Synthesis and neuropharmacological activity of N-1-adamantylcytisine-12-carbamide and its 12-thiocarbonyl analog

Tsypysheva, I. P.; Koval’skaya, A. V.; Лобов, А. Н.; Salimgareeva, M. Kh.; Fatkullina, U. Sh.; Petrova, P. R.; Габдрахманова, С. Ф.; Makara, N. S.; Suponitskii, K. Yu.; Vakhitova, Yu. V.; Zarudii, F. S.; Yunusov, M. S.

doi:10.1007/s10600-013-0713-y

Cited by 20 publications

(5 citation statements)

References 13 publications

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“…Two-dimensional 1 H-1 H COSY, 1 H-13 C HSQC, 1 H-13 C HMBC, and 1 H-1 H NOESY spectra were recorded using standard multi-pulse sequences of the instrument software. Physicochemical constants of 2, 3, 6, and 10-23 agreed with the published values [9,10,[12][13][14][15][16][17][18].…”

Section: Methodssupporting

confidence: 86%

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

et al. 2014

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A library of derivatives of the quinolizidine alkaloid (-)-cytisine with amine, amide, and thio-and carboxamides in the 3-, 5-, and 12-positions were synthesized. Their activity with respect to NFAT transcription factor was studied. It was shown that NFAT modulation activity was a function of the nature of the substituent.The discovery of compounds that modulate transcription factor (TF) activity is currently used to select potential targeting drug candidates. Numerous studies showed that activation of NFAT (nuclear factor of activated T-cells) TF plays an important role in the normal functioning of the immune system. However, excessive activation of this TF causes the development of immunopathological reactions such as autoimmune processes, inflammation, transplant rejection, carcinogenesis, and metastasis. Thus, the search for new NFAT modulators is extremely critical [1][2][3].A sufficient number of NFAT inhibitors/activators of natural and synthetic origin have now been identified [4][5][6]. However, such studies of the quinolizidine alkaloid (-)-cytisine and its derivatives have not been conducted.This TF was chosen as the screening target because the anti-inflammatory and immunomodulating activities of several quinolizidine alkaloids were reported [7,8].

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Section: Methodssupporting

confidence: 86%

“…These supplemented the library of (-)-cytisine (1) derivatives with variously shaped thio-and carboxamide groups that were prepared by us earlier [9,10].…”

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confidence: 99%

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

et al. 2014

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“…The addition of ethyl isothiocyanate to cytisine gives compound 1 containing the carbothioamide group, where the second N15 nitrogen atom with a planar trigonal configuration is also involved in conjugation with the C=S bond (Table 1). This configuration of N1 and N2 nitrogen atoms of the carbothioamide group is also observed in three cytisine derivatives: N-adamantylcytisine-12-thiocarbamide (6) [18], N-cytisinyl-N′-(2,3,4,6-tetrakis(O-acetyl)-β-D-glucopyranosil)thiocarbamide monohydrate (7) [19], cytisine-N-(2-hydroxyethyl)thiocarbamide (8) [20]. However, the C(sp 3 )-N1-C=S torsion angle greatly deviates from zero in the molecules of 1, 6-8, compared to the respective angle in the molecules of 2-5.…”

Section: Introductionsupporting

confidence: 56%

Synthesis and Crystal Structure of N-Ethyl-N-Cytisinocarbothioamide

et al. 2021

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Based on (-)-cytisine alkaloid and ethyl isothiocyanate, N-ethyl-N-cytisinocarbothioamide is synthesized and its structure is proved by 1 H NMR spectroscopy and single crystal X-ray diffraction. The mesomeric effect is shown in the carbothioamide group formed. It is found that π-conjugation between nitrogen atoms and the thiocarbonyl group is weakened due to the steric hindrance between hydrogen atoms of the piperidine ring and the thioamide group.

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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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Synthesis and neuropharmacological activity of N-1-adamantylcytisine-12-carbamide and its 12-thiocarbonyl analog

Cited by 20 publications

References 13 publications

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

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

Synthesis and Crystal Structure of N-Ethyl-N-Cytisinocarbothioamide

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

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