RESUMO
Cytisine derivatives are a group of alkaloids containing the structural core of cytisine, which are mainly distributed in Fabaceae plants with a wide range of pharmacological activities, such as resisting inflammation, tumors, and viruses, and affecting the central nervous system. At present, a total of 193 natural cytisine and its derivatives have been reported, all of which are derived from L-lysine. In this study, natural cytisine derivatives were classified into eight types, namely cytisine type, sparteine type, albine type, angustifoline type, camoensidine type, cytisine-like type, tsukushinamine type, and lupanacosmine type. This study reviewed the research progress on the structures, plant sources, biosynthesis, and pharmacological activities of alkaloids of various types.
Assuntos
Alcaloides , Fabaceae , Alcaloides/farmacologia , Alcaloides/química , Quinolizinas/farmacologia , Azocinas/farmacologia , Azocinas/químicaRESUMO
Nicotinic partial agonists provide an accepted aid for smoking cessation and thus contribute to decreasing tobacco-related disease. Improved drugs constitute a continued area of study. However, there remains no reductionist method to examine the cellular and subcellular pharmacokinetic properties of these compounds in living cells. Here, we developed new intensity-based drug-sensing fluorescent reporters (iDrugSnFRs) for the nicotinic partial agonists dianicline, cytisine, and two cytisine derivatives - 10-fluorocytisine and 9-bromo-10-ethylcytisine. We report the first atomic-scale structures of liganded periplasmic binding protein-based biosensors, accelerating development of iDrugSnFRs and also explaining the activation mechanism. The nicotinic iDrugSnFRs detect their drug partners in solution, as well as at the plasma membrane (PM) and in the endoplasmic reticulum (ER) of cell lines and mouse hippocampal neurons. At the PM, the speed of solution changes limits the growth and decay rates of the fluorescence response in almost all cases. In contrast, we found that rates of membrane crossing differ among these nicotinic drugs by >30-fold. The new nicotinic iDrugSnFRs provide insight into the real-time pharmacokinetic properties of nicotinic agonists and provide a methodology whereby iDrugSnFRs can inform both pharmaceutical neuroscience and addiction neuroscience.
Assuntos
Alcaloides/química , Azepinas/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Agonistas Nicotínicos/química , Abandono do Hábito de Fumar , Alcaloides/metabolismo , Animais , Azocinas/química , Azocinas/metabolismo , Fluorescência , Humanos , Ligantes , Camundongos , Quinolizinas/química , Quinolizinas/metabolismoRESUMO
Thousands of known alkaloids contain a nitrogen (N) heterocycle. While five-, six- and seven-membered N-heterocycles (ie: pyrroles, imidazoles, indoles, pyridines and azepines and their saturated variants) are common, those with an eight-membered N-heterocycle are comparatively rare. This review discusses the structure and bioactivity of alkaloids that contain an azocine (or saturated azocane) ring, and the array of sources whence they originate.
Assuntos
Alcaloides/farmacologia , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/farmacologia , Antimaláricos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Inseticidas/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Antimaláricos/química , Antimaláricos/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Compostos Azabicíclicos/química , Compostos Azabicíclicos/isolamento & purificação , Compostos Azabicíclicos/farmacologia , Azocinas/química , Azocinas/isolamento & purificação , Azocinas/farmacologia , Humanos , Inseticidas/química , Inseticidas/isolamento & purificação , Estrutura MolecularRESUMO
Herein we describe a method for inducing cancer cell death, which relies on the use of a H2O2-responsive glycan metabolic precursor in conjunction with antibody-dependent cellular cytotoxicity (ADCC) or photodynamic therapy (PDT).
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Azidas/metabolismo , Compostos de Boro/metabolismo , Peróxido de Hidrogênio/metabolismo , Manosídeos/metabolismo , Citotoxicidade Celular Dependente de Anticorpos , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Azidas/química , Azocinas/química , Azocinas/farmacologia , Compostos de Boro/química , Linhagem Celular Tumoral , Química Click , Dinitrobenzenos/química , Dinitrobenzenos/imunologia , Dinitrobenzenos/farmacologia , Humanos , Peróxido de Hidrogênio/química , Luz , Manosídeos/química , Metaloporfirinas/química , Metaloporfirinas/farmacologia , Metaloporfirinas/efeitos da radiação , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/efeitos da radiação , Polissacarídeos/biossíntese , Polissacarídeos/química , Oxigênio Singlete/metabolismoRESUMO
Cytisine N-methylene-(5,7-dihydroxy-4'-methoxy)-isoflavone (CNF2) is a new compound isolated from the Chinese herbal medicine Sophora alopecuroides. Preliminary pharmacodynamic studies demonstrated its activity in inhibiting breast cancer cell metastasis. This study examined the pharmacokinetics, absolute bioavailability, and tissue distribution of CNF2 in rats, and combined computer-aided technology to predict the druggability of CNF2. The binding site of CNF2 and the breast cancer target human epidermal growth factor receptor-2 (HER2) were examined with molecular docking technology. Next, ACD/Percepta software was used to predict the druggability of CNF2 based on the quantitative structure-activity relationship (QSAR). Finally, a simple and effective HPLC method was used to determine plasma pharmacokinetics and tissue distribution of CNF2 in rats. Prediction and experimental results show that compared with the positive control HER2 inhibitor SYR127063, CNF2 has a stronger binding affinity with HER2, suggesting that its efficacy is stronger; and the structure of CNF2 complies with the Lipinski's Rule of Five and has good drug-likeness. The residence time of CNF2 in rats is less than 4 h, and the metabolic rate is relatively fast; But the absolute bioavailability of CNF2 in rats was 6.6%, mainly distributed in the stomach, intestine, and lung tissues, where the CNF2 contents were 401.20, 144.01, and 245.82 µg/g, respectively. This study constructed rapid screening and preliminary evaluation of active compounds, which provided important references for the development and further research of such compounds.
Assuntos
Alcaloides/química , Alcaloides/farmacocinética , Antineoplásicos/química , Antineoplásicos/farmacocinética , Isoflavonas/química , Isoflavonas/farmacocinética , Alcaloides/sangue , Animais , Antineoplásicos/sangue , Azocinas/sangue , Azocinas/química , Azocinas/farmacocinética , Feminino , Isoflavonas/sangue , Fígado/metabolismo , Simulação de Acoplamento Molecular , Quinolizinas/sangue , Quinolizinas/química , Quinolizinas/farmacocinética , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
Cytisine, a natural product with high affinity for clinically relevant nicotinic acetylcholine receptors (nAChRs), is used as a smoking-cessation agent. The compound displays an excellent clinical profile and hence there is an interest in derivatives that may be further improved or find use in the treatment of other conditions. Here, the binding of a cytisine derivative modified by the addition of a 3-(hydroxypropyl) moiety (ligand 4) to Aplysia californica acetylcholine-binding protein (AcAChBP), a surrogate for nAChR orthosteric binding sites, was investigated. Isothermal titration calorimetry revealed that the favorable binding of cytisine and its derivative to AcAChBP is driven by the enthalpic contribution, which dominates an unfavorable entropic component. Although ligand 4 had a less unfavorable entropic contribution compared with cytisine, the affinity for AcAChBP was significantly diminished owing to the magnitude of the reduction in the enthalpic component. The high-resolution crystal structure of the AcAChBP-4 complex indicated close similarities in the protein-ligand interactions involving the parts of 4 common to cytisine. The point of difference, the 3-(hydroxypropyl) substituent, appears to influence the conformation of the Met133 side chain and helps to form an ordered solvent structure at the edge of the orthosteric binding site.
Assuntos
Alcaloides/metabolismo , Aplysia/metabolismo , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Conformação Proteica , Receptores Nicotínicos/metabolismo , Termodinâmica , Alcaloides/química , Animais , Azocinas/química , Azocinas/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Humanos , Ligantes , Modelos Moleculares , Ligação Proteica , Quinolizinas/química , Quinolizinas/metabolismoRESUMO
To understand the structure-activity correlation of a group of tetrahydrodibenzazocines as inhibitors of 17ß-hydroxysteroid dehydrogenase type 3, we have performed a combined genetic algorithm (GA) and four-dimensional quantitative structure-activity relationship (4D-QSAR) modeling study. The computed electronic and geometry structure descriptors were regulated as a matrix and named as electron-conformational matrix of contiguity (ECMC). A chemical property-based pharmacophore model was developed for series of tetrahydrodibenzazocines by EMRE software package. GA was employed to choose an optimal combination of parameters. A model has been developed for estimating anticancer activity quantitatively. All QSAR models were established with 40 compounds (training set), then they were considered for selective capability with additional nine compounds (test set). A statistically valid 4D-QSAR ( Rtraining2=0.856 , Rtest2=0.851 and q2 = 0.650) with good external set prediction was obtained.
Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Antineoplásicos/química , Azocinas/química , Inibidores Enzimáticos/química , Algoritmos , Ensaios de Seleção de Medicamentos Antitumorais , Elétrons , Modelos Moleculares , Conformação Molecular , Relação Quantitativa Estrutura-AtividadeRESUMO
A novel approach for the synthesis of unsymmetrically substituted dibenzo[b,f][1,5]diazocine-6,12(5H,11H)diones has been developed. This facile three-step method uses variously substituted 1H-benzo[d][1,3]oxazine-2,4-diones (isatoic anhydrides) and 2-aminobenzoic acids as a starting materials. The obtained products were further transformed into N-alkyl-, N-acetyl- and dithio analogues. Developed procedures allowed the synthesis of unsymmetrical dibenzo[b,f][1,5]diazocine-6,12(5H,11H)diones and three novel heterocyclic scaffolds: benzo[b]naphtho[2,3-f][1,5]diazocine-6,14(5H,13H)dione, pyrido[3,2-c][1,5]benzodiazocine-5,11(6H,12H)-dione and pyrazino[3,2-c][1,5]benzodiazocine-6,12(5H,11H)dione. For 11 of the compounds crystal structures were obtained. The preliminary cytotoxic effect against two cancer (HeLa, U87) and two normal lines (HEK293, EUFA30) as well as antibacterial activity were determined. The obtained dibenzo[b,f][1,5]diazocine(5H,11H)6,12-dione framework could serve as a privileged structure for the drug design and development.
Assuntos
Azocinas/química , Benzeno/química , Desenho de Fármacos , Antibacterianos/farmacologia , Azocinas/síntese química , Benzeno/síntese química , Morte Celular , Cristalografia por Raios X , Ciclização , Citometria de Fluxo , Células HEK293 , Células HeLa , HumanosRESUMO
Cytisine is a quinolizidine alkaloid isolated from various Leguminosae plants. Cytisine and its derivatives exhibit a broad range of biological properties, such as smoking cessation aid, antidepressant, neuroprotective, nootropic, anticancer, antiviral, antiparasitic, antidiabetic, insecticidal, and nematicidal activities. In this review, the progress of cytisine and its derivatives in regard to bioactivities, total synthesis, structural modifications focusing on their N-12 position and lactam ring is reported. Additionally, the structure-activity relationships of cytisine and its derivatives are also discussed.
Assuntos
Alcaloides/química , Alcaloides/síntese química , Alcaloides/farmacologia , Quinolizidinas/química , Quinolizidinas/síntese química , Quinolizidinas/farmacologia , Animais , Azocinas/síntese química , Azocinas/química , Azocinas/farmacologia , Humanos , Estrutura Molecular , Quinolizinas/síntese química , Quinolizinas/química , Quinolizinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor and an attractive therapeutic target for cancer and other human diseases. Despite 20 years of persistent research efforts, targeting STAT3 has been very challenging. We report herein the structure-based discovery of potent small-molecule STAT3 degraders based upon the proteolysis targeting chimera (PROTAC) concept. We first designed SI-109 as a potent, small-molecule inhibitor of the STAT3 SH2 domain. Employing ligands for cereblon/cullin 4A E3 ligase and SI-109, we obtained a series of potent PROTAC STAT3 degraders, exemplified by SD-36. SD-36 induces rapid STAT3 degradation at low nanomolar concentrations in cells and fails to degrade other STAT proteins. SD-36 achieves nanomolar cell growth inhibitory activity in leukemia and lymphoma cell lines with high levels of phosphorylated STAT3. A single dose of SD-36 results in complete STAT3 protein degradation in xenograft tumor tissue and normal mouse tissues. SD-36 achieves complete and long-lasting tumor regression in the Molm-16 xenograft tumor model at well-tolerated dose-schedules. SD-36 is a potent, selective, and efficacious STAT3 degrader.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Azocinas/química , Desenho de Fármacos , Descoberta de Drogas , Indóis/química , Indóis/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Organofosfonatos/química , Proteólise/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Animais , Antineoplásicos/farmacocinética , Apoptose , Azocinas/farmacocinética , Azocinas/farmacologia , Proliferação de Células , Feminino , Humanos , Indóis/farmacocinética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos SCID , Estrutura Molecular , Organofosfonatos/farmacocinética , Organofosfonatos/farmacologia , Conformação Proteica , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/química , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Nicotinic acetylcholine receptors (nAChRs) are crucial for communication between synapses in the central nervous system. As such, they are also implicated in several neuropsychiatric and addictive diseases. Cytisine is a partial agonist of some nAChRs and has been used for smoking cessation. Previous studies have established a binding model for several agonists to several nAChR subtypes. Here, we evaluate the extent to which this model applies to cytisine at the α4ß2 nAChR, which is a subtype that is known to play a prominent role in nicotine addiction. Along with the commonly seen cation-π interaction and two hydrogen bonds, we find that cytisine makes a second cation-π interaction at the agonist binding site. We also evaluated a series of C(10)-substituted cytisine derivatives, using two-electrode voltage-clamp electrophysiology and noncanonical amino acid mutagenesis. Double-mutant cycle analyses revealed that C(10) substitution generally strengthens the newly established second cation-π interaction, while it weakens the hydrogen bond typically seen to LeuE in the complementary subunit. The results suggest a model for how cytisine derivatives substituted at C(10) (as well as C(9)/C(10)) adjust their binding orientation, in response to pyridone ring substitution.
Assuntos
Alcaloides/química , Agonistas Nicotínicos/química , Receptores Nicotínicos/química , Alcaloides/genética , Animais , Azocinas/química , Sítios de Ligação , Relação Dose-Resposta a Droga , Eletrofisiologia , Ligação de Hidrogênio , Estrutura Molecular , Mutagênese Sítio-Dirigida , Mutação , Oócitos/metabolismo , Técnicas de Patch-Clamp , Ligação Proteica , Quinolizinas/química , Ratos , Receptores Nicotínicos/genética , Xenopus laevisRESUMO
Cytisine-pterocarpan-derived compounds were biomimetically synthesized with (-)-cytisine and (-)-maackiain via a N,N-4-dimethyl-4-aminopyridine (DMAP)-mediated synthetic strategy in a mild manner. In the present study, tonkinensine B (4) was elaborated in good and high yields with the optimized reaction conditions. The in vitro cytotoxicity of compound 4 was evaluated against breast cancer cell lines and showed that 4 had a better cytotoxicity against MDA-MB-231 cells (IC50 = 19.2 µM). Depending on the research on cytotoxicities of 4 against RAW 264.7 and BV2 cells, it was suggested that 4 produced low cytotoxic effects on the central nervous system. Further study indicated that 4 demonstrated cytotoxic activity against MDA-MB-231 cells and the cytotoxic activity was induced by apoptosis. The results implied that the apoptosis might be induced by mitochondrion-mediated apoptosis via regulating the ratio of Bax/Bcl-2 and promoting the release of cytochrome c from the mitochondrion to the cytoplasm in MDA-MB-231 cells.
Assuntos
Neoplasias da Mama/metabolismo , Citocromos c/metabolismo , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Mitocôndrias/metabolismo , Alcaloides/química , Animais , Azocinas/química , Mimetismo Biológico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Compostos Heterocíclicos com 2 Anéis/química , Humanos , Células MCF-7 , Camundongos , Estrutura Molecular , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pterocarpanos/química , Quinolizinas/química , Células RAW 264.7 , Proteína X Associada a bcl-2/metabolismoRESUMO
In this study, bornyl- and cytisine-based cyanopyrrolidines as potent dipeptidyl peptidase-IV (DPP-IV) inhibitors were synthesised. The in vitro inhibiting activities of bornyl- and cytisine derivatives towards DPP-IV were evaluated. Bornyl-based cyanopyrrolidines were shown to have moderate inhibitory activity with regard to DPP-IV (1.27-15.78⯵M). A docking study was performed to elucidate the structure-activity relationship of the obtained compounds. The in vivo hypoglycemic activities of the same compounds were evaluated with the oral glucose tolerance test (OGTT) in mice. Bornyl-based cyanopyrrolidines were shown to have good hypoglycemic activity.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/síntese química , Hipoglicemiantes/uso terapêutico , Pirrolidinas/química , Alcaloides/química , Animais , Azocinas/química , Sítios de Ligação , Cânfora/química , Domínio Catalítico , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/síntese química , Masculino , Camundongos , Simulação de Acoplamento Molecular , Pirrolidinas/uso terapêutico , Quinolizinas/química , Relação Estrutura-AtividadeRESUMO
Spectral and photophysical properties of (-)-cytisine that is used as a smoking cessation aid, and which derivatives are promising tools in a treatment of neurological diseases, were investigated in acetonitrile, non-specifically interacting solvent with a polarity similar to water. The two chair conformers of cytisine were found the most stable in the ground state S0 and the lowest excited singlet state S1(π,π*), wherein axial one was characterized by a significantly larger abundance, fluorescence lifetime 0.15â¯ns and fluorescence quantum yield 0.008. The S1(π,π*) excited state of both cytisine conformers deactivated almost exclusively via internal conversion.
Assuntos
Acetonitrilas/química , Alcaloides/análise , Modelos Moleculares , Análise Espectral , Alcaloides/química , Azocinas/análise , Azocinas/química , Elétrons , Conformação Molecular , Teoria Quântica , Quinolizinas/análise , Quinolizinas/química , TermodinâmicaRESUMO
Cytisine-linked isoflavonoids (CLIFs) inhibited PC-3 prostate and LS174T colon cancer cell proliferation by inhibiting a peroxisomal bifunctional enzyme. A pull-down assay using a biologically active, biotin-modified CLIF identified the target of these agents as the bifunctional peroxisomal enzyme, hydroxysteroid 17ß-dehydrogenase-4 (HSD17B4). Additional studies with truncated versions of HSD17B4 established that CLIFs specifically bind the C-terminus of HSD17B4 and selectively inhibited the enoyl CoA hydratase but not the d-3-hydroxyacyl CoA dehydrogenase activity. HSD17B4 was overexpressed in prostate and colon cancer tissues, knocking down HSD17B4 inhibited cancer cell proliferation, suggesting that HSD17B4 is a potential biomarker and drug target and that CLIFs are potential probes or therapeutic agents for these cancers.
Assuntos
Alcaloides/farmacologia , Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Isoflavonas/farmacologia , Proteína Multifuncional do Peroxissomo-2/antagonistas & inibidores , Alcaloides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Azocinas/química , Azocinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Isoflavonas/síntese química , Isoflavonas/química , Estrutura Molecular , Proteína Multifuncional do Peroxissomo-2/metabolismo , Quinolizinas/química , Quinolizinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Cytisine (Cy) is one of the alkaloids that exist naturally in the plant genera Laburnum of the family Fabaceae. With strong bioactivities, Cy is commercialized for smoking cessation for years. In this work, the study of intermolecular interactions between Cy and bovine serum albumin (BSA) was performed by applying fluorescence spectroscopic methods under simulated physiological conditions. The mechanism of fluorescence quenching of BSA by Cy was also studied. Parameters such as bathing temperature, time and solution pH were investigated to optimize the fluorescence quenching. The binding type, binding ratio and binding constant between BSA and Cy were calculated by using the Stem-Volmer equation. Experimental results indicated that Cy can quench the fluorescent emission of BSA statically by forming a 1 : 1 type non-covalent complex and the binding constant is 5.6 x 10(3) L x mol(-1). Synchronous fluorescence spectral research shows Cy may affect the fluorescence emission of Trp residues of BSA. Furthermore, molecular docking is utilized to model the complex and probe the plausible quenching mechanism. It can be noted that the hydrogen bindings and hydrophobic interactions between Cy and BSA change the micro-environment of Trp213, which leads to the fluorescence quenching of BSA.
Assuntos
Alcaloides/química , Simulação de Acoplamento Molecular , Soroalbumina Bovina/química , Espectrometria de Fluorescência , Azocinas/química , Interações Hidrofóbicas e Hidrofílicas , Quinolizinas/químicaRESUMO
The natural product-like compound 1 was identified as a direct inhibitor of the menin-MLL interaction by in silico screening. Structure-based optimization furnished analogue 1a, which showed significantly higher potency than both the lead structure 1 and the reference compound MI-2.
Assuntos
Alcaloides/química , Antineoplásicos/química , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Proteína de Leucina Linfoide-Mieloide/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Alcaloides/farmacologia , Antineoplásicos/farmacologia , Azocinas/química , Azocinas/farmacologia , Células Hep G2 , Humanos , Modelos Moleculares , Ligação Proteica , Quinolizinas/química , Quinolizinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Cytisine, an α4ß2 nicotinic receptor partial agonist, is a plant alkaloid widely used as a smoking cessation agent. Despite long history of use, knowledge on pharmacokinetics of cytisine still demands an extension. This work is aimed at theoretical determination of physicochemical parameters that affect the bioavailability of cytisine. The acidic dissociation constant, Gibbs free energy of solvation in water and n-octanol as well as n-octanol/water partition coefficient and n-octanol/water distribution coefficient of cytisine were calculated as quantities corresponding to its solubility and permeability. Cytisine structure was optimized with several quantum chemical methods-ab initio: HF and MP2, and DFT functionals (B3LYP, B3LYP-D3, CAM-B3LYP, M06-2X, TPSS, VSXC) with 6-311++G(d,p) basis set. Solvation of cytisine in water and n-octanol was determined with the SMD continuum model. It was shown that lipophilicity of cytisine depends on the pH of an environment. Protonated cytisine, the most populated state under acidic conditions, is characterized by enhanced hydrophilicity. Then neutral cytisine, dominating in a basic environment, demonstrates more lipophilic character. It appears that cytisine is very well soluble in the gastrointestinal (GI) tract fluids. Then the distribution of cytisine ought to occur very rapidly. However, permeability of cytisine through the mucous membrane of the GI tract may be limited, leading to the diminished bioavailability.
Assuntos
Alcaloides/química , Modelos Químicos , Modelos Moleculares , Prótons , Azocinas/química , Disponibilidade Biológica , Humanos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Cinética , Mucosa/metabolismo , Nicotina/antagonistas & inibidores , Permeabilidade , Quinolizinas/química , Solubilidade , Soluções , Termodinâmica , Dispositivos para o Abandono do Uso de TabacoRESUMO
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.
Assuntos
Alcaloides/química , NF-kappa B/biossíntese , Fator de Transcrição STAT1/biossíntese , Relação Estrutura-Atividade , Alcaloides/síntese química , Alcaloides/farmacologia , Azocinas/síntese química , Azocinas/química , Azocinas/farmacologia , Células HEK293 , Humanos , Interferon gama/farmacologia , Luciferases/química , NF-kappa B/antagonistas & inibidores , Quinolizinas/síntese química , Quinolizinas/química , Quinolizinas/farmacologia , Fator de Transcrição STAT1/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transfecção , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
The limited clinical efficacy of many cancer therapeutics has initiated intense research efforts toward the discovery of novel chemical entities in this field. In this study, 31 hit candidates were selected from nearly 800,000 database compounds in a ligand-based virtual screening campaign. In turn, three of these hits were found to have (sub)micromolar potencies in proliferation assays with the Jurkat acute lymphatic leukemic cell line. In this assay, the three hits were found to exhibit higher potency than clinically tested cell-death inducers (GDC-0152, AT-406, and birinapant). Importantly, antiproliferative activity toward non-cancer peripheral blood mononuclear cells (PBMCs) was found to be marginal. Further biological characterization demonstrated the cell-death-inducing properties of these compounds. Biological testing of hit congeners excluded a nonspecific, toxic effect of the novel structures. Altogether, these findings may have profound relevance for the development of clinical candidates in tumor therapy.