New Adamantane Phenylalkylamines with σ‑Receptor Binding Affinity and Anticancer Activity, Associated with Putative Antagonism of Neuropathic Pain

The synthesis of the adamantane phenylalkylamines <b>2a</b>–<b>d</b>, <b>3a</b>–<b>c</b>, and <b>4a</b>–<b>e</b> is described. These compounds exhibited significant antiproliferative activity, in vitro, against eight cancer cell lines tested. The σ₁, σ₂, and sodium channel binding affinities of compounds <b>2a</b>, <b>3a</b>, <b>4a</b>, and <b>4c</b>–<b>e</b> were investigated. The most interesting analogue, <b>4a</b>, exhibited significant in vivo anticancer profile on pancreas, prostate, leukemia, and ovarian cancer cell line xenografts together with apoptosis and caspase-3 activation. Inhibition of the cancer cells cycle at the sub-G1 level was also obtained with <b>4a</b>. Finally, encouraging results were observed with <b>4a</b> in vivo on mice, suggesting putative antimetastatic and analgesic activities of this compound