Chemical manipulations on the 1,4-dioxane ring of 5-HT 1A receptor agonists lead to antagonists endowed with antitumor activity in prostate cancer cells
Articolo
Data di Pubblicazione:
2019
Citazione:
Chemical manipulations on the 1,4-dioxane ring of 5-HT 1A receptor agonists lead to antagonists endowed with antitumor activity in prostate cancer cells / F. Del Bello, A. Bonifazi, G. Giorgioni, W. Quaglia, C. Amantini, M.B. Morelli, G. Santoni, F.O. Battiti, G. Vistoli, A. Cilia, A. Piergentili. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 168(2019), pp. 461-473. [10.1016/j.ejmech.2019.02.056]
Abstract:
A series of derivatives obtained by moving the aromatic moiety on the 1,4-dioxane ring of compounds 1–3 from position 6 to position 2 or 3 was prepared and evaluated for the affinity for 5-HT 1A receptor (5-HT 1A R) and α 1 -adrenoceptor (α 1 -AR) subtypes. Moreover, the flexible 2-ethanolamine linker of the most interesting compounds was replaced by the more conformationally constrained piperazine ring. In vitro functional studies performed on derivatives showing the highest affinities for 5-HT 1A R highlighted that the shifting of the diphenyl moiety of derivatives 2 and 13 from position 6 to position 3 of the 1,4-dioxane nucleus, affording 11 and 16, respectively, modulated the 5-HT 1A R functional profile from agonism to antagonism. Docking simulations, performed on the human 5-HT 1A R, further rationalized the biological results, delving into the features which modulate the shift between agonist and antagonist activity. Interestingly, compound 11, endowed with mixed 5-HT 1A R/α 1d -AR antagonist profile, showed antiproliferative and cytotoxic effects on both PC-3 and DU-145 prostate cancer cell lines higher than those of the α 1d -AR antagonist 2 and the 5-HT 1A R antagonist 16. The experiments performed in the presence of the endogenous agonists norepinephrine and serotonin confirmed the involvement of both receptor systems in the antitumor activity of 11.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
1,4-Dioxane compounds; 5-HT ; 1A; receptor antagonists ; Antitumor activity; Docking studies; Functional profile modulation; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dioxanes; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Male; Models, Molecular; Molecular Structure; Prostatic Neoplasms; Receptor, Serotonin, 5-HT1A; Structure-Activity Relationship
Elenco autori:
F. Del Bello, A. Bonifazi, G. Giorgioni, W. Quaglia, C. Amantini, M.B. Morelli, G. Santoni, F.O. Battiti, G. Vistoli, A. Cilia, A. Piergentili
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