Copolymeric systems bearing side-chain thioxanthone and α-aminoacetophenone moieties as photoinitiators for ultraviolet-curable pigmented coatings

Copolymers of 1-(4-morpholinophenyl)-2-benzyl-2-[N-methyl-N-(3-meth-acryloyloxy propyl)]aminopropan-1-one and of 1-(4-morpholinophenyl)-2-benzyl-2-[N-methyl-N-(3-methacryloyloxypropyl)]aminobutan-1-one with 1-[(2-methacryloyloxy)ethoxycarbonyl]thioxanthone were prepared and structurally characterized. The above systems were also checked in the ultraviolet cure of an acrylic mixture upon irradiation over 380 nm, thus simulating the conditions of a TiO₂-pigmented formulation. The curing results were compared with those obtained in the presence of the mixtures of the corresponding homopolymers as well as of their low-molecular-weight models. The copolymeric systems display synergistic effects of activity with respect to the structural models but show lower photoinitiation efficiency against the homopolymers mixtures. These data are discussed and interpreted in terms of structural requirements and photochemical mechanistic aspects of the above systems. © 1997 John Wiley & Sons, Inc. J Appl Polym Sci 64: 2247–2258, 1997     

The effect of aromatic aminoalcohols on UV-cured films

It has been shown that the following three substituted α-aminoalcohols, 2-(N-methyl-N-phenylamino-1-phenyl) ethanol (1), 2-methyl-1-[4-(methylthio) phenyl-2-morpholino]propane-1-ol (2) and 2-benzyl-2-dimethylamino-1-(4-morpholinophenyl)-butan-1-ol (3) fragment upon irradiation to give radicals which initiate polymerisation of trimethylolpropane triacrylate (TMPTA). The effectiveness of aminoalcohol (1) as an amelioration of oxygen inhibition was investigated and found to be less effective than N-methyldiethanolamine. Aminoalcohol (1) is a good synergist for isopropylthioxanthone, but due to the absorption characteristic of benzophenone, which absorbs poorly above 300 nm, it is not a suitable initiator.     

Copolymeric systems with pendant thioxanthone and α-morpholinoacetophenone moieties as photosensitizing and photoinitiating agents for UV-curable pigmented coatings

The synthesis and structural characterization of copolymers of 1-[(2-acryloyloxy) ethoxycarbonyl]thioxanthone (ATX) with 1-[4-(2-acryloyloxyethylthio)phenyl]-2-methyl-2-morpholino-propan-1-one (AMMP), as well as ATX, AMMP and n-butyl acrylate (BA) terpolymers, is reported. These copolymeric systems have been checked in the photoinitiated polymerization in film matrix of the 1,6-hexanediol diacrylate (HDDA)–BA equimolar mixture under UV irradiation over 380 nm, i.e., under conditions simulating a TiO₂-pigmented acrylic coating formulation, and compared with the corresponding mixture of low-molecular-weight structural models 1-[(2-isobutyroyloxy)ethoxycarbonyl]thioxanthone (ITX) and 1-[4-(2-isobutyroyloxyethylthio)phenyl]-2-methyl-2-morpholino-propan-1-one (IMMP). The much higher photoinitiation activity shown by the copolymers is discussed in terms of close vicinity of thioxanthone and α-morpholinoacetophenone moieties along the backbone, which favors the excitation energy transfer from the former to the latter photosensitive group. © 1995 John Wiley & Sons, Inc.     

The role of reaction medium on the coordination environment of terbium in complexes with 4-acylpyrazol-5-ones

[Tb(Q)₃(H₂O)] and [Tb(Q)₃(H₂O)(EtOH)] derivatives of novel 1-phenyl-3-methyl-4-R-pyrazol-5-one (HQ=HQ^CP: R=cyclopentylcarbonyl, HQ^ETCP: R=cyclopentylpropionyl) have been prepared and shown to be seven- and eight-coordinate, respectively, by IR, X-ray and elemental analyses. The role of the reaction medium on the coordination number of Tb is discussed.     

Spiroheterocyclic system. Part IV: Novel azo dye sulpha drugs of spiroheterocyclic naphthenes

Novel azo-dyes have been synthesized by diazotization of 4-amino benzene-4′-(substituted heterocyclo) sulphonamide derivatives and coupling with 1-oxa-4-thia-spiro[4,4]nonan-2-one (I) and/or with l-oxa-4-thia-spiro[4,5]decan-2-one (I′) in acid medium to give the corresponding 3-azo-(4′-substituted benzenesulphonamido)-l-oxa-4-thia-spiro[4,4]nonan-2-one (II-IX) and/or l-oxa-4-thia-spiro[4,5]decan-2-one (II′-IX′] as spiro-ligands. Treatment of these ligands with metal salts of iron (Fe³⁺), copper (Cu²⁺) and mercury (Hg²⁺) as chlorides in ethanolic solution furnished the corresponding metal chelates (II_a-c-IX_a-c) and/or (II′_a-c-IX′_a-c). The compounds were tested in vitro for antimicrobial activity to study the structure-activity relationship.     

4-苄基-2-[(R)-1-[3,5-二(三氟甲基)苯基]乙氧基]吗啉-3-酮的不对称转化的动态动力学拆分

以4-苄基-2-羟基吗啉-3-酮为原料,经两步反应制备得到一对非对映异构体4-苄基-2-[(R)-1-[3,5-二(三氟甲基)苯基]乙氧基]吗啉-3-酮,然后以叔丁醇钾为碱环境,利用不对称转化的动态动力学拆分,转化为手性纯(R)-4-苄基-2-[(R)-1-[3,5-二(三氟甲基)苯基]乙氧基]吗啉-3-酮。转化后手性产物与非对映异构体的比例为96∶4,在工业化制备神经激肽-1(NK-1)受体阻滞剂阿瑞吡坦过程中有较好的应用价值。     

Synthesis and Structure-Activity Relationships of 3-Arylisoquinolone Analogues as Highly Specific hCES2A Inhibitors

Mammalian carboxylesterases (CES) are key enzymes that participate in the hydrolytic metabolism of various endogenous and exogenous substrates. Human carboxylesterase 2A (hCES2A), mainly distributed in the small intestine and colon, plays a significant role in the hydrolysis of many drugs. In this study, 3-arylisoquinolones 3 h [3-(4-(benzyloxy)-3-methoxyphenyl)-7,8-dimethoxyisoquinolin-1(2H)-one] and 4 a [3-(4-(benzyloxy)-3-methoxyphenyl)-4-bromo-7,8-dimethoxyisoquinolin-1(2H)-one] were found to have potent inhibitory effects on hCES2A (IC₅₀=0.68 μΜ, K_i=0.36 μΜ) and excellent specificity (more than 147.05-fold over hCES1 A). Moreover, 4 a exhibited threefold improved inhibition on intracellular hCES2A in living HepG2 cells relative to 3 h , with an IC₅₀ value of 0.41 μΜ. Results of inhibition kinetics studies and molecular docking simulations demonstrate that both 3 h and 4 a can bind to multiple sites on hCES2A, functioning as mixed inhibitors. Structure−activity relationship analysis revealed that the lactam moiety on the B ring is crucial for specificity towards hCES2A, while a benzyloxy group is optimal for hCES2A inhibitory potency; the introduction of a bromine atom may enhance cell permeability, thereby increasing the intracellular hCES2A inhibitory activity.     

Copper(II) Complexes Containing Natural Flavonoid Pomiferin Show Considerable In Vitro Cytotoxicity and Anti-inflammatory Effects

A series of new heteroleptic copper(II) complexes of the composition [Cu(L)(bpy)]NO₃·2MeOH (1), [Cu(L)(dimebpy)]NO₃·2H₂O (2), [Cu(L)(phen)]NO₃·2MeOH (3), [Cu(L)(bphen)]NO₃·MeOH (4), [Cu(L)(dppz)]NO₃·MeOH (5) was prepared, where HL = 3-(3,4-dihydroxyphenyl)-5-hydroxy-8,8-dimethyl-6-(3-methylbut-2-ene-1-yl)-4H,8H-benzo[1,2-b:3,4-b′]dipyran-4-one, (pomiferin) and bpy = 2,2′-bipyridine, dimebpy = 4,4′-dimethyl-2,2′-bipyridine, phen = 1,10-phenanthroline, bphen = 4,7-diphenyl-1,10-phenanthroline, and dppz = dipyrido[3,2-a:2′,3′-c]phenazine. The complexes were characterized using elemental analysis, infrared and UV/Vis spectroscopies, mass spectrometry, thermal analysis and conductivity measurements. The in vitro cytotoxicity, screened against eight human cancer cell lines (breast adenocarcinoma (MCF-7), osteosarcoma (HOS), lung adenocarcinoma (A549), prostate adenocarcinoma (PC-3), ovarian carcinoma (A2780), cisplatin-resistant ovarian carcinoma (A2780R), colorectal adenocarcinoma (Caco-2) and monocytic leukemia (THP-1), revealed the complexes as effective antiproliferative agents, with the IC₅₀ values of 2.2–13.0 μM for the best performing complexes 3 and 5. All the complexes 1–5 showed the best activity against the A2780R cells (IC₅₀ = 2.2–6.6 μM), and moreover, the complexes demonstrated relatively low toxicity on healthy human hepatocytes, with IC₅₀ > 100 μM. The complexes were evaluated by the Annexin V/propidium iodide apoptosis assay, induction of cell cycle modifications in A2780 cells, production of reactive oxygen species (ROS), perturbation of mitochondrial membrane potential, inhibition of apoptosis and inflammation-related signaling pathways (NF-κB/AP-1 activity, NF-κB translocation, TNF-α secretion), and tested for nuclease mimicking activity. The obtained results revealed the corresponding complexes to be effective antiproliferative and anti-inflammatory agents.     

Synthesis,spectral and structural study of sulfur-containing copper(II) complexes

A series of four new copper(II) complexes [Cu(H₂L)(L¹)] 1, [Cu(H₂L)(PMDT)] 2, [Cu(H₂L)(Dien)] 3 and [Cu(H₂L)(L²)] 4 have been synthesized by template condensation (H₂L=thiodiglycolic acid, L¹=N-[(1)-1-(4-methylphenyl)ethylidene]benzohydrazide, PMDT=N,N,N′,N′,N ^′′-pentamethyldiethylene- triamine, Dien=diethylenetriamine L²=N-[(1)-pyridin-2-ylmethylidene]benzohydrazide). The bonding and stereochemistry of the complexes have been characterized by molar conductance, elemental analysis, magnetic susceptibility, infrared, UV–visible, electron paramagnetic resonance structural studies and electrochemical studies. g-Values were calculated for all complexes in polycrystalline form as well as in DMSO solution. The magnetic and spectral data indicate square pyramidal geometry for 1 and octahedral geometry for 2–4 complexes. Cyclic voltammograms for all the complexes are similar and involve two irreversible redox processes. Their biological properties have also been studied. The thio complexes show more antibacterial activity than the controlled one. The antibacterial activities of the compounds have also been tested against Escherichia coli with different concentrations.     

Inter-ligand interactions and the selective formation of the unusual metal–N3(adenine) bond in ternary copper(II) complexes with N-benzyliminodiacetato(2−) ligands

A novel mixed-ligand copper(II) complex with N-(p-methoxybenzyl)-iminodiacetato(2−) ligand (MOBIDA) and adenine (AdeH) of formula [Cu(MOBIDA)(AdeH)(H₂O)]·H₂O has been obtained. Its crystal structure reveals the selective formation of a rare Cu–N3(AdeH) bond, closely related to those reported by first time for compounds of general formula [Cu(B)(AdeH)(H₂O)]·H₂O, with B=N-benzyl- or N-(p-methylbenzyl)-iminodiacetato(2−) ligands. Appropriate structural comparison reveals that the copper(II) coordination by less basic N3 heterocyclic donor of the nucleobase is controlled by a molecular recognition process involving the formation of an intra-molecular inter-ligand N7(imidazole-like)–H⋯O(carboxyl) bond and the inter-molecular inter-ligand π,π-stacking interaction between six membered rings of benzyl (MOBIDA) and AdeH. This stack generates multi-stacked infinite chains along the b-axis of the crystal.     

Regio- and stereoselectivity of 1-(Pyridazin-3-yl)-3-oxidopyridinium Betaines towards 2π- and 4π-conjugated olefins

1-(6-Phenyl) and 1-(6-(4-tolyl)-3-oxidopyridinium betaines ( 1a , b ) react as 1,3-dipoles with conjugated olefines, namely 4-vinylpyridine, ethyl cinnamate and styrene as 2π-1,3-dipolarophiles to give 2,6-cycloadducts [6-substituted-8-azabicyclo[3,2,1]oct-3-en-2-ones ( 3a , b , 4a , b and 5b )] and with butadiene and furan as 4π-dipolarophiles to give 2,4-cycloadducts [7-substituted-7-azabicyclo[4,3,1]deca-3,8-diene-10-one] and 3-6-phenylpyridazin-3-yl)-3-aza-10-oxatricyclo-[5,2,1,1^2,6]undeca-4,8-diene-11-one ( 9a ). Structural and configurational assignments were based on H.n.m.r. spectral analysis.     

Discovery of Benzo[f]indole-4,9-dione Derivatives as New Types of Anti-Inflammatory Agents

Certain benzo[f]indole-4,9-dione derivatives were synthesized and evaluated for their inhibitory effects on superoxide anion generation and neutrophil elastase (NE) release in formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLF)-activated human neutrophils. Results indicated that (Z)-1-benzyl-4-(hydroxyimino)-1H-benzo[f]indol-9(4H)-one (10) showed a potent dual inhibitory effect on NE release and superoxide anion generation with IC₅₀ value of 2.78 and 2.74 μM respectively. The action mechanisms of 10 in human neutrophils were further investigated. Our results showed that compound 10 did not alter fMLF-induced phosphorylation of Src (Src family Y416). Notably, phosphorylation of Akt (S473) and mobilization of [Ca²⁺]_i caused by fMLF was inhibited by compound 10. Further structural optimization of 10 is ongoing.     

双苯并吡喃酮1，3，4-噁二唑基哒嗪酮衍生物的合成

以DMF为溶剂,碳酸钾为催化剂,2-（2H-苯并吡喃-2-酮-3基）-5-巯基-1,3,4-噁二唑与4,5-二氯-2-苄基-哒嗪-3-酮于125℃反应6 h,合成了4-｛2-[（2H-苯并吡喃）-2-酮]-1,3,4-噁二唑-5-硫醚｝-2-苄基-5-｛2-[（2H-苯并吡喃）-2-酮]-1,3,4-噁二唑-5-硫醚｝哒嗪-3（2H）-酮化合物,收率68.6％,其结构经1H NMR、 IR以及元素分析确证。     

（S）-5-苄基-2，2，3-三甲基-4-硫咪唑烷酮的制备方法

成功研究了以P2S5／Al2O3体系作为硫代试剂，将（S）-5-苄基-2，2，3-三甲基-4-氧咪唑烷酮转化为（S）-5-苄基-2，2，3-三甲基-4-硫咪唑烷酮的方法，且反应条件温和，收率较高。     

Total synthesis of tumor inhibiting didemnenone analogues

We have previously described an enantioselective total synthesis of the tumor inhibiting didemnenones 1a , b and 2 . Our investigations reported here shed light on the structure–activity relationships of these natural products. The significantly lower activity found for (3aS*, 6aS*)-3 [(E)-allyliden]-2-oxo-6a-(-hydroxymethyl)-2,3,3a,6a-tetrahydro-4H-cyclo-penta[b]furan]2(3H)-one ( 4 ) supported the hypothesis that the oxonium intermediate 3 is the active species. The strategy of the synthesis of the natural products was used to prepare acceptor substituted analogues (3aS*, 6aS*) [(E)-[3-(4-oxo-pent-2-(E)-enylidene]-6a-(4-hydroxymethyl)-2-methoxy-2,3,3a, 6a-tetrahydro[4H-cyclopenta[b]furan]-4-one ( 18 ) and (3aS*, 6aS*) [(E)-[3-(4-oxo-pent-2-(E)-enylidene]-6a-(4-hydroxymethyl)-2,3,3a,6a-tetrahydro-[4H-cyclopenta[b]furan]-2-(3H)-one ( 20 ). Although there were only moderate structural changes some of the key transformations differed remarkably in yield and general performance from those employed in the former synthesis. Optimization of the synthesis rewardingly led to compounds with increased biological activity against human gastric carcinoma cell-lines.     

Die Nitril-Carboxamid-Umlagerung

The Nitrile Carboxamide Rearrangement By reaction of cyclohexanone-2-carboxamide ( 4 ) with cyan amide 1-cyano-cyclohex-1-en-2-yl-urea ( 6 ) is formed via nitrile carboxamide rearrangement. Whilst compound 6 with 1,2-diaminobenzene hydrochloride forms 11-amino-1 H-2,3,4,5-tetrahydrodibenzo[b,e][1,4]diazepin hydrochloride ( 8 and 8a ), compound 6 and 1,2-diaminobenzene form hexahydro-benzimidazo[1,2-c]-quinazolin-6-one ( 12 ). Compound 8 with sodium hydroxide yields 11-amino-1 H-2,3,4,11a-tetrahydrodibenzo[b,e]-[1,4]diazepin ( 9 ). Compound 6 reacts with cyclohexylamine to form N-(1-cyanocyclohex-1-en-2-yl)-N′-cyclohexyl urea ( 10 ). Compound 10 with 1,4- or 1,2-diaminobenzene hydrochloride yields compound 7 and 8 . In alkaline solution 10 cyclises to 4-amino-3-cyclohexyl-2,3,5,6,7,8-hexahydroquinazolin-2-one ( 11 ). Compound 4 and malonitrile form either 3-amino-4-cyano-1,2,5,6,7,8-hexahydro-isoquinol-1-one ( 13 ) or 1-amino-4-cyano-2,3,5,6,7,8-hexahydro-isoquinol-3-one ( 14 ). Compound 13 and alkaline formaldehyde react to cyanooctahydroisoquinoline-[2,3-c] [1,3,5]oxdiazin-6-one ( 17 ). 2-Cyanoethyl-cyclohexan-one-2-carboxamide ( 22 ), prepared by Michael-reaction from 4 and acrylonitrile, forms via nitrile carboxamide rearrangement 10-cyano-1,2,3,4,5,6,7,10-octahydroquinolin-2-one ( 24 ) and 2-(1′-cyano-cyclohexyl-2′-one)-propionic acid ( 25 ). Nucleophilic attack of the NH₂-group at the cyanogroup of compound 22 forms 5-(spirocyclohexan-2′-one)-hexahydropyridin-2,6-dione ( 27 ).     

Eindeutige Synthese des 4,7-Dihydro-4-oxo-1 H-pyrazolo[3,4-b]pyridins – Bemerkungen zur „(N?C)-Umlagerung”︁ von (2-Alkoxycarbonyl-vinyl-amino)pyrazolen

Unambiguous Synthesis of 4,7-Dihydro-4-oxo-1H-pyrazolo[3,4-b]pyridine — Further Comments on the “(N C)-Rearrangement” of (2-Alkoxycarbonyl-vinyl-amino)pyrazols 4,7-Dihydro-4-oxo-1H-pyrazolo[3,4-b]pyridine 1a is synthesized by decarboxylation of 1-benzyl-5-carboxy-4-hydroxy-pyrazolo[3,4-b]pyridine 4b and debenzylation of 1-benzyl-4,7-dihydro-4-oxo-pyrazolo[3,4-b]pyridine 1b with sodium in liquid ammonia. The product from 3-amino-pyrazol and methyl propiolate, formerly described as 1a , obviously is the 6-oxo isomer 2a . Use of the parameter δ¹³(CO) for the structural assignment of pyrazolo[3,4-b]pyridones is only permitted, if in the corresponding media mainly the oxo-tautomer is existing. It is again demonstrated that DMSO is often an insufficient medium. Debenzylation of 1b and similar compounds with SeO₂ is only possible, if the α-position of CO is blocked by a substituent. Otherwise diselenids of type 6 are formed. This obviously is a general reaction of cyclic lactames. The cyclisation of (2-alkoxycarbonyl-vinyl-amino)pyrazols 7 in acidic media, and with catalytical amounts of the corresponding amino-pyrazols gives 6,7-dihydro-6-oxo-pyrazolo[3,4-b]pyridines 2 via amino 4-(2-alkoxycarbonyl-vinyl)pyrazols 8 , i.e. via products of an “(N C)-rearrangement”, while by thermal cyclisation of 7 4,7-dihydro-4-oxo-pyrazolo[3,4-b]pyridines 1 are formed.     

Structural conversion of cubane-type thallium complex to hexagon silver complex by solid-state mechanochemical reaction

Solid-state structural transformation of Tl^I supramolecular polymer comprised from cubane-type thallium complex of [Tl₄(μ₃-4-BN)₄] (1) (4-HBN = 4-hydroxy benzonitrile) to Ag^I coordination polymer with three nuclear units of [Ag₃(μ₃-4-BN)₂(μ₄-4-BN)] (2) has been studied upon mechanochemical reaction of compound 1 with AgNO₃.     

cryoEM-Guided Development of Antibiotics for Drug-Resistant Bacteria

While the ribosome is a common target for antibiotics, challenges with crystallography can impede the development of new bioactives using structure-based drug design approaches. In this study we exploit common structural features present in linezolid-resistant forms of both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) to redesign the antibiotic. Enabled by rapid and facile cryoEM structures, this process has identified (S)-2,2-dichloro-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (LZD- 5 ) and (S)-2-chloro-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl) acetamide (LZD- 6 ), which inhibit the ribosomal function and growth of linezolid-resistant MRSA and VRE. The strategy discussed highlights the potential for cryoEM to facilitate the development of novel bioactive materials.