
Maria
M
Piergentili
Alessandro
A
Gentili
Francesco
F
Buccioni
Michela
M
Mosca
Michela
M
Lucciarini
Roberta
R
Amantini
Consuelo
C
Nabissi
Massimo Ivan
MI
Ballarini
Patrizia
P
Poggesi
Elena
E
Leonardi
Amedeo
A
Giannella
Mario
M
D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D016466:CHO Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006224:Cricetinae; D003412:Cricetulus; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D010647:Phenyl Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000473:pathology*; D011869:Radioligand Assay; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D013329:Structure-Activity Relationship
C507721:(2-(2-(4-chlorobenzyloxy)phenoxy)ethyl)-(2-(2,6-dimethoxyphenoxy)ethyl)amine; C547716:ADRA1B protein, human; C547719:ADRA1D protein, human; D000317:Adrenergic alpha-Antagonists; D000970:Antineoplastic Agents; D010647:Phenyl Ethers; D018340:Receptors, Adrenergic, alpha-1