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1.
Tob Control ; 32(e1): e113-e117, 2023 04.
Article in English | MEDLINE | ID: mdl-34493630

ABSTRACT

The introduction of a new product line of the popular disposable electronic cigarette brand Puffbar, advertised as containing synthetic nicotine, has drawn attention to the increasing use of synthetic nicotine in marketed products and its uncertain regulatory status. A search of the Truth Tobacco Industry Documents revealed that the industry considered using synthetic nicotine already in the 1960s, efforts that were abandoned due to high costs and insufficient purity. Recent patents revealed renewed efforts to develop more efficient strategies for the synthesis of nicotine. Nicotine exists as two stereoisomers, S-nicotine and R-nicotine. While S-nicotine is the prevalent (>99%) form of nicotine in tobacco, a market-leading form of synthetic nicotine contains both stereoisomers at equal amounts, raising concerns about inaccurate labelling and the poorly understood health effects of R-nicotine. Other manufacturers, including a leading vendor of pharmaceutical grade nicotine, developed stereospecific strategies to synthesise pure S-nicotine, now added to electronic cigarette products marketed in the USA and UK. While S-nicotine and R-nicotine can be differentiated by enantioselective High Performance Liquid Chromatography (HPLC), differentiation of synthetic (fossil-derived) from tobacco-derived S-nicotine will require development of methods to measure carbon isotope (14C or 13C) content. Vendors claim that the FDA has no authority to regulate synthetic nicotine as a tobacco product, allowing them to circumvent the premarket tobacco product application process. However, legal analysis suggests that FDA may have the authority to regulate synthetic nicotine as a drug. Alternatively, Congress needs to include nicotine from any source within the legal definition of tobacco products.


Subject(s)
Electronic Nicotine Delivery Systems , Nicotine , Tobacco Products , Nicotine/analysis , Nicotine/chemical synthesis , Nicotine/metabolism , Nicotine/pharmacology , Tobacco Products/legislation & jurisprudence , United States Food and Drug Administration/legislation & jurisprudence , United States , Humans , Tobacco Industry
2.
Molecules ; 26(24)2021 Dec 13.
Article in English | MEDLINE | ID: mdl-34946630

ABSTRACT

In the context of naturally occurring nitrogen heterocycles, nicotine is a chiral alkaloid present in tobacco plants, which can target and stimulate nicotinic acetylcholine receptors (nAChRs), a class of ligand-gated ion channels commonly located throughout the human brain. Due to its well-known toxicity for humans, there is considerable interest in the development of synthetic analogues; in particular, conformationally restricted analogues of nicotine have emerged as promising drug molecules for selective nAChR-targeting ligands. In the present mini-review, we will describe the synthesis of the conformationally restricted analogues of nicotine involving one or more catalytic processes. In particular, we will follow a systematic approach as a function of the heteroarene structure, considering: (a) 2,3-annulated tricyclic derivatives; (b) 3,4-annulated tricyclic derivatives; (c) tetracyclic derivatives; and (d) other polycyclic derivatives. For each of them we will also consider, when carried out, biological studies on their activity for specific nAChR subunits.


Subject(s)
Drug Delivery Systems , Nicotine , Nicotinic Agonists , Animals , Humans , Nicotine/analogs & derivatives , Nicotine/chemical synthesis , Nicotine/chemistry , Nicotine/therapeutic use , Nicotinic Agonists/chemical synthesis , Nicotinic Agonists/chemistry , Nicotinic Agonists/therapeutic use
3.
Angew Chem Int Ed Engl ; 59(40): 17565-17571, 2020 09 28.
Article in English | MEDLINE | ID: mdl-32652746

ABSTRACT

The dealkenylative alkenylation of alkene C(sp3 )-C(sp2 ) bonds has been an unexplored area for C-C bond formation. Herein 64 examples of ß-alkylated styrene derivatives, synthesized through the reactions of readily accessible feedstock olefins with ß-nitrostyrenes by ozone/FeII -mediated radical substitutions, are reported. These reactions proceed with good efficiencies and high stereoselectivities under mild reaction conditions and tolerate an array of functional groups. Also demonstrated is the applicability of the strategy through several synthetic transformations of the products, as well as the syntheses of the natural product iso-moracin and the drug (E)-metanicotine.


Subject(s)
Alkenes/chemistry , Carbon/chemistry , Alkenes/chemical synthesis , Alkylation , Catalysis , Metals/chemistry , Molecular Conformation , Nicotine/analogs & derivatives , Nicotine/chemical synthesis , Nicotine/chemistry , Stereoisomerism , Styrenes/chemical synthesis , Styrenes/chemistry
4.
Pak J Pharm Sci ; 33(2): 675-683, 2020 Mar.
Article in English | MEDLINE | ID: mdl-32276914

ABSTRACT

The present work reports the synthesis of Schiff base series of nicotinic hydrazide (C-1-C-5) and it's antibacterial and wound healing evaluation. The synthetic molecules were characterized with different spectroscopic techniques and explored for their antibacterial potential. The objective of this work was to explore antimicrobial agent using two types of microorganisms, one Gram-positive (S. aureus ATCC 9144) and one Gram-negative (E. coli ATCC 10536). C-2, C-4 and C-5 potentially inhibit bacterial growth (p<0.001). Atomic force microscopy (AFM) imaging was obtained to get high-resolution images of the effect of treated drugs on the bacterial morphology. The images obtained also revealed the antibacterial effects of potent molecule. The magnified pictures captured under AFM suggest significantly damaged cell surface and disturbed morphology. The compounds were further analyzed for in vivo wound healing potential on mice. The compound C-2, C-4 and C-5 heal the wounds comparatively in less time duration as compared to control group (p<0.001). Compound C-1 and C-3 took more time to heal the wound as compare to compound C-2, C-4 and C-5. The re-epithelialization process of wound in animals group treated with potent compound was highly significant (p<0.001) and faster than control. Results of this study suggest that the compounds C-2, C-4 andC-5 possess pronounced antibacterial and wound healing potential and need to be further evaluated for mechanism of action.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Cell Wall/drug effects , Microscopy, Atomic Force/methods , Nicotine/analogs & derivatives , Schiff Bases/chemical synthesis , Wound Healing/drug effects , Animals , Anti-Bacterial Agents/pharmacology , Cell Wall/physiology , Escherichia coli/drug effects , Escherichia coli/physiology , Mice , Microbial Sensitivity Tests/methods , Nicotine/chemical synthesis , Nicotine/pharmacology , Schiff Bases/pharmacology , Staphylococcus aureus/drug effects , Staphylococcus aureus/physiology , Wound Healing/physiology
5.
Molecules ; 24(20)2019 Oct 22.
Article in English | MEDLINE | ID: mdl-31652614

ABSTRACT

Nicotinic acetylcholine receptors (nAChRs), serotonin transporters (SERT) and dopamine transporters (DAT) represent targets for the development of novel nicotinic derivatives acting as multiligands associated with different health conditions, such as depressive, anxiety and addiction disorders. In the present work, a series of functionalized esters structurally related to acetylcholine and nicotine were synthesized and pharmacologically assayed with respect to these targets. The synthesized compounds were studied in radioligand binding assays at α4ß2 nAChR, h-SERT and h-DAT. SERT experiments showed not radioligand [3H]-paroxetine displacement, but rather an increase in the radioligand binding percentage at the central binding site was observed. Compound 20 showed Ki values of 1.008 ± 0.230 µM for h-DAT and 0.031 ± 0.006 µM for α4ß2 nAChR, and [3H]-paroxetine binding of 191.50% in h-SERT displacement studies, being the only compound displaying triple affinity. Compound 21 displayed Ki values of 0.113 ± 0.037 µM for α4ß2 nAChR and 0.075 ± 0.009 µM for h-DAT acting as a dual ligand. Molecular docking studies on homology models of α4ß2 nAChR, h-DAT and h-SERT suggested potential interactions among the compounds and agonist binding site at the α4/ß2 subunit interfaces of α4ß2 nAChR, central binding site of h-DAT and allosteric modulator effect in h-SERT.


Subject(s)
Acetylcholine/analogs & derivatives , Dopamine Plasma Membrane Transport Proteins/chemistry , Nicotine/analogs & derivatives , Receptors, Nicotinic/chemistry , Serotonin Plasma Membrane Transport Proteins/chemistry , Acetylcholine/agonists , Acetylcholine/chemical synthesis , Acetylcholine/chemistry , Allosteric Regulation , Binding Sites , Dopamine/chemistry , Dopamine Agonists/chemistry , Dopamine Plasma Membrane Transport Proteins/agonists , Esters/chemistry , HEK293 Cells , Humans , Ligands , Molecular Docking Simulation , Nicotine/agonists , Nicotine/chemical synthesis , Nicotine/chemistry , Nicotinic Agonists/chemistry , Pyrrolidines/chemistry , Radioligand Assay , Serotonin Plasma Membrane Transport Proteins/agonists , Structure-Activity Relationship
6.
Bioorg Med Chem ; 27(1): 100-109, 2019 01 01.
Article in English | MEDLINE | ID: mdl-30503413

ABSTRACT

The pyridine-derived biomolecules are of considerable interest in developing medicinal compounds with various specific activities. Novel ammonium salts of pyridoxine, (S)-(-)-nicotine and nicotinamide with O,O-diorganyl dithiophosphoric acids (DTPA) were synthesized and characterized. The complexation of chiral monoterpenyl DTPA, including (S)-(-)-menthyl, (R)-(+)-menthyl, (1R)-endo-(+)-fenchyl, (1S,2S,3S,5R)-(+)-isopinocampheolyl derivatives, with pyridoxine and nicotine provided effective antibacterial compounds 3a,b,e,f, and 5a,b,d,f with MIC values against Gram-positive bacteria as low as 10 µM (6 µg/mL). Two selected pyridoxine and nicotine salts based on menthyl DTPA 3a and 5a were similarly active against antibiotic-resistant bacteria from burn wounds including MRSA. The compounds had enhanced amphiphilic and hemolytic properties and effectively altered surface characteristics and matrix-secreting ability of P. aeroginosa and S. aureus. MBC/MIC ratios of 3a and 5a suggested the bactericidal mode of their action. Furthermore, the compounds exhibited moderate cytotoxicity towards human skin fibroblasts (IC50 = 48.6 and 57.6 µM, respectively, 72 h), encouraging their further investigation as potential antimicrobials against skin and wound infections.


Subject(s)
Anti-Bacterial Agents/pharmacology , Niacinamide/pharmacology , Nicotine/pharmacology , Phosphates/pharmacology , Pyridoxine/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/toxicity , Fibroblasts/drug effects , Gram-Negative Bacteria/drug effects , Hemolysis/drug effects , Humans , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Niacinamide/chemical synthesis , Niacinamide/chemistry , Niacinamide/toxicity , Nicotine/chemical synthesis , Nicotine/chemistry , Nicotine/toxicity , Phosphates/chemical synthesis , Phosphates/chemistry , Phosphates/toxicity , Pyridoxine/chemical synthesis , Pyridoxine/chemistry , Pyridoxine/toxicity , Staphylococcus epidermidis/drug effects
7.
Appl Radiat Isot ; 140: 76-82, 2018 Oct.
Article in English | MEDLINE | ID: mdl-29957537

ABSTRACT

A novel, rapid, and automated loop method for the synthesis of [11C]nicotine was developed and optimized. The method involves, a reaction of the precursor, (+) nornicotine or (-) nornicotine, with a gas-phase produced [11C]CH3I in an 800 µL loop at 75 °C for 5 min followed by a semi-preparatory Reversed-Phase High-Performance Liquid Chromatography (RP-HPLC) purification. The optimized synthesis and purification process was complete in < 30 min and produced [11C]nicotine with > 99.9% Radiochemical Purity (RCP), no [11C]CH3I, no (+) nornicotine, 105 mCi/µmole specific activity, 7.0 - 7.2 pH, and 16.6% ethanol. The current method can be optimized, to reduce the ethanol content (<10%), and can be translated to a cGMP production of [11C]nicotine for human clinical trials.


Subject(s)
Carbon Radioisotopes/chemistry , Nicotine/analogs & derivatives , Radiopharmaceuticals/chemical synthesis , Carbon Radioisotopes/standards , Equipment Design , Ethanol/analysis , Humans , Nicotine/chemical synthesis , Nicotine/chemistry , Quality Control , Radiochemistry/instrumentation , Radiochemistry/methods , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/standards
8.
Nat Chem Biol ; 14(7): 723-729, 2018 07.
Article in English | MEDLINE | ID: mdl-29686358

ABSTRACT

Strategies for expanding the sensor space of designer receptors are urgently needed to tailor cell-based therapies to respond to any type of medically relevant molecules. Here, we describe a universal approach to designing receptor scaffolds that enables antibody-specific molecular input to activate JAK/STAT, MAPK, PLCG or PI3K/Akt signaling rewired to transgene expression driven by synthetic promoters. To demonstrate its scope, we equipped the GEMS (generalized extracellular molecule sensor) platform with antibody fragments targeting a synthetic azo dye, nicotine, a peptide tag and the PSA (prostate-specific antigen) biomarker, thereby covering inputs ranging from small molecules to proteins. These four GEMS devices provided robust signaling and transgene expression with high signal-to-noise ratios in response to their specific ligands. The sensitivity of the nicotine- and PSA-specific GEMS devices matched the clinically relevant concentration ranges, and PSA-specific GEMS were able to detect pathological PSA levels in the serum of patients diagnosed with prostate cancer.


Subject(s)
Biomarkers, Tumor/analysis , Fluorescent Dyes/chemistry , Nicotine/chemistry , Prostate-Specific Antigen/chemistry , Prostatic Neoplasms/diagnostic imaging , Cells, Cultured , Fluorescent Dyes/chemical synthesis , HEK293 Cells , Humans , Male , Nicotine/chemical synthesis , Prostate-Specific Antigen/chemical synthesis
9.
J Org Chem ; 81(22): 11529-11534, 2016 11 18.
Article in English | MEDLINE | ID: mdl-27768301

ABSTRACT

The syntheses of seven novel amido nicotine derivatives 12-18 from (S)-nicotine are presented. (S)-Nicotine and (S)-6-chloronicotine derivatives were cross-coupled with the corresponding amides 6-10 at the C-4 position of the pyridine ring via copper(I)-mediated reactions. Derivatives 16-18 were also obtained via copper(II)-mediated reactions from (S)-nicotine containing a C-4 boronic acid pinacol ester group. The optimization of reaction conditions for both routes provided a useful method for preparing C-4 amide-containing nicotine analogs.


Subject(s)
Amides/chemistry , Copper/chemistry , Nicotine/chemical synthesis , Carbon-13 Magnetic Resonance Spectroscopy , Catalysis , Mass Spectrometry , Nicotine/chemistry , Proton Magnetic Resonance Spectroscopy
10.
J Med Chem ; 59(14): 6671-89, 2016 07 28.
Article in English | MEDLINE | ID: mdl-27433829

ABSTRACT

Over the past decade, first and second generation EGFR inhibitors have significantly improved outcomes for lung cancer patients with activating mutations in EGFR. However, both resistance through a secondary T790M mutation at the gatekeeper residue and dose-limiting toxicities from wild-type (WT) EGFR inhibition ultimately limit the full potential of these therapies to control mutant EGFR-driven tumors and new therapies are urgently needed. Herein, we describe our approach toward the discovery of 47 (EGF816, nazartinib), a novel, covalent mutant-selective EGFR inhibitor with equipotent activity on both oncogenic and T790M-resistant EGFR mutations. Through molecular docking studies we converted a mutant-selective high-throughput screening hit (7) into a number of targeted covalent EGFR inhibitors with equipotent activity across mutants EGFR and good WT-EGFR selectivity. We used an abbreviated in vivo efficacy study for prioritizing compounds with good tolerability and efficacy that ultimately led to the selection of 47 as the clinical candidate.


Subject(s)
Antineoplastic Agents/pharmacology , Benzimidazoles/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Discovery , ErbB Receptors/antagonists & inhibitors , Lung Neoplasms/drug therapy , Nicotine/analogs & derivatives , Protein Kinase Inhibitors/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Carcinoma, Non-Small-Cell Lung/enzymology , Carcinoma, Non-Small-Cell Lung/pathology , Cell Proliferation/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , ErbB Receptors/genetics , ErbB Receptors/metabolism , Humans , Lung Neoplasms/enzymology , Lung Neoplasms/pathology , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Models, Molecular , Molecular Conformation , Mutation , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Nicotine/chemical synthesis , Nicotine/chemistry , Nicotine/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Rats , Rats, Wistar , Structure-Activity Relationship
11.
Bioorg Med Chem Lett ; 26(13): 3195-3201, 2016 07 01.
Article in English | MEDLINE | ID: mdl-27216999

ABSTRACT

In hypoxic-ischemic injury of the brain of neonates, the level of caspase-3 was found to be aberrantly activated. Its overexpression leads to the alteration of cytoskeleton protein fodrin and loss of DNA repair enzyme which ultimately results in neurological impairment and disability. Concerning this, the present study was intended to develop novel nicotine hydrazide analogues as caspase inhibitors via efficient synthetic route. These compounds were subsequently tested for inhibitory activity against caspase-3 and -7 where they exhibit highly potent activity against caspase-3 revealing compound 5k as most potent inhibitor (IC50=19.4±2.5µM). In Western blot analysis, 5k considerably inhibits the overexpression of caspase-3. The aryl nicotinate of compound 5k, as indicated by molecular docking was found to engage His121 and critical enzyme thiols, i.e., Cys163 of caspase-3 for its potent activity. Moreover, histopathological examination of brain tissues and hippocampus neurons showed that compound 5k considerably improves the brain injury and exert neuroprotective effects in hypoxic-ischemic (HI). In brain homogenate, 5k significantly improves the activity of MDA, SOD, GSH-Px, CAT and T-AOC to exert its beneficial effect against oxidative stress induced by HI injury.


Subject(s)
Caspase 3/metabolism , Caspase 7/metabolism , Caspase Inhibitors/pharmacology , Hypoxia-Ischemia, Brain/drug therapy , Neuroprotective Agents/pharmacology , Nicotine/analogs & derivatives , Animals , Caspase Inhibitors/chemical synthesis , Caspase Inhibitors/chemistry , Dose-Response Relationship, Drug , Hypoxia-Ischemia, Brain/metabolism , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Nicotine/chemical synthesis , Nicotine/chemistry , Nicotine/pharmacology , Rats , Structure-Activity Relationship
12.
Bioorg Med Chem Lett ; 26(8): 2077-83, 2016 Apr 15.
Article in English | MEDLINE | ID: mdl-26948540

ABSTRACT

A series of anilinonicotinyl linked pyrazolo[1,5-a]pyrimidine conjugates (6a-x) were synthesized and evaluated for their antiproliferative activity. Some of these conjugates exhibited promising cytotoxic effects in the MCF-7 cell line and among these 6a and 6c exhibited significant effects, apart from G2/M cell cycle arrest. Interestingly they showed profound effects on cyclin D1, Bcl-2 and survivin proteins that regulate breast cancer cell proliferation. Moreover, ER alpha protein expression was studied to understand regulatory role of these conjugates on estrogen activity in estrogen positive breast cancer cells like MCF-7 and compounds 6a and 6c reduced their activity.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Estrogens/metabolism , Nicotine/analogs & derivatives , Pyrimidines/pharmacology , Signal Transduction/drug effects , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , MCF-7 Cells , Molecular Structure , Nicotine/chemical synthesis , Nicotine/chemistry , Nicotine/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship
13.
Eur J Med Chem ; 110: 246-58, 2016 Mar 03.
Article in English | MEDLINE | ID: mdl-26840365

ABSTRACT

As a continuation of previous work on quinoline derivatives, which showed some preference (2-3 times) for the α7 with respect to α4ß2 acetylcholine nicotinic receptors (nAChRs), we synthesized a series of novel azabicyclic or diazabicyclic compounds carrying a quinoline or isoquinoline ring, with the aim of searching for more selective α7 nAChR compounds. Radioligand binding studies on α7* and α4ß2* nAChRs (rat brain homogenate) revealed one compound (7) with a 2-fold higher affinity for the α4ß2*-subtype, and four compounds (11, 13, 14 and 16) with at least 3-fold higher affinity for α7* nAChR. The most promising was 11, showing Ki∼100 nM and over 10-fold selectivity for α7* nAChR. Compounds 7, 11, 13 and 16 at 50 µM suppressed ion currents induced in the rat α4ß2 nAChR and the chimeric nAChR composed of the ligand-binding domain of the chick α7 and transmembrane domain of the α1 glycine receptor, expressed in Xenopus oocytes. Calcium imaging experiments on the human α7 nAChR expressed in the Neuro2a cells and potentiated by PNU-120596 confirmed the antagonistic activity for 7; on the contrary, 11, 13 and 16 were agonists with the EC50 values in the range of 1.0-1.6 µM. Thus, the introduced modifications allowed us to enhance the selectivity of quinolines towards α7 nAChR and to get novel compounds with agonistic activity.


Subject(s)
Quinolines/chemistry , Quinolines/pharmacology , Receptors, Nicotinic/metabolism , alpha7 Nicotinic Acetylcholine Receptor/metabolism , Animals , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacology , Calcium/metabolism , Cell Line, Tumor , Humans , Mice , Molecular Docking Simulation , Nicotine/analogs & derivatives , Nicotine/chemical synthesis , Nicotine/pharmacology , Nicotinic Agonists/chemical synthesis , Nicotinic Agonists/chemistry , Nicotinic Agonists/pharmacology , Nicotinic Antagonists/chemical synthesis , Nicotinic Antagonists/chemistry , Nicotinic Antagonists/pharmacology , Quinolines/chemical synthesis , Rats , Xenopus , alpha7 Nicotinic Acetylcholine Receptor/agonists , alpha7 Nicotinic Acetylcholine Receptor/antagonists & inhibitors
14.
J Am Chem Soc ; 137(1): 90-3, 2015 Jan 14.
Article in English | MEDLINE | ID: mdl-25548865

ABSTRACT

A highly efficient asymmetric hydrogenation of cyclic imines containing a pyridyl moiety was established by using iridium catalysts with chiral spiro phosphine-oxazoline ligands. This process will facilitate the development of new nicotine-related pharmaceuticals. The introduction of a substituent at the ortho position of the pyridyl ring to reduce its coordinating ability ensures the success of the hydrogenation and excellent enantioselectivity.


Subject(s)
Imines/chemistry , Iridium/chemistry , Nicotine/analogs & derivatives , Nicotine/chemical synthesis , Pyridines/chemistry , Catalysis , Hydrogenation , Molecular Structure , Nicotine/chemistry , Stereoisomerism
15.
Org Biomol Chem ; 12(36): 7068-82, 2014 Sep 28.
Article in English | MEDLINE | ID: mdl-25087489

ABSTRACT

A practical one-pot synthesis of nicotine analogs from Ugi 4-CR/propargyl adducts is reported. This methodology allows the rapid construction of the pyrrolidine moiety present in nicotine through an intramolecular base-promoted 5-endo cycloisomerization process, followed by a reduction of the resulting mixture of 2- and 3-pyrrolines to afford nicotine analogs in good overall yields.


Subject(s)
Combinatorial Chemistry Techniques/methods , Nicotine/analogs & derivatives , Nicotine/chemical synthesis , Catalysis , Cyclization , Hydroxybenzoate Ethers/chemistry , Molecular Structure , Nicotine/chemistry , Oxidation-Reduction , Palladium/chemistry , Pargyline/analogs & derivatives , Pargyline/chemistry , Propylamines/chemistry , Pyridines/chemistry , Stereoisomerism
16.
Spectrochim Acta A Mol Biomol Spectrosc ; 128: 773-80, 2014 Jul 15.
Article in English | MEDLINE | ID: mdl-24699296

ABSTRACT

The selenoanalogue of nicotine has been synthesized and characterized by spectroscopic and X-ray diffraction methods. The crystals of selenonicotine are isomorphic with the thionicotine homologue and consist of molecules engaged in columnar π⋯π stacking interactions between antiparallely arranged pyridine moieties. These interactions, absent in other crystals containing nicotine fragments, seem to be induced by the presence of a lactam group. The molecular structures in the vacuum of the oxo-, thio- and selenonicotine homologues have been calculated by the DFT method and compared with the available X-ray data. The delocalized structure of thionicotine is stabilized by intramolecular C-H⋯S hydrogen bond, which becomes weaker in the partial zwitterionic resonance structure of selenonicotine in favor of multiple C-H⋯Se intermolecular hydrogen-bonds. The calculated data allow a complete assignment of vibration modes in the solid state FTIR spectra. The (1)H and (13)C NMR chemical shifts were calculated by the GIAO method with B3LYP/6-311G(3df) level. A comparison between experimental and calculated theoretical results indicates that the density functional B3LYP method provided satisfactory results for predicting FTIR, (1)H, (13)C NMR spectra properties.


Subject(s)
Lactams/chemistry , Lactams/chemical synthesis , Models, Molecular , Nicotine/chemistry , Nicotine/chemical synthesis , Magnetic Resonance Spectroscopy , Molecular Structure , Spectroscopy, Fourier Transform Infrared , X-Ray Diffraction
17.
Bioorg Med Chem Lett ; 24(4): 1104-7, 2014 Feb 15.
Article in English | MEDLINE | ID: mdl-24461290

ABSTRACT

A series of novel salts made of nicotine alkaloids and bile acids were synthesized and their haemolytic activity was examined in vitro using human erythrocytes. All compounds were characterized by spectroscopic methods. The novel salts show membrane-perturbing properties inducing the erythrocyte shape alterations and haemolysis in dose-dependent manner. Nicotine decreases the membrane interacting potential of bile acids in the novel compounds. The presence of sulfur or selenium atom in the nicotine molecule affects the haemolytic activity of its novel salts depending on the hydrophobicity of bile acids.


Subject(s)
Alkaloids/pharmacology , Bile Acids and Salts/pharmacology , Hemolysis/drug effects , Nicotine/pharmacology , Alkaloids/chemical synthesis , Alkaloids/chemistry , Bile Acids and Salts/chemical synthesis , Bile Acids and Salts/chemistry , Dose-Response Relationship, Drug , Erythrocytes/drug effects , Humans , Molecular Structure , Nicotine/chemical synthesis , Nicotine/chemistry , Salts/chemical synthesis , Salts/chemistry , Salts/pharmacology , Structure-Activity Relationship
18.
Yao Xue Xue Bao ; 48(11): 1671-6, 2013 Nov.
Article in Chinese | MEDLINE | ID: mdl-24475704

ABSTRACT

A novel series of bis-nicotine derivatives (3a-3i) were designed, synthesized and evaluated as bivalent anti-Alzheimer's disease agents. The pharmacological results indicated that compounds 3e-3i inhibited both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the micromolar range (IC50, 2.28-117.86 micromol x L(-1) for AChE and 1.67-125 micromol x L(-1) for BChE), which was at the same potency as rivastigmine. A Lineweaver-Burk plot and molecular modeling study showed that these derivatives targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds could significantly inhibit the self-induced Abeta aggregation with inhibition activity (11.85%-62.14%) at the concentration of 20 micromol x L(-1).


Subject(s)
Acetylcholinesterase/metabolism , Amyloid beta-Peptides , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Nicotine/analogs & derivatives , Nicotine/chemical synthesis , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Binding Sites , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Nicotine/chemistry , Nicotine/pharmacology
19.
AAPS PharmSciTech ; 12(2): 683-92, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21594728

ABSTRACT

Nicotine (NCT) buccal tablets consisting of sodium alginate (SA) and nicotine-magnesium aluminum silicate (NCT-MAS) complexes acting as drug carriers were prepared using the direct compression method. The effects of the preparation pH levels of the NCT-MAS complexes and the complex/SA ratios on NCT release, permeation across mucosa, and mucoadhesive properties of the tablets were investigated. The NCT-MAS complex-loaded SA tablets had good physical properties and zero-order release kinetics of NCT, which indicate a swelling/erosion-controlled release mechanism. Measurement of unidirectional NCT release and permeation across porcine esophageal mucosa using a modified USP dissolution apparatus 2 showed that NCT delivery was controlled by the swollen gel matrix of the tablets. This matrix, which controlled drug diffusion, resulted from the molecular interactions of SA and MAS. Tablets containing the NCT-MAS complexes prepared at pH 9 showed remarkably higher NCT permeation rates than those containing the complexes prepared at acidic and neutral pH levels. Larger amounts of SA in the tablets decreased NCT release and permeation rates. Additionally, the presence of SA could enhance the mucoadhesive properties of the tablets. These findings suggest that SA plays the important role not only in controlling release and permeation of NCT but also for enhancing the mucoadhesive properties of the NCT-MAS complex-loaded SA tablets, and these tablets demonstrate a promising buccal delivery system for NCT.


Subject(s)
Alginates/chemical synthesis , Aluminum Compounds/chemical synthesis , Drug Carriers/chemical synthesis , Magnesium Compounds/chemical synthesis , Nicotine/chemical synthesis , Silicates/chemical synthesis , Administration, Buccal , Alginates/administration & dosage , Alginates/pharmacokinetics , Aluminum Compounds/administration & dosage , Aluminum Compounds/pharmacokinetics , Animals , Drug Carriers/administration & dosage , Drug Carriers/pharmacokinetics , Drug Delivery Systems/methods , Drug Delivery Systems/standards , Glucuronic Acid/administration & dosage , Glucuronic Acid/chemical synthesis , Glucuronic Acid/pharmacokinetics , Hexuronic Acids/administration & dosage , Hexuronic Acids/chemical synthesis , Hexuronic Acids/pharmacokinetics , Hydrogen-Ion Concentration , Magnesium Compounds/administration & dosage , Magnesium Compounds/pharmacokinetics , Mouth Mucosa/drug effects , Mouth Mucosa/metabolism , Nicotine/administration & dosage , Nicotine/pharmacokinetics , Silicates/administration & dosage , Silicates/pharmacokinetics , Swine , Tablets
20.
Org Lett ; 12(21): 4760-3, 2010 Nov 05.
Article in English | MEDLINE | ID: mdl-20882970

ABSTRACT

Addition of 5-alkylaminopenta-2,4-dienals onto N-acyliminium ions, generated in situ from α-hydroxycarbamates derived from pyrrolidine or piperidine, in the presence of zinc triflate, followed by dehydrative cyclization, allowed the formation of pyridinium salts substituted at their 3-position by a five- or six-membered nitrogen heterocycle. Subsequent N-dealkylation of the pyridinium moiety and deprotection of the secondary amine or reduction of the carbamate function led to (±)-nicotine and analogs.


Subject(s)
Acrylates/chemistry , Amines/chemistry , Imines/chemistry , Nicotine/chemical synthesis , Piperidines/chemistry , Pyridinium Compounds/chemistry , Pyrrolidines/chemistry , Alkylation , Ions/chemistry , Molecular Structure , Nicotine/analogs & derivatives
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