Search for (-)-cytisine derivatives as potential inhibitors of NF-κB and STAT1

Design and synthesis of new derivatives of (-)-cytisine with a wide spectrum of pharmacological activity, represents a potential therapeutic interest for development of drug candidates for neurodegenerative disorders, inflammatory diseases, and treatment of nicotine addiction. We used HEK293 cell line, transiently transfected with NF-κB and STAT1 luciferase reporter constructs, to select (-)-cytisine derivatives for their potency to modulate basal and induced NF-κB and STAT1 activity. Currently, NF-κB, STAT1 and components of their signaling pathways, are considered as attractive targets for pharmacological intervention, primarily in chronic inflammation, cancer, autoimmune, neurodegenerative and infectious diseases. Library of tested compounds included derivatives of (-)-cytisine with amino, amide, thionyl and carboxamide groups at the 3rd, 5th and 12th position in the original molecule, as well as other bimolecular derivatives. Our experimental results revealed compounds with moderate inducing, as well as inhibitory, effects on basal NF-κB and STAT1 activity (IC50 or EC50 values are mainly in the micromolar range). The structure-activity relationship analysis demonstrated that mode of activity (activation or inhibition of NF-κB and STAT1) is determined by the topology of substituents in (-)-cytisine molecule, whereas the nature of substitutions determines the severity of the effect (introduction of aromatic and adamantyl substitutions, as well as thionyl or ketone groups are of principal importance). Assessments of effects of (-)-cytisine derivatives on activity of NF-κB and STAT1, induced by specific agents (TNFα and IFNγ, respectively), revealed that certain compounds inhibited both basal and stimulated activity of NF-κB and STAT1, whereas other compounds showed a dual effect (increase in basal and decrease in stimulated NF-κB activity), in turn, several compounds increased both basal and induced activity of NF-κB and STAT1. In summary, obtained results indicate that one possible mechanism of biological action of (-)-cytisine derivatives lies is their ability to influence components of NF-κB and STAT1 signaling pathways.