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Research in Microbiology 2015A novel strain, Pusillimonas sp. T2, which is capable of degrading nicotine, was isolated and identified. This strain could completely degrade 500 mg/L nicotine within...
A novel strain, Pusillimonas sp. T2, which is capable of degrading nicotine, was isolated and identified. This strain could completely degrade 500 mg/L nicotine within 8 h at 30 °C, pH 7.0. Six intermediates were detected and identified as 6-hydroxy-nicotine, 6-hydroxy-N-methylmyosmine, 6-hydroxypseudooxynicotine, 2,6-dihydroxypyridine, 6-hydroxy-3-succinoyl-pyridine and 2,5-dihydroxypyridine. Activities of 6-hydroxy-3-succinoyl-pyridine hydroxylase and 2,6-dihydroxypyridine hydroxylase were demonstrated in the cell extracts of strain T2, indicating that this strain may employ a novel variant of the pyridine and pyrrolidine pathways that is different from those of other species. This study provides the first evidence that Pusillimonas bacteria participate in nicotine degradation.
Topics: Base Sequence; Betaproteobacteria; Biodegradation, Environmental; China; Mixed Function Oxygenases; Nicotine; Phylogeny; Pyridines; Pyrrolidines; Sewage; Succinates
PubMed: 25546833
DOI: 10.1016/j.resmic.2014.12.009 -
Molecules (Basel, Switzerland) Mar 2023While platinum-based compounds such as cisplatin form the backbone of chemotherapy, the use of these compounds is limited by resistance and toxicity, driving the...
While platinum-based compounds such as cisplatin form the backbone of chemotherapy, the use of these compounds is limited by resistance and toxicity, driving the development of novel complexes with cytostatic properties. In this study, we synthesized a set of half-sandwich complexes of platinum-group metal ions (Ru(II), Os(II), Ir(III) and Rh(III)) with an N,N-bidentate ligand comprising a -glucosaminyl group and a heterocycle, such as pyridine, pyridazine, pyrimidine, pyrazine or quinoline. The sugar-containing ligands themselves are unknown compounds and were obtained by nucleophilic additions of lithiated heterocycles to -perbenzylated 2-nitro-glucal. Reduction of the adducts and, where necessary, subsequent protecting group manipulations furnished the above -glucosaminyl heterocycles in their -perbenzylated, -perbenzoylated and -unprotected forms. The derived complexes were tested on A2780 ovarian cancer cells. Pyridine, pyrazine and pyridazine-containing complexes proved to be cytostatic and cytotoxic on A2780 cells, while pyrimidine and quinoline derivatives were inactive. The best complexes contained pyridine as the heterocycle. The metal ion with polyhapto arene/arenyl moiety also impacted on the biological activity of the complexes. Ruthenium complexes with -cymene and iridium complexes with Cp* had the best performance in ovarian cancer cells, followed by osmium complexes with -cymene and rhodium complexes with Cp*. Finally, the chemical nature of the protective groups on the hydroxyl groups of the carbohydrate moiety were also key determinants of bioactivity; in particular, -benzyl groups were superior to -benzoyl groups. The IC values of the complexes were in the low micromolar range, and, importantly, the complexes were less active against primary, untransformed human dermal fibroblasts; however, the anticipated therapeutic window is narrow. The bioactive complexes exerted cytostasis on a set of carcinomas such as cell models of glioblastoma, as well as breast and pancreatic cancers. Furthermore, the same complexes exhibited bacteriostatic properties against multiresistant Gram-positive and clinical isolates in the low micromolar range.
Topics: Humans; Female; Coordination Complexes; Cytostatic Agents; Cell Line, Tumor; Ovarian Neoplasms; Antineoplastic Agents; Metals; Azo Compounds; Quinolines; Pyridines; Anti-Infective Agents; Ruthenium
PubMed: 37049820
DOI: 10.3390/molecules28073058 -
Bioorganic Chemistry Nov 2022The imidazo[1,2-a]pyridine-3-carboxyamides (IAPs) are a unique class of compounds endowed with impressive nanomolar in vitro potency against Mycobacterium tuberculosis...
The imidazo[1,2-a]pyridine-3-carboxyamides (IAPs) are a unique class of compounds endowed with impressive nanomolar in vitro potency against Mycobacterium tuberculosis (Mtb) as exemplified by clinical candidate Telacebec (Q203). These compounds target mycobacterial respiration through inhibition of the QcrB subunit of cytochrome bc1:aa super complex resulting in bacteriostatic efficacy in vivo. Our labs have had a long-standing interest in the design and development of IAPs. However, some of these compounds suffer from short in vivo half-lives, requiring multiple daily dosing or the addition of a cytochrome P450 inhibitor for murine efficacy evaluations. Deuteration has been shown to decrease metabolism as the C-D bond is stronger than the CH bond. Herein we describe our efforts on design and synthesis of potent deuterated IAPs and the effect that deuteration has upon metabolism through microsomal stability studies.
Topics: Animals; Antitubercular Agents; Humans; Mice; Mycobacterium tuberculosis; Pyridines; Tuberculosis
PubMed: 35987188
DOI: 10.1016/j.bioorg.2022.106074 -
Molecules (Basel, Switzerland) Sep 2023Two series of pyrazolo[3,4-]pyridine derivatives, - and -, are synthesized and evaluated for their anti-cancer potency towards Hela, MCF7, and HCT-116 cancer cell lines....
Synthesis and In Vitro Anticancer Activity of Novel 4-Aryl-3-(4-methoxyphenyl)-1-phenyl-1-pyrazolo[3,4-]pyridines Arrest Cell Cycle and Induce Cell Apoptosis by Inhibiting CDK2 and/or CDK9.
Two series of pyrazolo[3,4-]pyridine derivatives, - and -, are synthesized and evaluated for their anti-cancer potency towards Hela, MCF7, and HCT-116 cancer cell lines. Compound showed the highest anticancer activity with IC = 2.59 µM against Hela when compared with doxorubicin (IC = 2.35 µM). Compound revealed cytotoxicity IC = 4.66 and 1.98 µM towards MCF7 and HCT-116 compared to doxorubicin with IC = 4.57 and 2.11 µM, respectively. Compound exhibited cell cycle arrest at the S phase for Hela, whereas revealed an arresting cell cycle for MCF7 at G2/M phase and an arresting cell cycle at S phase in HCT-116. In addition, induced a significant level of early and late apoptosis in Hela when compared with the control cells, whereas induced an apoptosis in MCF7 and HCT-116, respectively. Compounds (IC = 26.44 ± 3.23 µM) and (IC = 21.81 ± 2.96 µM) showed good safety profiles on normal cell line WI-38. Compounds and showed good inhibition activity towards CDK2, with IC = 1.630 ± 0.009 and 0.460 ± 0.024 µM, respectively, when compared with ribociclib (IC = 0.068 ± 0.004). Furthermore, and showed inhibitory activity towards CDK9 with IC = 0.262 ± 0.013 and 0.801 ± 0.041 µM, respectively, related to IC of ribociclib = 0.050 ± 0.003. Docking study for and exhibited good fitting in the CDK2 and CDK9 active sites.
Topics: Cell Cycle; Cell Division; Pyridines; Analgesics, Opioid; Apoptosis
PubMed: 37687256
DOI: 10.3390/molecules28176428 -
Inorganic Chemistry Jun 2022As an element-equivalent theranostic pair, lead-203 (Pb, 100% EC, half-life = 51.92 h) and lead-212 (Pb, 100% β, half-life = 10.64 h), through the emission of γ rays...
As an element-equivalent theranostic pair, lead-203 (Pb, 100% EC, half-life = 51.92 h) and lead-212 (Pb, 100% β, half-life = 10.64 h), through the emission of γ rays and an α particle in its decay chain, respectively, can aid in the development of personalized targeted radionuclide treatment for advanced and currently untreatable cancers. With these isotopes currently being used in clinical trials, an understanding of the relationship between the chelator structure, ability to incorporate the radiometal, and metal-complex stability is needed to help design appropriate chelators for clinical use. Herein, we report an investigation into the effect of ring size in macrocyclic chelators where pyridine, an intermediate Lewis base, acts as an electron donor toward lead. Crown-4Py (4,7,13,16-tetrakis(pyridin-2-ylmethyl)-1,10-dioxa-4,7,13,16-tetraazacyclooctadecane), cyclen-4Py (1,4,7,10-tetrakis(pyridin-2-ylmethyl)-1,4,7,10-tetraazacyclododecane), and NOON-2Py (7,16-bis(pyridin-2-ylmethyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane) were synthesized and analyzed for their ability to coordinate Pb. Metal complex stability was investigated via [Pb]Pb radiolabeling studies, H NMR spectroscopy, X-ray crystallography, and potentiometry. With the smallest macrocyclic backbone, cyclen-4Py had the highest radiochemical yield, while, in descending order, crown-4Py and NOON-2Py had the lowest. Thermodynamic stability constants (log ) of 19.95(3), 13.29(5), and 11.67 for [Pb(Cyclen-4Py)], [Pb(Crown-4Py)], and [Pb(NOON-2Py)], respectively, correlated with their radiochemical yields. The X-ray crystal structure of the least stable complexes [Pb(NOON-2Py)] revealed a hemidirected Pb center, as reflected by a void within the coordination sphere, and [Pb(Crown-4Py)] showed an average Pb-N pyridine interatomic distance of >3 Å. By contrast, the crystal structure of [Pb(Cyclen-4Py)] showed shorter Pb-N pyridine interactions, and in solution, only one highly symmetric isomer existed for this complex, whereas conformational flexibility was observed for both [Pb(Crown-4Py)] and [Pb(NOON-2Py)] at the NMR timescale. This study illustrates the importance of the macrocyclic backbone size when incorporating bulky electron-donor groups into the design of a macrocyclic chelator as it affects the accessibility of lead to the donor arms. Our results show that cyclen-4Py is a promising chelator for future studies with this theranostic pair.
Topics: Chelating Agents; Coordination Complexes; Crystallography, X-Ray; Cyclams; Lead; Ligands; Pyridines
PubMed: 35704752
DOI: 10.1021/acs.inorgchem.2c01114 -
Molecules (Basel, Switzerland) Nov 2022The synthesis of the products of the 1,3-propanesultone ring opening during its interaction with amides of pyridinecarboxylic acids has been carried out. The dependence...
The synthesis of the products of the 1,3-propanesultone ring opening during its interaction with amides of pyridinecarboxylic acids has been carried out. The dependence of the yield of the reaction products on the position (-, -, -) of the substituent in the heteroaromatic fragment and temperature condition was revealed. In contrast to the - and -substituted substrates, the reaction involving -derivatives at the boiling point of methanol unexpectedly led to the formation of a salt. On the basis of spectroscopic, X-Ray, and quantum-chemical calculation data, a model of the transition-state, as well as a mechanism for this alkylation reaction of pyridine carboxamides with sultone were proposed in order to explain the higher yields obtained with the nicotinamide and its -methyl analog compared to or parents. Based on the analysis of ESP maps, the positions of the binding sites of reagents with a potential complexing agent in space were determined. The in silico evaluation of possible biological activity showed that the synthetized compounds revealed some promising pharmacological effects and low acute toxicity.
Topics: Pyridines; Amides; Betaine; Alkylation
PubMed: 36364369
DOI: 10.3390/molecules27217542 -
International Journal of Molecular... Apr 2023About twenty molecules sharing 1-chromeno[3,2-]pyridine as the scaffold and differing in the degree of saturation of the pyridine ring, oxidation at C10, 1-phenylethynyl...
About twenty molecules sharing 1-chromeno[3,2-]pyridine as the scaffold and differing in the degree of saturation of the pyridine ring, oxidation at C10, 1-phenylethynyl at C1 and 1-indol-3-yl fragments at C10, as well as a few small substituents at C6 and C8, were synthesized starting from 1,2,3,4-tetrahydro-2-methylchromeno[3,2-]pyridin-10-ones (1,2,3,4-THCP-10-ones, ) or 2,3-dihydro-2-methyl-1-chromeno[3,2-]pyridines (2,3-DHPCs, ). The newly synthesized compounds were tested as inhibitors of the human isoforms of monoamine oxidase (MAO A and B) and cholinesterase (AChE and BChE), and the following main SARs were inferred: (i) The 2,3-DHCP derivatives inhibit MAO A (IC about 1 μM) preferentially; (ii) the 1,2,3,4-THCP-10-one , bearing the phenylethynyl fragment at C1, returned as a potent MAO B inhibitor (IC 0.51 μM) and moderate inhibitor of both ChEs (ICs 7-8 μM); (iii) the 1-indol-3-yl fragment at C10 slightly increases the MAO B inhibition potency, with the analog achieving MAO B IC of 3.51 μM. The MAO B inhibitor deserves further pharmacological studies as a remedy in the symptomatic treatment of Parkinson's disease and neuroprotectant for Alzheimer's disease. Besides the established neuroprotective effects of MAO inhibitors, the role of MAOs in tumor insurgence and progression has been recently reported. Herein, antiproliferative assays with breast (MCF-7), colon (HCT116) and cisplatin-resistant ovarian (SK-OV-3) tumor cells revealed that the 10-indolyl-bearing 2,3,4,10-THCP analog exerts anti-tumor activity with ICs in the range 4.83-11.3 μM.
Topics: Humans; Monoamine Oxidase Inhibitors; Structure-Activity Relationship; Monoamine Oxidase; Pyridines; Cholinesterase Inhibitors
PubMed: 37175433
DOI: 10.3390/ijms24097724 -
Journal of Molecular and Cellular... Dec 2019Voltage-gated potassium (Kv) channels control myocardial repolarization. Pore-forming Kvα proteins associate with intracellular Kvβ subunits, which bind pyridine...
Voltage-gated potassium (Kv) channels control myocardial repolarization. Pore-forming Kvα proteins associate with intracellular Kvβ subunits, which bind pyridine nucleotides with high affinity and differentially regulate channel trafficking, plasmalemmal localization and gating properties. Nevertheless, it is unclear how Kvβ subunits regulate myocardial K currents and repolarization. Here, we tested the hypothesis that Kvβ2 subunits regulate the expression of myocardial Kv channels and confer redox sensitivity to Kv current and cardiac repolarization. Co-immunoprecipitation and in situ proximity ligation showed that in cardiac myocytes, Kvβ2 interacts with Kv1.4, Kv1.5, Kv4.2, and Kv4.3. Cardiac myocytes from mice lacking Kcnab2 (Kvβ2) had smaller cross sectional areas, reduced sarcolemmal abundance of Kvα binding partners, reduced I, I, and I densities, and prolonged action potential duration compared with myocytes from wild type mice. These differences in Kvβ2 mice were associated with greater P wave duration and QT interval in electrocardiograms, and lower ejection fraction, fractional shortening, and left ventricular mass in echocardiographic and morphological assessments. Direct intracellular dialysis with a high NAD(P)H:NAD(P) accelerated Kv inactivation in wild type, but not Kvβ2 myocytes. Furthermore, elevated extracellular levels of lactate increased [NADH] and prolonged action potential duration in wild type cardiac myocytes and perfused wild type, but not Kvβ2, hearts. Taken together, these results suggest that Kvβ2 regulates myocardial electrical activity by supporting the functional expression of proteins that generate I and I, and imparting redox and metabolic sensitivity to Kv channels, thereby coupling cardiac repolarization to myocyte metabolism.
Topics: Action Potentials; Animals; Heart Function Tests; Ion Channel Gating; Lactic Acid; Mice; Mice, Inbred C57BL; Myocardium; Myocytes, Cardiac; Nucleotides; Oxidation-Reduction; Protein Subunits; Pyridines; Shaker Superfamily of Potassium Channels; Shal Potassium Channels
PubMed: 31639389
DOI: 10.1016/j.yjmcc.2019.09.013 -
Bioorganic & Medicinal Chemistry Dec 2020CADA compounds selectively down-modulate human cell-surface CD4 protein and are of interest as HIV entry inhibitors and as drugs for asthma, rheumatoid arthritis,...
CADA compounds selectively down-modulate human cell-surface CD4 protein and are of interest as HIV entry inhibitors and as drugs for asthma, rheumatoid arthritis, diabetes and some cancers. Postulating that fusing a pyridine ring bearing hydrophobic substituents into the macrocyclic scaffold of CADA compounds may lead to potent compounds with improved properties, 17 macrocycles were synthesized, 14 with 12-membered rings having an isobutylene head group, two arenesulfonyl side arms, and fused pyridine rings bearing a para substituent. The analogs display a wide range of CD4 down-modulating and anti-HIV potencies, including some with greater potency than CADA, proving that a highly basic nitrogen atom in the 12-membered ring is not required for potency and that hydrophobic substituents enhance potency of pyridine-fused CADA compounds. Cytotoxicities of the new compounds compared favorably with those of CADA, showing that incorporation of a pyridine ring into the macrocyclic scaffold can produce selective compounds for potently down-modulating proteins of medicinal interest.
Topics: Animals; Anti-HIV Agents; CD4 Antigens; CHO Cells; Cell Line; Cell Survival; Cricetinae; Cricetulus; Down-Regulation; HIV-1; Heterocyclic Compounds; Humans; Pyridines; Solubility; Structure-Activity Relationship; Sulfonamides; Thermodynamics; Virus Replication
PubMed: 33181479
DOI: 10.1016/j.bmc.2020.115816 -
Journal of the American Chemical Society Aug 2021The direct position-selective C-4 alkylation of pyridines has been a long-standing challenge in heterocyclic chemistry, particularly from pyridine itself. Historically...
The direct position-selective C-4 alkylation of pyridines has been a long-standing challenge in heterocyclic chemistry, particularly from pyridine itself. Historically this has been addressed using prefunctionalized materials to avoid overalkylation and mixtures of regioisomers. This study reports the invention of a simple maleate-derived blocking group for pyridines that enables exquisite control for Minisci-type decarboxylative alkylation at C-4 that allows for inexpensive access to these valuable building blocks. The method is employed on a variety of different pyridines and carboxylic acid alkyl donors, is operationally simple and scalable, and is applied to access known structures in a rapid and inexpensive fashion. Finally, this work points to an interesting strategic departure for the use of Minisci chemistry at the earliest possible stage (native pyridine) rather than current dogma that almost exclusively employs Minisci chemistry as a late-stage functionalization technique.
Topics: Alkylation; Carboxylic Acids; Molecular Structure; Pyridines; Stereoisomerism
PubMed: 34318659
DOI: 10.1021/jacs.1c05278