L. F. Zainullina

Synthesis and in vitro cytotoxicity evaluation of some N-substituted α-amino acid derivatives containing a hexahydropyrimidine moiety

This work reports a one-pot synthesis of diastereomerically pure N-substituted derivatives of natural amino acids containing a hexahydropyrimidine moiety in 71–89% yields by Mannich reaction of ethyl acetoacetate or 3-oxobutanamide with formaldehyde and amino acid hydrochlorides in acetate buffer (AcONa–AcOH, pH 4) at room temperature. The in vitro cytotoxic activities of the compounds obtained were determined in cancer (Jurkat and SH-SY5Y) and conditionally normal (HEK293) human cells.

Conjugates of natural chlorins and isobornylphenols with a different length of the spacer between the chlorin and terpenephenolic fragments: synthesis and antioxidant activity

Conjugates containing chlorine and isobornylphenolic fragments, which are connected by spacers of different lengths, were synthesized from methyl pheophorbide a. The toxicity and antioxidant activity of the obtained compounds were studied. Derivatives of pyropheophorbide a containing the most distant from the macrocycle terpenephenolic fragment combine a low toxicity with the high antioxidant activity, and are the most promising for further designing of new medicinal agents for the treatment of diseases associated with a disorder in oxidation-reduction processes in the body.

Anti-Inflammatory Activity of Novel 12-N-methylcytisine Derivatives

BACKGROUND AND OBJECTIVES Neurodegenerative diseases and inflammation are always linked to each other; therefore the elaboration of new chemical compounds, which interact with pharmacological targets involved into these two processes, can become one of ways of correction of these types of human CNS pathology. In the field of this problem the anti-inflammatory activity of ten 3-amino derivatives of quinolizidine alkaloid (.)-cytisine (the data about nootropic activity of these compounds are outlined by us previously) was studied by using in vivo, in vitro and in silico approaches. METHODS The anti-inflammatory activity of novel compounds was investigated on carrageenan- induced model of inflammation in Rat paw following an established protocol. COX-1 (ovin) and COX-2 (human recombinant) inhibition activities of tested compounds assessed using a COX Fluorescent Inhibitor Screening Assay Kit. And as part of an in silico screening the leading compounds were docked into the tyrosine sites of COX-1/COX-2 enzymes (PDB code: 1DIY and 1CVU). RESULTS It was established that ability of 3-(2-hydroxyphenyl)amino, 3-(4-hydroxyphenyl) amino and 3-(3-phenylprop-2-en-1-yl)amino derivatives of 12-N-metylcytisine to inhibit the carrageenan-induced paw oedema in rats is comparable with reference drug diclofenac. The results of in vitro COX-1/COX-2 inhibition assay showed no significant activity of tested compounds, except compounds with 2-hydroxyphenyl, 3-phenylprop-2-en-1-yl, furyl and thiophenyl fragments which slightly reduce the activity of COX-2. CONCLUSION The tendency to occurrence of anti-inflammatory properties of synthesized derivatives of quinolizidine alkaloid (-)-cytisine can be explained on the basis of molecular docking results, which assume the possibility of interaction of more potent compounds with key amino acids of COX-1/COX-2 active sites.

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.

Synthesis and Nootropic Activity of new 3-Amino-12- N -Methylcytisine Derivatives

Reductive alkylation of 3-amino-12-N-methylcytisine by aromatic aldehydes synthesized a series of secondary amines. The nootropic activity of the synthesized compounds was studied in vivo (mnestic and antihypoxic properties) and in vitro (antiradical properties and ability to affect transcription factor HIF-1 DNA-binding activity). The cytotoxicity of the synthesized compounds was assessed. The lead compound was identified.

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

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.

Cellular test systems for the search of transcription factors activity modulators

Test systems for monitoring activities and the search for substances activating or inhibiting transcription factors as biological targets have been designed on the basis of luciferase constructs containing binding sites for transcription factors CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, HSF1, and HIF1α. An assessment of the functional activity of reporter constructs has been carried out using their transient transfection into HEK293 cells followed by treatment with specific inducers. The functional activity of all reporter constructs was observed based on the increased luciferase expression. In order to evaluate the efficiency of the suggested test systems, aspirin was used. Incubation of cells transfected with the above-mentioned constructs treated with aspirin was accompanied by the suppression of NF-κB, HIF1α, GAS, VDR, and HSF binding activity. The findings revealed for NF-κB, NFAT, and STAT1 confirm the published data concerning the mechanisms of aspirin action. The detected effects of this drug on the HIF1α, GAS, VDR, and CREB activity have been demonstrated for the first time.

Design, synthesis and evaluation of the antioxidant and neuroprotective properties of alkyl- and terpenylphenolchlorin conjugates

The new amide conjugates were synthesized from methyl pheophorbide a and its carboxyl derivatives by reactions with aminomethyl derivatives of 2,4-dimethylphenol, 2-isocamphyl-4- methylphenol, 2-bornyl-4-methylphenol, and 2-isobornyl-4-methylphenol. The antioxidant activity of some conjugates was established by investigation of their ability to inhibit the accumulation of secondary products of lipid peroxidation in a brain of laboratory mice in vitro. The neuroprotective properties of porphyrin and terpenylphenol conjugates have been studied on the model of H2O2-induced oxidative stress in SH-SY5Y cells (neuroblastoma).

Branching tryptamines as a tool to tune their antiproliferative activity

The influence of a series of tryptamine derivatives on the viability of normal (HEK293) and tumor (HepG2, Jurkat and SH-SY5Y) cells has been evaluated. All tryptamines tested were three different substitution types: C- and N-branching, and indole benzylation. All the derivations enhance the activity of compounds separately, although the effects of different substitutions were not additive. Thus, combinations of C- and N-branchings as well as C-branching and indole benzylation gave little or no increase in activity.

Synthesis and Cytotoxic Activity of Conjugates of (–)-Cytisine and Thermopsin Amine Derivatives with 1,3-Dimethyl-5-Formyluracil

New conjugates of the quinolizidine alkaloids (–)-cytisine and thermopsin were synthesized by alkylating their 9-amino derivatives with 1,3-dimethyl-5-formyluracil. The cytotoxic properties of the synthesized conjugates against cell lines HEK293, HepG2, and Jurkat were studied. Screening identified the lead compound 5-{[(3-benzyl-8-oxo-1,3,4,5,6,8-hexahydro-2H-1,5-methanopyrido[1,2-a][1,5]diazocin-9-yl)amino]methyl}-1,3-dimethylpyrimidine-2,4-(1H,3H)-dione, which suppressed metabolic activity of lymphoblastic leukemia cells with inhibitory concentration (IC50) 20.6 ± 2.1 μM (IC50 of reference compound 5-fluorouracil was 18.5 ± 3.3 μM).