574-98-1Relevant academic research and scientific papers
Synthesis of lariat diazacrown ethers with terminal amino groups in the side chains
Lukyanenko,Kirichenko,Shcherbakov
, p. 343 - 350 (2004)
Treatment of diazacrown ethers with N-(haloalkyl)- and N-(haloethoxy) phthalimides gives the corresponding N,N′- substituted diazacrown ether. Hydrazinolysis of the latter then gives diazacrown ethers with terminal primary amino groups in the side chain. Their reductive methylation using formaldehyde in formic acid gives the dimethylamino derivatives. The presence of a lariat effect was demonstrated by treating the compounds obtained with picrates of alkali and alkaline-earth metals.
Synthesis and Bioevaluation of Novel [18F]FDG-Conjugated 2-Nitroimidazole Derivatives for Tumor Hypoxia Imaging
Yang, Xianteng,Wang, Fan,Zhu, Hua,Yang, Zhi,Chu, Taiwei
, p. 2118 - 2128 (2019)
Hypoxia imaging can guide tumor treatment and monitor changes in hypoxia during treatment. However, there is still no ideal hypoxia imaging agent for clinical applications. In this study, two novel 2-nitromidazole derivatives were synthesized and directly radiolabeled by [18F]FDG in high radiochemical yield and excellent radiochemical purity. Cell experiments, biodistribution, and positron emission tomography (PET) imaging studies were also conducted in mice-bearing S180 or OS732 tumors. [18F]FDG-2NNC2ON [(2R,3S,4R,E)-2-18F-fluoro-3,4,5,6-tetrahydroxyhexanal O-3-(2-(2-nitro-1H-imidazole-1-yl)ethylamino)-2-oxopropyl oxime] and [18F]FDG-2NNC5ON [(2R,3S,4R,E)-2-18F-fluoro-3,4,5,6-tetrahydroxyhexanal-O-3-(5-(2-nitro-1H-imidazole-1-yl)pentylamino)-2-oxopropyl oxime] can be cleared from the blood quickly and specifically target hypoxic tumor cells. The uptake of the probes by hypoxic cells gradually increases with time. After 4 h, the uptake value of [18F]FDG-2NNC2ON in hypoxic cells is 3.2 times higher than that in normoxia cells. In contrast, there is no difference in the uptake of [18F]FDG between hypoxic cells and normoxia cells. Biodistribution resulting from two tumor models indicate that the uptake values of the two radiotracers in the tumor are higher at 1 h than those at 2 and 4 h. At 1 and 2 h, the tumors are clearly observed on the PET images and the imaging features of [18F]FDG-2NNC5ON and [18F]FDG-2NNC2ON are distinct from those of [18F]FDG. Compared with [18F]FDG-2NNC5ON, [18F]FDG-2NNC2ON has a higher proportion of renal excretion, lower digestive tract uptake, and better imaging contrast because of its higher hydrophilicity. At 2 h, [18F]FDG-2NNC2ON shows a good tumor-to-blood (T/B) ratio, tumor-to-muscle ratio based on biodistribution (Bio-T/M ratio), and tumor-to-muscle ratio based on regions of interest on the PET images [region of interest (ROI)-T/M ratio] in the two tumor models (T/B, Bio-T/M, and ROI-T/M ratios are 3.2, 2.6, and 3.9 in the S180 tumor model and are 3.4, 4.2, and 4.6 in the OS732 tumor model, respectively). The imaging features visualized with autoradiography mostly coincided with the positive areas of HIF1α staining by immunofluorescence. Meanwhile, the biodistribution study and PET imaging revealed that the uptake of the radiotracers in the tumor cannot be competed by 5% glucose, confirming that [18F]FDG-2NNC2ON targets the hypoxic regions of the tumors instead of targeting tumors through the glucose metabolism pathway. These results suggest that the new 2-nitroimidazole derivative conjugated with [18F]FDG, [18F]FDG-2NNC2ON, has potential as an imaging agent for hypoxia.
Lanthanide(iii) complexes of aminoethyl-DO3A as PARACEST contrast agents based on decoordination of the weakly bound amino group
Krchova, Tereza,Kotek, Jan,Jirak, Daniel,Havlickova, Jana,Cisarova, Ivana,Hermann, Petr
, p. 15735 - 15747 (2013)
2-Aminoethyl DOTA analogues with unsubstituted (H3L 1), monomethylated (H3L2) and dimethylated (H3L3) amino groups were prepared by improved synthetic procedures. Their solid-state structures exhibit an extensive system of intramolecular hydrogen bonds, which is probably present in solution and leads to the rather high value of the last dissociation constant. The protonation sequence of H3L1 in solution corresponds to that found in the solid state. The stability constants of the H3L1 complexes with La3+ and Gd3+ (20.02 and 22.23, respectively) are similar to those of DO3A and the reduction of the pK A value of the pendant amino group from 10.51 in the free ligand to 6.06 and 5.83 in the La3+ and Gd3+ complexes, respectively, points to coordination of the amino group. It was confirmed in the solid state structure of the [Yb(L1)] complex, where disorder between the SA′ and TSA′ isomers was found. A similar situation is expected in solution, where a fast equilibration among the isomers hampers the unambiguous determination of the isomer ratio in solution. The PARACEST effect was observed in Eu(iii)-H3L1/H3L2 and Yb(iii)-H3L1/H3L2 complexes, being dependent on pH in the region of 4.5-7.5 and pH-independent in more alkaline solutions. The decrease of the PARACEST effect parallels with the increasing abundance of the complex protonated species, where the pendant amino group is not coordinating. Surprisingly, a small PARACEST effect was also observed in solutions of Eu(iii)/Yb(iii)-H3L3 complexes, where the pendant amino group is dimethylated. The effect is detectable in a narrow pH region, where both protonated and deprotonated complex species are present in equilibrium. The data points to the new mechanism of the PARACEST effect, where the slow coordination-decoordination of the pendant amine is coupled with the fast proton exchange between the free amino group and bulk water mediates the magnetization transfer. The pH-dependence of the effect was proved to be measurable by MRI and, thus, the complexes extend the family of pH-sensitive probes. This journal is The Royal Society of Chemistry 2013.
Study of the structure-bioactivity of fleximers: synthesis, crystal structure, Hirshfeld surface analysis, and anti-inflammatory assays
Singh, Ved Prakash,Dowarah, Jayanta,Marak, Brilliant N.,Sran, Balkaran Singh,Tewari, Ashish Kumar
, (2021/05/05)
Synthesized and natural pyridones/pyridines derivatives exhibiting diverse biological activities. 2-pyridone has lactam-lactim tautomerization like thymine and uracil bases. In this study, COX-2 target based series of pyridone/pyridine linked fleximers were designed, synthesized and studied. All analogues binding affinity with COX-2 active site were studied through molecular docking, and anti-inflammatory activity studied by in vivo analysis. Weak interactions were studied to find binding sites among analogues through crystal packing, Hirshfeld surface analysis and in silico analysis. All the analogues exhibited anti-inflammatory activity, while compound (3) is the most active analogue among the series. In contrast, since compound (3) is a pyridine-phthalimide ring-containing analogue, the presence of a phthalimide group probably favors anti-inflammatory activity over other types of rings. The results suggested further investigations on compounds as anti-inflammatory prodrugs.
Tuning DNA Supramolecular Polymers by the Addition of Small, Functionalized Nucleobase Mimics
Lachance-Brais, Christophe,Hennecker, Christopher D.,Alenaizan, Asem,Luo, Xin,Toader, Violeta,Taing, Monica,Sherrill, C. David,Mittermaier, Anthony K.,Sleiman, Hanadi F.
supporting information, p. 19824 - 19833 (2021/11/30)
Nucleobase mimicking small molecules able to reconfigure DNA are a recently discovered strategy that promises to extend the structural and functional diversity of nucleic acids. However, only simple, unfunctionalized molecules such as cyanuric acid and melamine have so far been used in this approach. In this work, we show that the addition of substituted cyanuric acid molecules can successfully program polyadenine strands to assemble into supramolecular fibers. Unlike conventional DNA nanostructure functionalization, which typically end-labels DNA strands, our approach incorporates functional groups into DNA with high density using small molecules and results in new DNA triple helices coated with alkylamine or alcohol units that grow into micrometer-long fibers. We find that small changes in the small molecule functional group can result in large structural and energetic variation in the overall assembly. A combination of circular dichroism, atomic force microscopy, molecular dynamics simulations, and a new thermodynamic method, transient equilibrium mapping, elucidated the molecular factors behind these large changes. In particular, we identify substantial DNA sugar and phosphate group deformations to accommodate a hydrogen bond between the phosphate and the small-molecule functional groups, as well as a critical chain length of the functional group which switches this interaction from intra- to interfiber. These parameters allow the controlled formation of hierarchical, hybrid DNA assemblies simply through the addition and variation of small, functionalized molecules.
Synthesis of hydroxyethyl methyl morpholinium azide (HEM Morph)N3: A highly efficient new task specific azide-based ionic liquid and its dual application as an azide source and media for synthesis of some novel aromatic O-oxime ethers-1,2,3-triazole conjugates as a potential antihistaminic agents
Rad, Mohammad Navid Soltani,Behrouz, Somayeh,Saremi, Hossein,Mohammadtaghi-Nezhad, Javad
, (2019/12/27)
The synthesis, characterization and application of hydroxyethyl methyl morpholinium azide (HEM Morph)N3 as a new azide-based ionic liquid (ABIL) has been described. (HEM Morph)N3 is used as a source of azide and reaction media for three components ‘Click’ Huisgen cycloaddition reaction between O-propargyl oxime ether and alkyl bromide to acquire novel aromatic O-oxime ethers-1,2,3-triazole conjugates as potential antihistaminic agents in good yields. The influence of parameters like temperature, amount of IL, type of azide-based ionic liquids and its reusability is investigated. The (HEM Morph)N3 is proved to be an efficient, thermally stable, inexpensive and recyclable azide-based ionic liquid which can be easily synthesized and used as both azide's source and reaction media for ‘Click’ Huisgen cycloaddition reaction.
COMPOUND INHIBITING BUTYRYLCHOLINESTERASE
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Page/Page column 9, (2020/07/31)
The invention concerns a compound according to formula (I), wherein 3 n 11, wherein R comprises or consists of a heterocycle comprising one tertiary amino group providing the binding of R to the rest of the molecule and at least three carbon atoms, wherein all carbon atoms of the heterocycle are unsubstituted or wherein R is a fused bicyclic compound comprising the heterocycle and one further cyclic compound.
ω-Quinazolinonylalkyl aryl ureas as reversible inhibitors of monoacylglycerol lipase
Dato, Florian M.,Neud?rfl, J?rg-Martin,Gütschow, Michael,Goldfuss, Bernd,Pietsch, Markus
supporting information, (2019/11/13)
The serine hydrolase monoacylglycerol lipase (MAGL) is involved in a plethora of pathological conditions, in particular pain and inflammation, various types of cancer, metabolic, neurological and cardiovascular disorders, and is therefore a promising target for drug development. Although a large number of irreversible-acting MAGL inhibitors have been discovered over the past years, there are only few compounds known so far which inhibit the enzyme in a reversible manner. Therefore, much effort is put into the development of novel chemical entities showing reversible inhibitory behavior, which is thought to cause less undesired side effects. To explore a wide range of chemical structures as MAGL binders, we have applied a virtual screening approach by docking small molecules into the crystal structure of human MAGL (hMAGL) and envisaged a library of 45 selected compounds which were then synthesized. Biochemical investigations included the determination of the inhibitory potency on hMAGL and two related hydrolases, i.e. human fatty acid amide hydrolase (hFAAH) and murine cholesterol esterase (mCEase). The most promising candidates from theses analyses, i.e. three ω-quinazolinonylalkyl aryl ureas bearing alkyl spacers of three to five methylene groups, exhibited IC50 values of 20–41 μM and reversible, detergent-insensitive behavior towards hMAGL. Among these compounds, the inhibitor 1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)butyl)urea (96) was selected for further kinetic characterization, yielding a dissociation constant Ki = 15.4 μM and a mixed-type inhibition with a pronounced competitive component (α = 8.94). This mode of inhibition was further supported by a docking experiment, which suggested that the inhibitor occupies the substrate binding pocket of hMAGL.
Identification of novel lysine demethylase 5-selective inhibitors by inhibitor-based fragment merging strategy
Miyake, Yuka,Itoh, Yukihiro,Hatanaka, Atsushi,Suzuma, Yoshinori,Suzuki, Miki,Kodama, Hidehiko,Arai, Yoshinobu,Suzuki, Takayoshi
, p. 1119 - 1129 (2019/02/13)
Histone lysine demethylases (KDMs) have drawn much attention as targets of therapeutic agents. KDM5 proteins, which are Fe(II)/α-ketoglutarate-dependent demethylases, are associated with oncogenesis and drug resistance in cancer cells, and KDM5-selective inhibitors are expected to be anticancer drugs. However, few cell-active KDM5 inhibitors have been reported and there is an obvious need to discover more. In this study, we pursued the identification of highly potent and cell-active KDM5-selective inhibitors. Based on the reported KDM5 inhibitors, we designed several compounds by strategically merging two fragments for competitive inhibition with α-ketoglutarate and for KDM5-selective inhibition. Among them, compounds 10 and 13, which have a 3-cyano pyrazolo[1,5-a]pyrimidin-7-one scaffold, exhibited strong KDM5-inhibitory activity and significant KDM5 selectivity. In cellular assays using human lung cancer cell line A549, 10 and 13 increased the levels of trimethylated lysine 4 on histone H3, which is a specific substrate of KDM5s, and induced growth inhibition of A549 cells. These results should provide a basis for the development of cell-active KDM5 inhibitors to highlight the validity of our inhibitor-based fragment merging strategy.
9,10-anthraquinone compound, pharmaceutically-acceptable salts and pharmaceutical application thereof
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Paragraph 0036-0039; 0216; 0218-0220, (2019/10/22)
The invention belongs to the field of pharmaceutical chemistry and relates to a 9,10-anthraquinone compound and a pharmaceutical application thereof, in particular to the 9,10-anthraquinone compound and the application thereof in the preparation of a phosphoglycerate mutase inhibitor and in the preparation of drugs for treating cancer. In particular, the invention discloses the application of the9,10-anthraquinone compound shown in the structure of a formula I, pharmaceutically-acceptable salts thereof, or a pharmaceutical composition taking the 9,10-anthraquinone compound as an effective active ingredient in preparing drugs for preventing and treating tumors. The compound can inhibit phosphoglycerate mutase activity and reduce cell metabolism level, and can be used for treating diseasessuch as solid tumors and blood tumors, and the tumors involved are pancreatic cancer, lung cancer, liver cancer, gastric cancer, esophageal cancer, intestinal cancer, breast cancer, cervical cancer, leukemia and melanoma.
