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

The synthesis of the adamantane phenylalkylamines 2a–d, 3a–c, and 4a–e 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 2a, 3a, 4a, and 4c–e were investigated. The most interesting analogue, 4a, 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 4a. Finally, encouraging results were observed with 4a in vivo on mice, suggesting putative antimetastatic and analgesic activities of this compound.