Synthesis and Cytotoxic Properties of N-Substituted Derivatives of Quinolizidine Alkaloid (–)-Cytisine and Their Thioanalogues

N-Substituted derivatives of the alkaloid (–)-cytisine and its thioanalogue were synthesized via a two-step ‘alkylation-thionation’ chemical transformation sequence. The ability of the obtained compounds to inhibit metabolic activity of conditionally normal (HEK293, human embryonic kidney cells) and cancerous cells (A549, lung adenocarcinoma; MCF-7, breast cancer) was assessed. It was found that N-hexyl-, -nonylcytisine and N-heptyl-, -octyl-, -nonyl- and -benzyl-thiocytisine demonstrated moderate cytotoxic properties. The hit-compound (1R,5S)-3-benzyl-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocine-8- thione (22) was identified with IC₅₀ values of 12.83 ± 1.2 μM (A-549) and 35.75 ± 7.43 μM (MCF-7). It was shown that the antiproliferative properties of compound 22 might be associated with alterations of cell cycle regulation in tumor cells (A549 and MCF-7), exhibiting mainly cytostatic effect, whereas in conditionally normal cells (HEK293), 22 promotes apoptosis, thus triggering the cytotoxic mechanisms.