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<p><i>N</i>-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 <i>N</i>-hexyl-, -nonylcytisine and <i>N</i>-heptyl-, -octyl-, -nonyl- and -benzyl-thiocytisine demonstrated moderate cytotoxic properties. The hit-compound (1<i>R</i>,5<i>S</i>)-3-benzyl-1,2,3,4,5,6-hexahydro-8<i>H</i>-1,5-methanopyrido[1,2-a][1,5]diazocine-8- thione (<b>22</b>) was identified with IC<sub>50</sub> 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 <b>22</b> 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), <b>22</b> promotes apoptosis, thus triggering the cytotoxic mechanisms.</p>

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

  • 期刊论文

  • 发表日期：

    2025年7月25日

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  • Alena Koval’skaya,
  • Alexander Lobov,
  • Vener Vakhitov,
  • Yulia Vakhitova,
  • Inna Tsypysheva

摘要

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.