Chemical manipulations on the 1,4-dioxane ring of 5-HT1A receptor agonists lead to antagonists endowed with antitumor activity in prostate cancer cells

摘要

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-HT1A receptor (5-HT1AR) and alpha(1)-adrenoceptor (alpha(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-HT1AR 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-HT1AR functional profile from agonism to antagonism. Docking simulations, performed on the human 5-HT1AR, 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-HT1AR/alpha(1d)-AR antagonist profile, showed anti-proliferative and cytotoxic effects on both PC-3 and DU-145 prostate cancer cell lines higher than those of the alpha(1)-AR antagonist 2 and the 5-HT1AR 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. (C) 2019 Elsevier Masson SAS. All rights reserved.