Amines, Amides, and Thio- and Carboxamides of (–)-Cytisine as Nfat Transcription Factor Modulators

Vakhitova, Yu. V.; Tsypysheva, I. P.; Salimgareeva, M. Kh.; Koval’skaya, A. V.; Лобов, А. Н.; Fatkullina, U. Sh.; Зайнуллина, Л. Ф.; Yunusov, M. S.

doi:10.1007/s10600-014-0996-7

Cited by 7 publications

(2 citation statements)

References 18 publications

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“…12 N methylcytisine, benzilcytisine and benzoilcytisine (2)-(4), and compounds (10) and (11) were synthesized according to published method ologies [8,[33][34][35][36][37]. Derivation of compounds (5)- (9) and (12)- (22) has been described previously [38][39][40][41]. Stock solutions were prepared in 100% DMSO.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2015

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Design and synthesis ofnew derivatives of (-)-cytisine with a wide spectrum of pharmacological activity, represents the 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 N F-κB and STATI luciferase reporter constructs to screen the (-)-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. The library of compounds included the derivatives of (-)-cytisine with amino-, amide-, thio- and carboxamide groups at 3, 5 and 12 position of the starting molecule, as well as some bimolecular derivatives. Our experimental data revealed compounds with moderate activating as well as inhibitory effects for basal NF-κB and STATI activity (IC50 or EC50 values are mainly in the micromolar range). The structure-activity relationship analysis demonstrated that the character of activity (activation or inhibition of NFκ-B and STAT1) is determined by the topology of the substituents at the (-)-cytisine molecule, whereas the nature of the substituents mainly contributes to severity of the effect (introduction of aromatic and adamantyl substituents, as well as thionyl or keto groups are of the principal importance). When evaluating the effect of (-)-cytisine derivatives on activity of NF-κB and STATI, induced by specific agents (TNFα and IFNγ, respectively) we observed that some compounds inhibited basal and stimulated activity of NF-κB and STAT1, another compounds showed the dual effect (an increase of basal- and a decrease of stimulated NF-κB activity) and several compounds increase both basal and induced activity of NF-κB and STAT1. Thus, obtained results suggest that one of the possible mechanisms of biological action of (-)-cytisine derivatives is their ability to influence the components of NF-κB and STAT1-dependent signaling pathways.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2015

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“…Consequently, to obtain compounds of therapeutic interest, the citisine underwent structural modification achieving selective ligands for neuronal acetylcholine receptors. Recently, we synthesized cytisine derivatives with pronounced pharmacological effects [[6], [7], [8]], between them are: N -allylcytisine-12-carbamide, cytisine-12-carbamide, N -1-adamantylcytisine-12-thiocarbamide.…”

Section: Introductionmentioning

confidence: 99%