Cytisine Derivatives Research Articles

Synthesis of Flavonoid Derivatives of Cytisine. 4. Synthesis of 3-aryl-7-[2-(cytisin-12-yl)ethoxy]Coumarins

The possibility of using the alkaloid cytisine to synthesize N 12-cytisinylethoxy 3-arylcoumarin derivatives was studied. A series of substituted 3-aryl-7-(N 12-cytisinylethoxy)coumarins with the coumarin and cytisine moieties connected by a linker were synthesized.

The cytisine derivatives, CC4 and CC26, reduce nicotine-induced conditioned place preference in zebrafish by acting on heteromeric neuronal nicotinic acetylcholine receptors.

Cigarette smoking is one of the most serious health problems worldwide and people trying to stop smoking have high rates of relapse. Zebrafish (Danio rerio), by combining pharmacological and behavioral assays, is a promising animal model for rapidly screening new compounds to induce smoking cessation. This study aims to identify possible acetylcholine nicotinic receptors (nAChRs) involved in mediating nicotine (NIC)-induced conditioned place preference (CPP) in zebrafish and investigate the effect of the CC4 and CC26 cytisine derivatives in reducing NIC-induced CPP. CPP was evaluated using a two-compartment chamber, and the zebrafish were given CC4 (0.001-5mg/kg), CC26 (0.001-1mg/kg), cytisine (0.1-2.5mg/kg), and varenicline (1-10mg/kg) alone or with NIC (0.001mg/kg). Swimming activity was evaluated using a square observational chamber. The affinity of the nicotinic ligands for native zebrafish brain nAChRs was evaluated by binding studies using [(3)H]-Epibatidine (Epi) and [(125)I]-αBungarotoxin (αBgtx) radioligands, and their subtype specificity was determined by means of electrophysiological assay of oocyte-expressed α4β2 and α7 subtypes. CC4 and CC26 induced CPP with an inverted U-shaped dose-response curve similar to that of NIC. However, when co-administered with NIC, they blocked its reinforcing or slightly aversive effect. Binding and electrophysiological studies showed that this effect was due to binding to high-affinity heteromeric but not α7-containing receptors. We have further characterized CC4 and identified a new compound (CC26) that may be active in inducing smoking cessation. Zebrafish is a very useful model for screening new compounds that can affect the rewarding properties of NIC.

The amide protonation of (–)-N-benzoylcytisine in its perchlorate salts

The 13C NMR spectrum of (–)-N-benzoylcytisine perchlorate does not show a double set of signals typical of amide compounds, although this effect has been observed for the other diamine derivatives of cytisine. This observation means that in solution there must be the state of equilibrium between two forms of the cation with the protonated amide groups. DFT calculations have indeed indicated two preferred tautomeric forms with protonated oxygen atoms of amide groups. In the solid state however, according to X-ray analysis of perchlorate and perchlorate hydrate of N-benzoylcytisine the oxygen atom of the amide group in the six-membered ring A is preferred protonation site as compared with the oxygen in benzoic moiety. (–)-N-benzoylcytisine salt is the first compound from among the known derivatives of quinolizidine alkaloids that are not N-oxides, in which in solid state only the oxygen atom at cyclic amide is protonated instead of nitrogen atom or oxygen in benzoic moiety.

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

The neuropharmacological activity of two (–)-cytisine derivatives with adamantyl fragments was studied. It was shown that N-1-adamantylcytisine-12-thiocarbamide exhibited in tests in vivo a pronounced mnestic effect, increased the lifespan of laboratory animals under hypoxic conditions, and also enhanced in vitro binding of transcription factors NFAT and NF-κB to the DNA sequences corresponding to them.

PP173—Cytisin Amidophosphate Shows Hepatoprotective Effect

The problem of effective and rational treatment of no viral hepatitis is still actual. During several last years, the screening of the bioactivity of the list of semi-synthetic derivatives of alkaloid cytisine was held in our laboratories. The result was the synthesis of O,O dimethyl-N-cytinizylphosphate (cytisin amidophosphate). Hepatoprotective properties were noted on the several models of acute and chronic hepatitis. Purpose: to study the efficacy and safety of cytisin amidophosphate under the name of Cytaphat in patients with toxic hepatopathy.

Synthesis and antiparasitic activity of N-benzyl cytisine derivatives

The antiparasitic (antihymenolepiatic and antileishmaniatic) activity of several N-benzyl derivatives of the alkaloid cytisine and 3-bromocytisine was studied. The structure–activity relationship in the series of synthesized compounds was analyzed. It was established that their activity depended on the presence and location of the halide atom in the molecular structure to a greater extent than the on presence of hydroxy or methoxy groups.

Synthesis and spatial structure of 1-(cytisin-1-ylmethyl)benzimidazole-2-thione

New derivatives of cytisine and anabasine alkaloids containing benzothiazole and benzimidazole fragments were discussed. Physicochemical characteristics of the new compounds were determined. The structure of 1-(cytisin-1-yl-methyl)benzimidazole-2-thione was studied by X-ray diffraction analysis.

First spin-labeled cytisine derivatives

Spin-labeled cytisine derivatives containing stable pyrrolidine and piperidine nitroxyl radicals were synthesized by acylation and alkylation of the secondary amine. Toxicological studies showed that introduction of the nitroxyl group decreased significantly the general toxicity.

Search for compounds with antiviral activity among synthetic (-)-cytisine derivatives

The antiviral activity of several amides and thio- and carboxamides of (-)-cytisine in addition to bromination and nitration products of its 2-pyridone core was studied. Compounds with a selectivity index close to 10 were found.

Synthesis of Flavonoid Derivatives of Cytisine. 3. Synthesis of 7-[2-(Cytisin-12-yl)ethoxy]isoflavones

The possibility of using the alkaloid cytisine to synthesize N12-cytisinylethoxy derivatives of isoflavonoids and their analogs was studied. A series of substituted 7-(N12-cytisinylethoxy)isoflavones containing chromone and cytisine fragments connected through a linker were synthesized.

Molecular design, synthesis and physical properties of novel Cytisine-derivatives – Experimental and theoretical study

The paper presented a comprehensive theoretical and experimental study on the molecular drugs-design, synthesis, isolation, physical spectroscopic and mass spectrometric elucidation of novel functionalization derivatives of Cytisine (Cyt), using nucleosidic residues. Since these alkaloids have established biochemical profile, related the binding affinity of the nicotinic acetylcholine receptors (nAChRs), particularly α7 sub-type, the presented correlation between the molecular structure and properties allowed to evaluated the highlights of the biochemical hypothesises related the Schizophrenia. The anticancer activity of α7 subtype agonists and the crucial role of the nucleoside-based medications in the cancer therapy provided opportunity for further study on the biochemical relationship between Schizophrenia and few kinds of cancers, which has been hypothesized recently. The physical electronic absorptions (EAs), circular dichroic (CD) and Raman spectroscopic (RS) properties as well as mass spectrometric (MS) data, obtained using electrospray ionization (ESI) and atmospheric-pressure chemical ionization (APCI) methods under the positive single (MS) and tandem (MS/MS) modes of operation are discussed. Taking into account reports on a fatal intoxication of Cyt, the presented data would be of interest in the field of forensic chemistry, through development of highly selective and sensitive analytical protocols. Quantum chemical method is used to predict the physical properties of the isolated alkaloids, their affinity to the receptor loop and gas-phase stabilized species, observed mass spectrometrically.

Synthesis and specific nootropic activity of (–)-cytisine derivatives with carbamide and thiocarbamide moieties in their structure

N-(methylcytisinyl)-N′-substituted ureas, N-substituted cytisine-12-carbamides, and cytisine-12-thiocarbamide were prepared by reaction of (–)-cytisine with urea and thiourea and of (–)-cytisine and its 12-N-methyl-3-amino derivative with isocyanates. Their specific nootropic activity was studied in vivo. The therapeutic index was determined for the lead compound. Promising candidates for further pharmacological testing were found.

The Role of Halogen Bonding in Crystal Structures of 3-Halogeno Cytisine Derivatives

The crystal structures of three 3-halogeno derivatives of 13N-substituted cytisine have been determined by X-ray diffraction. The two 13-acetyl substituted compounds, 3-bromo (1) and 3-iodo (2) are isostructural, with the isostructurality index as high as 99%. They both crystallize in monoclinic P21 space group, with unit cell parameters of a = 8.4709(10) A, b = 9.2266(12) A, c = 8.6051(10) A, β = 98.528(11)o (1) and a = 8.2322(6) A, b = 9.1724(7) A, c = 8.5494(6) A, β = 98.181(7)o (2). In turn, 3-bromo-13-t-butyl-carbonate derivative (3) crystallizes in orthorhombic P212121 space group with a = 6.8171(3) A, b = 7.8994(4) A, c = 31.4657(15) A. Conformation of the cytisine skeleton is similar in all three molecules, with almost planar A ring, sofa conformation of B-ring and C ring being an almost ideal chair. However, the orientations of the double C=O bonds in 13N-substituents are completely different: in 1 and 2 it is cis with respect to C12 (C12-N13-C14-O15 torsion angle is 3.3(4)o in 1 and 1.3(6)o in 2) while in 3 it is trans (−175.4(3)o). In the structures of 1 and 2 the driving force of the crystal architecture are quite strong C–H···X halogen bonds with C···X distances far shorter than the sums of van der Waals radii (C···Br in 1 is 2.9430(19) A and C···I in 2 2.974(3)). In contrast in 3–partially as the consequence of different orientation of the substituent—there are no halogen bondings but instead some weak C–H···O contacts organize the molecules into two-dimensional patterns. In two 3-halogeno-N-acetyl cytosine derivatives the strong, directional halogen bonds influence the crystal packing, while for 3-bromo-N-t-butyl-carbonate derivative only weak hydrogen bonds are observed.

Synthesis of cytisine derivatives of flavonoids. 2. Aminomethylation of 7-hydroxyisoflavones

Aminomethylation of natural 7-hydroxyisoflavones and their analogs by the alkaloid (−)cytisine was studied. Substituted 8-(cytisin-12-yl)methyl-7-hydroxyisoflavones were synthesized.

1,2,4-Thiadiazol derivatives of cytisine alkaloid: solvate formation and phase transitions

1,2,4-Thiadiazol derivatives of cytisine alkaloid—N-(3-methylthio-1,2,4-thiadiazol-5-yl-aminocarbonylmethyl) (1), N-(3-ethylthio-1,2,4-thiadiazol-5-yl-aminocarbonylmethyl) (2), N-(3-hexylthio-1,2,4-thiadiazol-5-yl-aminocarbonylmethyl) (3) cytisine have been crystallized from different solvents and by X-ray and TG–DSC method were studied. By X-ray analysis the structures of the crystal solvate of 2 with dioxane have been determined. By topology represented solvate belongs to tabulate type. In the crystal structure two conformers of the host molecules were determined. By TG–DSC method has been shown, that methyl-, ethyl-, and hexyl cytisine derivatives can exist in two phase forms. But, unlike methyl- and ethyl-derivatives, hexyl-derivative of cytisine not form inclusion compounds.

A comparative study of dynamic NMR spectroscopy in analysis of selected N-alkyl-, N-acyl-, and halogenated cytisine derivatives

New halogenated derivatives of (-)-cytisine were synthesized: 3-bromo- N-acetylcytisine, 5-bromo- N-acetylcytisine, 3,5-dibromo- N-acetylcytisine, 3-iodo- N-acetylcytisine, 5-iodo- N-acetylcytisine, 3,5-diiodo- N-acetylcytisine. Their structures were established on the basis of their NMR spectra and X-ray diffraction method. The crystal structures confirmed the chair conformation of ring C, while in solution all these compounds are in cis–trans conformational equilibrium with ring C in chair and boat conformation. Additionally, the correct X-ray structure of N-benzylcytisine was resolved.

Synthesis of flavonoid derivatives of cytisine. 1. aminomethylation of 7-hydroxy-3-arylcoumarins

Aminomethylation involving the natural alkaloid (–)-cytisine of analogs of natural 3-arylbenzopyran-2ones was studied. Substituted 8-(cytisin-12-yl)methyl-3-aryl-7-hydroxycoumarins were synthesized.

Identification of 9-fluoro substituted (−)-cytisine derivatives as ligands with high affinity for nicotinic receptors

(−)-9-Fluorocytisine, (−)-9-methylcytisine and (−)-9-trifluoromethylcytisine were synthesized from the natural product (−)-cytisine. 9-Methyl and 9-trifluoromethyl cytisines display a remarkable affinity at the α4β2 nicotinic receptor subtype (0.2nM) with a high selectivity versus the α7 nAChR subtype. Comparison of the affinity values suggests that the size of the substituent at the 9 position of (−)-cytisine seems more important than electronic factors for efficient binding and selectivity at α4β2 nAChRs.

Synthesis and intramolecular heterocyclization of n-allylthiocarbamide derivatives of the alkaloids cytisine and anabasine into 1,3-thiazoline derivatives and features of their molecular structures

Allylthiourea derivatives were synthesized from the alkaloids cytisine and anabasine and allylisothiocyanate. 1,3-Thiazoline derivatives were synthesized from them via intramolecular heterocyclization using HCl and heating in a sealed ampul. The structures of the synthesized compounds were proved by IR and PMR spectroscopy, mass spectrometry, and x-ray structure analysis.

Synthesis of pyridine-containing derivatives of the alkaloids cytisine and d-pseudoephedrine

N-(5-Bromopyridyl-2)-2-N′-cytisino-and N′-d-pseudoephedrineoacetamides were synthesized by reaction of the alkaloids cytisine and d-pseudoephedrine with N-(5-bromopyridin-2-yl)-2-bromoacetamide hydrobromide. The compositions and structures of the products were confirmed by IR and PMR spectroscopy and mass spectrometry.