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

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 receptor (5-HTR) and α-adrenoceptor (α-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-HTR 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-HTR functional profile from agonism to antagonism. Docking simulations, performed on the human 5-HTR, 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-HTR/α-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-AR antagonist 2 and the 5-HTR 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.