Probing BRD Inhibition Substituent Effects in Bulky Analogues of (+)-JQ1

A series of bulky organometallic and organic analogues of the bromodomain (BRD) inhibitor (+)-JQ1 have been prepared. The most potent, N-[(adamantan-1-yl)methyl]-2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide, 2e , showed excellent potency with an K_D=ca. 130 nm vs. BRD4(1) and a ca. 2-fold selectivity over BRD4(2) (K_D=ca. 260 nm ). Its binding to the first bromodomain of BRD4 was determined by a protein cocrystal structure.     

Synthesis,structure, ADME and biological activity of three 2,6-disubstituted thiosemicarbazone derivatives

Three new 2,6-disubstituted thiosemicarbazone derivatives of pyridine, namely, 2-{amino[6-(pyrrolidin-1-yl)pyridin-2-yl]methylidene}-N,N-dimethylhydrazine-1-carbothioamide, C₁₃H₂₀N₆S, 2-{amino[6-(piperidin-1-yl)pyridin-2-yl]methylidene}-N,N-dimethylhydrazine-1-carbothioamide, C₁₄H₂₂N₆S, and 2-[amino(6-phenoxypyridin-2-yl)methylidene]-N,N-dimethylhydrazine-1-carbothioamide monohydrate, C₁₅H₁₇N₅OS·H₂O, have been synthesized and characterized by NMR spectroscopy and low-temperature single-crystal X-ray diffraction. In addition, their antibacterial and anti-yeast activities have been determined. The ability of the tested compounds to inhibit bacterial growth was comparable to vancomycin as a reference drug. Compared to isoniazid (MIC 0.125 and 8 µg ml⁻¹), the compounds showed the ability to inhibit the growth of Mycobacterium tuberculosis to a moderate degree for the standard strain and at the same level or higher (MIC 4–8 µg ml⁻¹) for the resistant strain. All three compounds adopt the zwitterionic form in the crystal structure regardless of the presence or absence of solvent molecules.     

Synthesis and debenzoylation products of two perbenzoylated 2-substituted 5-D-galactosyl-1,3,4-oxadiazoles

The synthesis of 2-(p-chlorophenyl)-5-[1′,2′,3′,4′,5′-penta-O-benzoyl-D-galactopentitol-1-yl]-1,3,4-oxadiazole is described. Its debenzoylation gave an equilibrium mixture of the 1,3,4-oxadiazole derivative without protection of the hydroxyl group and the N-benzoyl-D-galactono-1,4-lactonehydrazone. A similar equilibrium was observed by debenzoylation of 2-phenyl-5-[1′,2′,3′,4′,5′-penta-O-benzoyl-D-galactopentitol-1-yl]-1,3,4-oxadiazole. The ¹H, ¹³C nmr and ms spectra of these compounds are presented.     

Click synthesis of N1-(β-D-ribofuranosyl)-C4-(coumarin-4″-yl)-1,2,3-triazoles

A series of eight N¹-(β-D-ribofuranosyl)-C⁴-(coumarin-4′′-yl)-1,2,3-triazoles have been synthesized by Cu(I)-catalyzed click reaction of 1-azido-1-deoxy-2,3,5-tri-O-benzoyl-β-D-ribofuranose with differently substituted 4-ethynylcoumarins followed by debenzoylation of the resulted N¹-(2′,3′,5′-tri-O-benzoyl-β-D-ribofuranosyl)-C⁴-(coumarin-4″-yl)-1,2,3-triazoles in 71 to 89% overall yields. The structures of all the synthesized compounds were established on the basis of their spectral data analysis that was further confirmed by X-ray data analysis of one of the model benzoylated compounds, i.e. N¹-(2′,3′,5′-tri-O-benzoyl-β-D-ribofuranosyl)-C⁴-(7″-isopropoxycoumarin-4″-yl)-1,2,3-triazole.     

Crystallographic study and molecular modeling on the oxidation product of <Emphasis Type="Italic">N</Emphasis>-[(8<Emphasis Type="Italic">R</Emphasis>)-2-methoxy-5,6,7,8,9,10-hexahydro-6,9-methanocyclohepta[<Emphasis Type="Italic">b</Emphasis>]indol-8-yl]acetamide

Crystallization of N-[(8R)-2-methoxy-5,6,7,8,9,10-hexahydro-6,9-methanocyclohepta[b]indol-8-yl]acetamide was accompanied by oxidation at the C^5a–C^10a bond with formation of N-[(5S)-10-methoxy-2,8-dioxo-1,2,3,4,5,6,7,8-octahydro-3,6-methano-1-benzazecin-5-yl]acetamide whose structure was determined by X-ray analysis. Docking of this compound into melatonin-binding pocket of MT_1A receptor was simulated by computer-assisted molecular modeling.     

Lanthanide Complexes of Polyacid Ligands derived from 2, 6-bis(pyrazol-1-yl)pyridine,pyrazine, and 6, 6′-bis(pyrazol-1-yl)-2, 2′-bipyridine: Synthesis and luminescence properties

The synthesis of three novel pyrazole-containing complexing acids, N,N,N′,N′-{2, 6-bis[3-(aminomethyl)pyrazol-1-yl]-4-methoxypyridine}tetrakis(acetic acid)( 1 ), N,N,N′,N′-{2, 6-bis[3-(aminomethyl)pyrazol-1-yl]pyrazine}-tetrakis(acetic acid) ( 2 ), and N,N,N′,N′-{6, 6′-bis[3-(aminomethyl)pyrazol-1-yl]-2, 2′-bipyridine}tetrakis(acetic acid) ( 3 ) is described. Ligands 1–3 formed stable complexes with Eu^III, Tb^III, Sm^III, and Dy^III in H₂O whose relative luminescence yields, triplet-state energies, and emission decay lifetimes were measured. The number of H₂O molecules in the first coordination sphere of the lanthanide ion were also determined. Comparison of data from the Eu^III and Tb^III complexes of 1–3 and those of the parent trisheterocycle N,N,N′,N′-{2, 6-bis[3-(aminomethyl)pyrazol-l-yl]pyridine}tetrakis(acetic acid) showed that the modification of the pyridine ring for pyrazine or 2, 2′-bipyridine strongly modify the luminescence properties of the complexes. MeO Substitution at C(4) of 1 maintain the excellent properties described for the parent compound and give an additional functional group that will serve for attaching the label to biomolecules in bioaffinity applications.     

Vinyltetrazoles: II. Synthesis of 5-substituted 1(2)-vinyltetrazoles

5-R-Substituted 1(2)-vinyltetrazoles (R = Ar, Alk, CH₂=CH, NH₂, H) were synthesized by alkylation of 5-R-tetrazoles with 1,2-dibromoethane in the presence of triethylamine in acetonitrile, followed by elimination of triethylamine hydrobromide. Vinylation of dinuclear substrates, such as bis(1H-tetrazol-5-yl)-methane and 1,3-bis(1H-tetrazol-5-yl)benzene, under analogous conditions gave the corresponding N ¹,N ^2′- and N ²,N ^2′-divinyl derivatives.     

Synthesis of some benzimidazole- and benzothiazole-derived ligand systems and their precursory diacids

Procedures are described for the preparation of various bidentate and linear tetradentate benzimidazoles and benzothiazoles incorporating units such as pyridyl and thioether, and for the preparation of certain thioether dicarboxylic acids precursory to them. Condensations of ortho-functinal anilines with carboxylic acids were carried out in polyphosphoric acid or refluxing HCl solution. Syntheses are reported for: [HO₂C(CH₂)2S(CH₂)₂]₂X (X = O, S), 1,9-bis(benzimidazol-2-yl)-2,5,8-trithianonane, 1,11-bis(N-methylbenzimidazol-2-yl)-3,6,9-trithiaundecane, 1,11-bis(2-benzimidazol-2-yl)-6-oxo-3,9-dithiaundecane, 2-(2-pyridyl)benzothiazole, 2,6-bis(benzothiazol-2-yl)pyridine, 2-(2-pyridyl)-N-methylbenzimidazole, 2-(2-pyridylmethyl)benzimidazole and 2-(N-methyl-2-piperidyl)benzimidazole. The compounds were characterized, where appropriate, by their mass, uv and ¹H-nmr spectra.     

Reactions of <Emphasis Type="Italic">N</Emphasis>-and <Emphasis Type="Italic">C</Emphasis>-Alkenylanilines: VII. Synthesis of Indole Heterocycles from Products of Reaction between <Emphasis Type="Italic">N</Emphasis>-Mesyl-2-(1-alken-1-yl)anilines and Halogens

N-Mesyl-2-(1-methyl-1-butenyl)-6-methylaniline reacted with Br₂ to afford N-mesyl-2-(3-bromo-1-penten-2-yl)aniline that under treatment with NH₃ or amines underwent cyclization into N-mesyl-7-methyl-3-methylene-2-ethylindoline. The reaction of N-mesyl-2-(1-methyl-1-buten-1-yl)-4-methyl- and 2-(1-methyl-1-buten-1-yl)aniline with Br₂ gave rise to the corresponding N-mesyl-2-(2-bromo-1-methyl-1-buten-1-yl)anilines. Under the similar conditions N-tosyl-2-(1-cyclohexen-1-yl)aniline was converted into N-tosyl-2-(6-bromo-1-cyclohexen-1-yl)aniline that under treatment with NH₃ furnished N-tosyl-1,2,3,9a-tetrahydrocarbazole. The reaction of N-mesyl-1,2,3,9a-tetrahydrocarbazole with CuBr₂ in MeOH afforded N-mesyl-4-methoxy-1,2,3,4-tetrahydrocarbazole. N-Mesyl-6-methyl-2-(1-cyclopenten-1-yl)aniline in reaction with Br₂ in the presence of NaHCO₃ was oxidized into the corresponding cyclopentenone, and with NBS it gave N-mesyl-2-(2-bromo-1-cyclopenten-1-yl)aniline.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 5, 2005, pp. 730–737.Original Russian Text Copyright © 2005 by Gataullin, Sotnikov, Spirikhin, Abdrakhmanov.     

基于杯[4]芳烃和S-联萘酚的荧光传感器的合成及其对N-Boc保护谷氨酸阴离子的对应选择性识别性能研究

合成了一种基于杯[4]芳烃和S-联萘酚单元的新型手性大环受体4,并用荧光光谱和核磁氢谱研究了该受体与阴离子的键合性质。非线性曲线拟合结果表明受体4与N-Boc保护L-和D-谷氨酸阴离子都能通过多重氢键形成1:1的络合物,而且对N-Boc保护谷氨酸阴离子对映体显示了较好的对应选择性识别性能（Kass(L) / Kass(D) = 4.65）。不同的荧光响应表明受体4可以用作N-Boc保护谷氨酸阴离子的对应选择性的荧光化学传感器。     

Synthesis and biological evaluation of 3-{[4-(4-[18F]fluorophenyl)methyl] piperazin-1-yl}-methyl-1H-pyrrolo[2,3-b]pyridine for in vivo studies of dopamine D4 receptor

The compound 3-{[4-(4-[¹⁸F]fluorophenyl)methyl]piperazin-1-yl}-methyl-1H-pyrrolo[2,3-b]pyridine ([¹⁸F]3), which is an analogue of L-745,870 binding D₄ This revised version was published online in July 2006 with corrections to the Cover Date.     

Synthesis and biological evaluation of 5-methyl-4-phenyl thiazole derivatives as anticancer agents

Abstract

New N-(5-methyl-4-phenylthiazol-2-yl)-2-(substituted thio)acetamides were synthesized and studied for their anticancer activity. The title compounds were procured by reacting 2-chloro-N-(5-methyl-4-phenylthiazol-2-yl)acetamide with some mercapto derivatives. The structural elucidation of the compounds was performed by ¹H-NMR, ¹³C-NMR and LC-MS/MS spectral data and elemental analyses. The synthesized compounds were investigated for their antitumor activities against A549 human lung adenocarcinoma cells and NIH/3T3 mouse embryoblast cell line for determining their selective cytotoxicity. 2-[(1-methyl-1H-tetrazol-5-yl)thio]-N-(5-methyl-4-phenylthiazol-2-yl)acetamide (4c) showed high selectivity, and whose IC₅₀ value was determined as 23.30?±?0.35?µM and >1000?µM against A549 human lung adenocarcinoma cells and NIH/3T3 mouse embryoblast cell lines, respectively. 2-[(1-Methyl-1H-imidazol-2-yl)thio]-N-(5-methyl-4-phenyl thiazol-2-yl)acetamide (4a) and 2-[(1-Methyl-1H-tetrazol-5-yl)thio]-N-(5-methyl-4-phenyl thiazol-2-yl)acetamide (4c) exhibited the highest apoptosis percentage among those tested, but not as high as the standard, cisplatin.     

Synthesis,crystal structure and fluorescence of a two-dimensional coordination polymer with 1-(pyrazin-2-yl)pyridine-2(1H)-one and thiocyanate as mixed bridge ligands

A two-dimensional sheet coordination polymer, [Cd(μ-C₉H₇N₃O)(μ-NCS)₂] _n , (C₉H₇N₃O=1-(pyrazin-2-yl)pyridin-2(1H)-one), has been synthesized with 1-(pyrazin-2-yl)pyridin-2(1H)-one and thiocyanate anion as bridging ligands, and its crystal structure determined by X-ray crystallography. The crystal belongs to monoclinic system with space group P2₁ /c, and its relevant crystal parameters are: a?=?7.5392(16) Å, b?=?18.343(4) Å, c?=?10.155(2) Å, β?=?106.362(3)°, Z?=?4, V?=?1347.4(5) ų, C₁₁H₇CdN₅OS₂, D _Calcd?=?1.980, R?=?0.0516. The crystal structure reveals that both 1-(pyrazin-2-yl)pyridin-2(1H)-one and thiocyanate anion connect adjacent Cd(II) ions resulting in a two-dimensional sheet structure in the bc plane. There are weak π–π stacking interactions between adjacent pyridine rings. The coordination polymer has weaker fluorescent emission in the solid state than 1-(pyrazin-2-yl)pyridin-2(1H)-one compound, attributed to the π–π stacking interaction and the coordination effect.     

Vinylene-Linked Covalent Organic Frameworks (COFs) with Symmetry-Tuned Polarity and Photocatalytic Activity

The polarity of a semiconducting molecule affects its intrinsic photophysical properties, which can be tuned by varying the molecular geometry. Herein, we developed a D_3h-symmetric tricyanomesitylene as a new monomer which could be reticulated into a vinylene-linked covalent organic framework (g-C₅₄N₆-COF) via Knoevenagel condensation with another D_3h-symmetric monomer 2,4,6-tris(4′-formyl-biphenyl-4-yl)-1,3,5-triazine. Replacing tricyanomesitylene with a C_2v-symmetric 3,5-dicyano-2,4,6-trimethylpyridine gave a less-symmetric vinylene-linked COF (g-C₅₂N₆-COF). The octupolar conjugated characters of g-C₅₄N₆-COF were reflected in its scarce solvatochromic effects either in ground or excited states, and endowed it with more promising semiconducting behavior as compared with g-C₅₂N₆-COF, such as enhanced light-harvesting and excellent photo-induced charge generation and separation. Along with the matched energy level, g-C₅₄N₆-COF enabled the two-half reactions of photocatalytic water splitting with an average O₂ evolution rate of 51.0 μmol h⁻¹ g⁻¹ and H₂ evolution rate of 2518.9 μmol h⁻¹ g⁻¹. Such values are among the highest of state-of-the-art COF photocatalysts.     

Kinetics,catalysis, and mechanism of isomerization of N-[(benzotriazol-1-yl)methyl]anilines into the benzotriazol-2-yl derivatives

The ¹H NMR technique was applied for the measurement of the isomerization rates of N-ethyl-N-[(benzotriazol-1-yl)methyl]aniline ( 4 ) and 4-butyl-N-[(benzotriazol-1-yl)methyl]aniline ( 7 ) to the corresponding benzotriazol-2-yl isomers in dioxane-d₈ at 35°C. The rate constants obtained for pure dioxane-d₈ were 1.62 and 0.28 h^?1 for 4 and 7 , respectively. For both compounds, addition to acetic acid to the dioxane solutions accelerated the isomerizations whereas addition of triethylamine retarded it strongly. Addition of water slowed the isomerization of 4 but accelerated that of 7 : the different effects operating in the two cases are discussed and rationalized. © 1995 John Wiley & Sons, Inc.     

SYNTHESIS OF NEW OXAMIDE DERIVATIVES OF D-GLUCOSAMINE AND ALIPHATIC OR AROMATIC AMINES

New oxamides, derivatives of D-glucosamine and aliphatic or aromatic amines were prepared by acylation of methyl 3,4,6-tri-O-acetyl-2-acetamido-2-deoxy-α- or -β-D-glucopyranoside (1c or 1d) with oxalyl chloride, followed by reaction with amine. The reaction was assumed to proceed by the intermediate of N-carbomethoxy N-(methyl 3,4,6-tri-O-acetyl-2-deoxy-α or β-D-glucopyranosid-2-yl) oxamic acid chloride which reacted with amines, and afforded N-acetyl, N-(methyl 3,4,6-tri-O-acetyl-2-deoxy-α- or -β-D-glucopyranosid-2-yl), N′-alkyl or aryloxamide (5–7), and N-(methyl 3,4,6-tri-O-acetyl-2-deoxy-α- or -β-D-glucopyranosid-2-yl), N′-alkyl or aryloxamide (8–13).     

Mass spectrometry of N-(Pyrimidin-2-yl)amino acids and their methyl esters

N(Pyrimidin-2-yl)-glycine, -alanine and -phenylalanine (1-3) and their methyl esters (4-6) were investigated using electron impact (EI) mass Spectrometry. The results showed that EI-induced decomposition occurs on the carboxylic group or involves the loss of R₂OH. In contrast to earlier investigations on N-(pyrimidin-4-yl)amino acids, elimination of water (in 1-3) or methanol (in 4-6) was found to be of EI-induced nature. The loss of 'COOH from M⁺ of ester 4 suggests the occurrence of a skeletal rearrangement leading to the isomeric N-methylamino acid.     

Synthesis of new carbamate derivatives of indole and their modification

Oximation of indoles having a methoxycarbonylamino group on C⁵ and an acyl group on C³ with hydroxylamine hydrochloride in the presence of pyridine gave the corresponding oximes. The reduction of the 3-C=O group with sodium tetrahydridoborate in the presence of sodium hydroxide was accompanied by removal of the methoxycarbonyl group at the pyrrole nitrogen atom with formation of racemic alcohols. 1,4-Addition of 1-(pyridin-3-yl)butane-1,3-dione to dimethyl 1,4-benzoquinone diimine N,N′-dicarboxylate in dioxane in the presence of sodium methoxide, followed by heating in boiling 22% hydrochloric acid, afforded methyl 2-methyl-5-(methoxycarbonylamino)-3-(pyridin-3-ylcarbonyl)-1H-indole-1-carboxylate. 3-(Dimethylamino)-1-(4-methyl-1,2,5-oxadiazol-3-yl)prop-2-en-1-one reacted with N,N′-bis(methoxycarbonyl)- and N,N′-bis(phenylsulfonyl)-1,4-benzoquinone diimines in methylene chloride and acetic acid, respectively, in the presence of BF₃ · Et₂O to produce indoles having a 1,2,5-oxadiazolylcarbonyl group on C₃.     

[1-芳基甲羰基-2-(1,2,4-三唑-1-基)]乙基-N,N-二烷基二硫代氨基甲酸酯衍生物的合成、结构表征及生物活性研究

以芳香基三唑类杀菌剂三唑酮为先导物设计并合成了5个含N,N-二烷基二硫代氨基甲酸酯的芳香三唑类化合物, 通过元素分析、红外光谱、核磁共振氢谱和质谱对其结构进行了表征. 用X射线单晶衍射测定了[α-(4-甲氧基苯甲酰基)-2-(1,2,4-三唑-1-基)]乙基-N,N-二甲基二硫代氨基甲酸酯的晶体结构, 晶体属于三斜晶系, 空间群, 晶胞参数为: a＝0.73482(15) nm, b＝1.1051(2) nm, c＝1.1209(2) nm, α＝90.32(3)°, β＝101.97(3)°, γ＝105.13(3)°, V＝0.8578(3) nm³, Z＝2, D_c＝1.357 g/cm³, F(000)＝368, µ＝0.324 mm^－1. 生物测试结果显示这5种有机化合物都具有杀菌性和植物生长调节活性     

New unsymmetrical μ-phenoxo bridged binuclear copper(II) complexes

A series of binuclear Cu^II complexes [Cu₂XL] ⁿ⁺ having two copper(II) ions bridged by different motifs (X = OH^–, MeCO₂ ^–, or Cl^–) have been prepared using the ligands: H₂L¹ = 4-methyl-2-[N-(2-{dimethylamino}ethyl-N-methyl)aminomethyl]-6-[(prolin-1-yl)methyl]phenol, H₂L² = 4-nitro-2-[N-(2-{dimethylamino}ethyl-N-methyl)aminomethyl]-6-[(prolin-1-yl)methyl]phenol, H₂L³ = 4-methyl-2-[N-(2-{diethylamino}ethyl-N-ethyl)aminomethyl]-6-[(prolin-1-yl)methyl]phenol and H₂L⁴ = 4-nitro-2-[N-(2-{diethylamino}ethyl-N-ethyl)aminomethyl]-6-[(prolin-1-yl)methyl]phenol. The complexes have been characterized by spectroscopic, analytical, magnetic and electrochemical measurements. Cryomagnetic investigations (80–300 K) revealed anti-ferromagnetic exchange between the Cu^II ions (–2J in the range –50 to –182 cm^–1). The strength of anti-ferromagnetic coupling lies in the order: OAc > OH > Cl. Cyclic voltammetry revealed the presence of two redox couples, assigned to Cu^II/Cu^II/Cu^II/Cu^I/Cu^I/Cu^I. The first reduction potential is sensitive to electronic effects from the aromatic ring substituents and steric effect on the donor nitrogens (side arm) of the ligand systems.