Nicotinic Derivatives Research Articles

Crystal structure, spectroscopic and magnetic properties, and antimicrobial activities of cobalt(II) 2-methylthionicotinate complexes with N-heterocyclic ligands

Synthesis and characterization of 10 new 2-methylthionicotinate (2-MeSnic) Co(II) complexes, namely, [Co(2-MeSnic)2L2(H2O)2] · nH2O (L is N,N-diethylnicotinamide—Et2nia, ethylnicotinate—Etnic, nicotinamide—nia, isonicotinamide—isonia, N-methylnicotinamide—N-Menia, furo[3,2-c]pyridine—fpy, 2,3-dimethylfuro[3,2-c]pyridine—Me2fpy or benzo[4,5]furo[3,2-c]pyridine—Bfp; n is 0, 1 or 2) as well as [Co(2-MeSnic)2L2] (L is ronicol—ron or 2-methylfuro[3,2-c]pyridine—Mefpy), are reported. The characterizations were based on physico-chemical and spectroscopic methods. The crystal structure of one of the complexes has been determined. In the molecular complex [Co(2-MeSnic)2(Me2fpy)2(H2O)2], the Co(II) central atom, located at a symmetry centre, is octahedrally coordinated by an oxygen atom of the unidentate 2-MeSnic carboxyl group, the nitrogen atom of the pyridine ring of Me2fpy, a water molecule and the corresponding centrosymmetrically located atoms. Also, biological activity of the complexes against various strains of bacteria and filamentous fungi has been investigated. It is concluded that by complexation of these nicotinate derivatives their biological activities are elevated.

Nicotine Derivatives in Wastewater and Surface Waters: Application as Chemical Markers for Domestic Wastewater

Nicotine is extensively metabolized in the human body to a number of compounds, which may enter natural waters via discharge of domestic wastewater. However, little is known on exposure of and potential effects on the aquatic environment. In this study, two major urinary metabolites, cotinine and 3'-hydroxycotinine, as well as a further tobacco alkaloid, N-formylnornicotine, were measured in wastewater and water from Swiss lakes using an analytical procedure based on SPE and LC-MS/MS SRM with cotinine-d3 as internal standard (LOQs, 1.0-1.5 ng/L). Typical concentrations of cotinine and 3'-hydroxycotinine were approximately 1-10 microg/L in untreated wastewater, but clearly less in treated wastewater (approximately 0.01-0.6 microg/L), corresponding to elimination efficiencies of 90-99%. N-Formylnornicotine, however,was found at similar concentrations in untreated and treated wastewater (0.02-0.15 microg/L). Its apparent persistence during wastewater treatment was further confirmed by incubation experiments with activated sludge. In lakes, cotinine, 3'-hydroxycotinine, and N-formylnornicotine were detected at concentrations up to 15, 80, and 6 ng/L, respectively. Concentrations in lakes correlated with the expected anthropogenic burden by domestic wastewater (ratio population per water throughflow), demonstrating the suitability of these nicotine derivatives as hydrophilic, anthropogenic markers. In small receiving waters with significant wastewater discharges, concentrations of a few hundred ng/L may be expected. Possible ecotoxicological risks associated with such environmental concentrations, can, however, not be assessed at present as data on effects on aquatic organisms are very limited, in particular on long-term effects.

Evaluation of anti-tubercular activity of nicotinic and isoniazid analogues

Several nicotinic and isoniazid derivatives, most of them containing nitro groups were synthesized by our group, and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv using the Alamar Blue susceptibility test and the activity expressed as the minimum inhibitory concentration (MIC) in mg/mL. The compound 11d exhibited the best result (1.2 µg/mL) when compared with first line drugs such as isoniazid (INH) and rifampicin (RIP). Therefore this class of compounds could be a good starting point to develop new lead compounds in the treatment of multi-drug resistant tuberculosis.

An In Silico Method for Screening Nicotine Derivatives as Cytochrome P450 2A6 Selective Inhibitors Based on Kernel Partial Least Squares

Nicotine and a variety of other drugs and toxins are metabolized by cytochromeP450 (CYP) 2A6. The aim of the present study was to build a quantitative structure-activityrelationship (QSAR) model to predict the activities of nicotine analogues on CYP2A6.Kernel partial least squares (K-PLS) regression was employed with the electro-topologicaldescriptors to build the computational models. Both the internal and external predictabilitiesof the models were evaluated with test sets to ensure their validity and reliability. As acomparison to K-PLS, a standard PLS algorithm was also applied on the same training andtest sets. Our results show that the K-PLS produced reasonable results that outperformed thePLS model on the datasets. The obtained K-PLS model will be helpful for the design ofnovel nicotine-like selective CYP2A6 inhibitors.

Synthesis of (S)-Brevicolline

The β-carboline alkaloid (S)-Brevicolline is synthesized in six steps from (S)-nicotine. Regioselective ortho-directed lithiation procedures gave a trisubstituted (S)-nicotine derivative which was used in a Suzuki coupling and intramolecular Buchwald amination to complete the synthesis.

(E)-metanicotine hemigalactarate (TC-2403-12) inhibits IL-8 production in cells of the inflamed mucosa

Nicotine is of therapeutic value in ulcerative colitis, but its administration is connected with adverse events. Nicotine derivatives are currently being tested to maintain the therapeutic effects and minimize adverse events. TC-2403-12 is a (E)-metanicotine hemigalactarate. The aim of this study was to determine the effectiveness of TC-2403-12 in the inhibition of TNF- and lipopolysaccharide (LPS)-induced cell activation. Colonic epithelial cells (CEC), monocytes (MM6), granulocytes, and the intestinal epithelial cell line HT-29 were stimulated with TNF and LPS and treated with TC-2403-12. IL-8 secretion in the cell supernatants and NF-kappaB activation were determined by ELISA. Apoptosis was quantified by flow cytometry. In MM6 cells, IL-8 secretion was significantly decreased to 30% of control after TC-2403-12 treatment, with best results after pretreatment for 24 h. This decrease in cell activation was not due to apoptosis and was not mediated by inhibition of NF-kappaB activation. IL-8 production in neutrophils and primary CEC also tended to be decreased after TC-2403-12 treatment. TC-2403-12 had no influence on IL-8 secretion of HT-29 cells. TC-2403-12 effectively inhibited TNF- and LPS-induced IL-8 production in different cell types. No toxic effects occurred at the concentrations used. Preincubation of cells with TC-2403-12 showed the best effects.

Regioselective C‐2 and C‐6 Substitution of (S)‐Nicotine and Nicotine Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

COX-2 in Cardiovascular Disease

Prostanoids are a large family of lipid mediators derived from the arachidonic acid metabolites of the cyclooxygenase (COX) enzymes. Therapeutically, COX is the target of the nonsteroid antiinflammatory drugs (NSAIDs), a chemically diverse group that includes ibuprofen, naproxen, and diclofenac, among dozens of others. Inhibition of prostanoid production by traditional NSAIDs accounts for all their major therapeutic effects, such as the dampening down of inflammation and the reduction of fever, and their potentially severe adverse side effects, most commonly within the gastrointestinal tract.1,2 See page 1137 Since the early 1990’s it has been clear there are two distinct enzymes responsible for the production of prostanoids: a constitutive COX-1 found in all tissues and an inflammation-associated enzyme COX-2.1,2 COX-2 is constitutively expressed in only a few sites, such as parts of the kidney and central nervous system, but is highly upregulated and active at sites of inflammation. These findings led to the hypothesis that selective COX-2 inhibitors could be antiinflammatory without the major side effects associated with traditional NSAIDs. Against this background several COX-2–selective inhibitors have been produced and brought to market, the first two being celecoxib (Celebrex) and rofecoxib (Vioxx). Preclinical studies of these COX-2–selective inhibitors were extremely promising. In animal models, for example, they were demonstrated to be as efficacious as traditional NSAIDs but to be lacking their toxic actions on the gastrointestinal tract. Clinical trials have, however, been marred by controversy. The CLASS trial for celecoxib, a 12-month osteoarthritis study of celecoxib, demonstrated celecoxib to have improved safety relative to ibuprofen but not …

Synthesis of C‐4 Substituted Nicotine Derivatives via an N‐Acylpyridinium Salt of (S)‐Nicotine.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Synthesis of Nicotine Derivatives via Reductive Disilylation of (S)-Nicotine

[reaction: see text] A variety of novel nicotine derivatives were prepared via reductive disilylation of (S)-nicotine. Treatment of nicotine with lithium powder and chlorotrimethylsilane afforded 1,4-bis(trimethylsilyl)-1,4-dihydronicotine in high yield. Addition of various carbonyl electrophiles and a catalytic amount of TBAF provided either C-5 substituted nicotines or 1,4-dihydronicotine derivatives.

Two novel luminescent zinc supramolecular networks with nicotinate derivatives by hydrothermal process

Two novel zinc compounds [Zn(Enic) 2] n ( 1) (Enic = 5-ethylnicotinate) and [Zn(H 2O) 6][6-OHnic] 2 ( 2) (6-OHnic = 6-hydroxynicotinate) have been synthesized under hydrothermal reaction conditions. The structure of the compound 1 is self-assembled from square-grid nets stacked via interdigitation while compound 2 forms a 3D supermolecular network structure via strong O–H⋯O hydrogen bond. In addition, the luminescent properties of two compounds were investigated in the crystalline state.

Synthesis of C-4 Substituted Nicotine Derivatives via an N-Acylpyridinium Salt of (S)-Nicotine

[reaction: see text] A variety of novel nicotine derivatives were prepared from (S)-nicotine via a two-step sequence. Addition of a cuprate reagent to an N-acylpyridinium salt of nicotine, followed by aromatization with elemental sulfur, afforded C-4 substituted nicotines in moderate to high yield. Using this method, 4-(dimethylphenylsilyl)nicotine was prepared and oxidized to afford (S)-4-hydroxynicotine.

Conformation‐Control and Stereoselective Reactions Using Cation‐π Interactions

AbstractFor Abstract see ChemInform Abstract in Full Text.

A novel mammalian expression system derived from components coordinating nicotine degradation in arthrobacter nicotinovorans pAO1

We describe the design and detailed characterization of 6-hydroxy-nicotine (6HNic)-adjustable transgene expression (NICE) systems engineered for lentiviral transduction and in vivo modulation of angiogenic responses. Arthrobacter nicotinovorans pAO1 encodes a unique catabolic machinery on its plasmid pAO1, which enables this Gram-positive soil bacterium to use the tobacco alkaloid nicotine as the exclusive carbon source. The 6HNic-responsive repressor-operator (HdnoR-ONIC) interaction, controlling 6HNic oxidase production in A.nicotinovorans pAO1, was engineered for generic 6HNic-adjustable transgene expression in mammalian cells. HdnoR fused to different transactivation domains retained its ONIC-binding capacity in mammalian cells and reversibly adjusted transgene transcription from chimeric ONIC-containing promoters (PNIC; ONIC fused to a minimal eukaryotic promoter [Pmin]) in a 6HNic-responsive manner. The combination of transactivators containing various transactivation domains with promoters differing in the number of operator modules as well as in their relative inter-ONIC and/or ONIC-Pmin spacing revealed steric constraints influencing overall NICE regulation performance in mammalian cells. Mice implanted with microencapsulated cells engineered for NICE-controlled expression of the human glycoprotein secreted placental alkaline phosphatase (SEAP) showed high SEAP serum levels in the absence of regulating 6HNic. 6HNic was unable to modulate SEAP expression, suggesting that this nicotine derivative exhibits control-incompatible pharmacokinetics in mice. However, chicken embryos transduced with HIV-1-derived self-inactivating lentiviral particles transgenic for NICE-adjustable expression of the human vascular endothelial growth factor 121 (VEGF121) showed graded 6HNic response following administration of different 6HNic concentrations. Owing to the clinically inert and highly water-soluble compound 6HNic, NICE-adjustable transgene control systems may become a welcome alternative to available drug-responsive homologs in basic research, therapeutic cell engineering and biopharmaceutical manufacturing.

カチオン‐π相互作用による立体配座制御と立体選択的反応

The existence of two types of intramolecular cation-π interactions between a phenyl and a pyridinium, and between a thiocarbonyl and a pyridinium in nicotinic amide derivatives have been clarified by 1H NMR and CD spectroscopies, X-ray structural analysis and calculations.These interactions resulted in the shielding of one side of the pyridinium face by the phenyl or the thiocarbonyl group, which enables nucleophiles to attack the pyridinium ring from the opposite side. Addition of organometallic reagents and ketene silyl acetals gave 1, 4-dihydropyridines in high regio- and stereoselectivities. The stereochemistry of the chiral center of the products was opposite depending on whether the chiral auxiliary is oxazolidine or thiazolidine-2-thione.Moreover, the DMAP derivatives bearing a thiazolidine-2-thione moiety served as asymmetric acylating catalysts. Kinetic resolution of a variety of sec-alcohols was performed in the presence of 0.5 mol% of the catalyst with the s values of 7-30.

On-line screening of conformationally constrained nicotines and anabasines for agonist activity at the α3β4- and α4β2-nicotinic acetylcholine receptors using immobilized receptor-based liquid chromatographic stationary phases

Liquid chromatography columns containing stationary phases based upon immobilized nicotinic acetylcholine receptors (nAChRs) were used to screen a series of conformationally constrained nicotine and anabasine derivatives for agonist activity. The α3β4 nAChR and α4β2 nAChR subtypes were used to prepare the chromatographic columns and [ 3H] epibatidine dihydrochloride ([ 3H] EB) was used as the marker ligand. Single displacement experiments were conducted with the test ligands and with nicotine and carbachol. Nicotine was used as an internal control for compounds with agonist activity and carbachol was used as an internal control for compounds with very weak agonistic activity ( K d > 4700 nM for α3β4). The displacement of [ 3H] EB by each of the test compounds and internal controls was calculated and expressed as Δml. Functional studies were then conducted using a stably transfected cell line that expresses the α3β4 nAChR and EC 50 values were determined for the test compounds and the internal controls. A comparison of the Δml and EC 50 values indicated that 9/11 compounds had been correctly identified as agonists or non-agonists of the α3β4 nAChR. A similar comparison could not be made for the α4β2 nAChR, since the intact cell line was not available for testing. The results of the study suggest that the immobilized nAChR columns can be used for the rapid on-line screening of compounds for their relative affinities for the immobilized receptor and as an initial determination of qualitative functional activities.

Recent Developments in the Synthesis of Nicotinic Acetylcholine Receptor Ligands

AbstractFor Abstract see ChemInform Abstract in Full Text.

A-186253, a specific antagonist of the α4β2 nAChRs: its properties and potential to study brain nicotinic acetylcholine receptors

Imaging the living brain and the distribution of the ligand gated channels that participate in the neurotransmission is one of the challenges that is hoped to bring new insights for the treatment of neurological diseases. Herein, we probed a new nicotinic derivative, A-186253 as a potential molecule to discriminate with high resolution the different neuronal nicotinic receptor subtypes that are expressed in distinct brain areas. Binding with a high affinity of 440 pM at the major brain α4β2 receptor subtype and presenting an excellent safety margin, properties of the A-186253 were thoroughly evaluated. While autoradiography confirmed its specificity for the α4β2 subtype, functional investigations revealed for short exposures a broader spectrum of action at receptors including the ganglionic α3β4 and the homomeric α7 subtypes. Specificity was, however, observed at α4β2 when receptors were exposed for several minutes with low concentration of the A-186253. In view of these promising results, the A-186253 was radiolabeled and tested in positron emission tomography on rats and pigs. Despite the high selectivity observed in vitro, the A-186253 displayed a complex binding profile and little displacement by the agonist cytisine. While the A-186253 can be valuable to discriminate receptor subtypes, improvements of this molecule must be brought for in vivo measurements.

Recent developments in the synthesis of nicotinic acetylcholine receptor ligands.

The extraordinary pharmacology of nicotine and epibatidine have indicated the potential for nicotinic acetylcholine receptor (nAChR) ligands to serve as a new therapeutic class for a host of CNS disorders. Many such ligands are natural products, or analogs thereof, which represent a significant challenge to the synthetic chemist. Synthesis of such molecules often serves as a showcase to demonstrate the potential of newly developed methodology. This synthetic challenge coupled with the promise of pharmacological activity in compounds possessing the nicotinic pharmacophore has stimulated a great deal of synthetic activity over the last five years. The present report provides an overview of novel synthetic methodology occurring during this period directed toward the synthesis of compounds with presumed affinity for the neuronal nAChR. Syntheses chosen for review here represent the major efforts toward molecules such as epibatidine analogs, anatoxin-a, nicotine and related alkaloids, conformationally constrained nicotine derivatives, cytisine and methyllycaconitine (MLA).

The first crystal structure of a free neutral form of a nicotine derivative

AbstractThe single crystal X-ray diffraction analysis of a racemic form of a nicotine derivative, 5-(2-hydroxy-2-methylbut-3-ynyl)-3-(1-methyl-2-pyrrolidinyl)pyridine (2), provides structural information on molecular geometry and intermolecular interactions that could be relevant for the transport and docking of nicotine ligands to nicotinic acetylcholine receptors (nAChRs), since it is the first crystal structure of a free neutral form of a nicotine derivative. Each enantiomer of the two independent molecules of the asymmetric unit is characterized by (i) anantiorientation of the N2 methyl substituent with respect to the pyridine ring (ii) an envelope form of the pyrrolidine ring (iii) an orientation roughly perpendicular of the pyridine and pyrrolidine rings. The crystal packing is characterized by the formation of OH...N1 hydrogen-bond cyclic dimers that are packed through van der Waals interactions. This selectivity of hydrogen-bonding site in favor of the N1 pyridine nitrogen found in the solid state for (2) agrees with the greater hydrogen-bond acceptor strength of the N1 pyridine nitrogen compared to the N2 pyrrolidine one previously found in solution for nicotine (1).