CavCOOH-in, was synthesized and crystallized with acetic acid to evaluate its molecular recognition properties towards this analyte in the solid state.Acetic acid is a by-product of peracetic acid with acute irritant properties when present in air. The cavitand 5,11,17,23-tetramethyl-4,24:6,10:12,16:18,22-tetrakis(methylenedioxy)resorcin[4]arene functionalized at the upper rim with a carboxylic acid group,  CavCOOH-in, of chemical formula C37H32O10, was synthesized in order to study its supramolecular interactions with acetic acid in the solid state. Crystals suitable for X-ray diffraction analysis were obtained by slow evaporation of a dichloromethane–acetone solution of CavCOOH-in, to which glacial acetic acid had been added. The resulting compound, C37H32O10·2C2H4O2 (1) crystallizes in the space group P1 is dominated by O—H⋯O and C—H⋯O hydrogen bonding due to the presence of acetic acid and of the carboxylic group functionalizing the upper rim. Further stabilization is provided by offset π–π stacking interactions between the aromatic walls of adjacent cavitands [intercentroid distance = 3.573 (1) Å].The cavitand 5,11,17,23-tetramethyl-4,24:6,10:12,16:18,22-tetrakis(methylenedioxy)resorcin[4]arene functionalized at the upper rim with a carboxylic acid group,  It is therefore important to find an accurate method to measure acetic acid vapour in order to assess the environmental air quality. In the literature, only one example of the environmental monitoring of gaseous acetic acid has been reported  is also shown in Fig. 11 crystallizes in the space group PC, while the methyl group of the acetic acid held inside the cavity forms C—H⋯π interactions with the aromatic rings of the walls , as can be seen from the C3—O1—C9—O2 torsion angles . This is probably due to the hydrogen bonding in which the carboxylic acid C9D/C10D/O3D/O4D is involved with adjacent cavitands, as will be described in Section 3.1 is dominated by hydrogen bonding. A chain which propagates along the c-axis direction is formed by strong O—H⋯O interactions involving the hydroxyl group O3D—H3D from the carboxylic acid at the methylene bridge and the bridging resorcinol oxygen atom O2Bi of an adjacent cavitand  −x + 2, −y + 1, −z + 1; see Fig. 4D-–H7D1⋯O1ii] and an intramolecular one with a methylene bridge [C9A—H9A1⋯O1]. These sets of interactions are completed by another intermolecular C—H⋯O hydrogen bond between methyl group C7C—H7C2 and the carboxyl oxygen atom O4Dii. Finally, the ribbons  C1A–C6A aromatic rings [Fig. 5While the main supramolecular contacts at play for the encapsulation of acetic acid inside the cavitand are C—H⋯π interactions Table 1, the crynd Fig. 3. Pairs o5H11 alkyl chains at the lower rim (XIDLEC) have been used to form supramolecular complexes with dimethylmethylphosphonate, DMMP, a nerve-gas simulant bearing a P=O group  has been used to form a heterodimeric capsule in a rim-to-rim fashion through the formation of four hydrogen bonds with a tetra(3-pyridyl)-cavitand. The previously cited cavitand A self-assembles into a one-dimensional chain (LOPKEG) or into dimeric capsules (KAHMOV) via hydrogen bonding with four 2-aminopyrimidine molecules. Similarly, OSIYIA and OSIYOG consist of supramolecular self-assembled polymers or capsules between tetracarboxylic acid functionalized cavitands and suitable N-heterocyclic linkers such as 4,4-bipyridine and 2-amino-5-bromo-4-chloro-6-methylpyrimidine.A resorcinarene-based cavitand in which one of the four methylenic bridges is functionalized with a carboxylic acid is unique to the present day. An isomer of the title compound (XIDLIG) and its analogue with four –CCavCOOH-in was carried out according to the procedure employed for the CavCOOH-out isomer  spectrometer. All chemical shifts (δ) are reported in p.p.m. relative to the proton resonances resulting from incomplete deuteration of the NMR solvents. 1H NMR  d = 1.91 , 2.01 , 3.23 , 4.31 , 4.51 , 5.85 , 6.73 , 6.94 .The synthesis of cavitand 1 were obtained by slow evaporation of a solution prepared by dissolving 0.005 mmol of the cavitand CavCOOH-in in 5 ml of a 1:1 dichloromethane and acetone solution, to which 1.1 µL (0.02 mmol) of glacial acetic acid were added.Colourless crystals of the inclusion complex Uiso(H) set to 1.2–1.5Ueq(C/O), the only exception being atom H9D, which was located in a difference-Fourier map and refined freely. A DIFX instruction was employed to avoid a short H⋯H contact between atoms H9D and H8D1. Atoms O1 and O2 were refined using the EADP command. The acetic acid guest is disordered over two positions with a refined occupancy ratio of 0.344 (4):0.656 (4).Crystal data, data collection and structure refinement details are summarized in Table 210.1107/S2056989019002512/su5481sup1.cifCrystal structure: contains datablock(s) I, Global. DOI: 10.1107/S2056989019002512/su5481Isup2.hklStructure factors: contains datablock(s) I. DOI: 1897735CCDC reference:  crystallographic information; 3D view; checkCIF reportAdditional supporting information:


Cervical sagittal parameters were closely related with clinical outcomes after multi-level ACDF. Our purpose was to evaluate the clinical outcomes and cervical sagittal parameters in patients with MCSM after ACDF and to identify the risk factors of poor clinical outcomes.ACDF was performed in 89 patients with MCSM. Based on average JOA recovery rate, patients were divided good-outcome group (group GO) and poor-outcome group (group PO). The cervical sagittal parameters including Cobb angle, SVA, T1S, cranial tilt and cervical tilt were measured. Multivariate logistic regression was used to identify risk factors.p < 0.001). △Cobb angle (p = 0.008) and △SVA (p = 0.009) showed significantly statistical differences between two groups. Longer symptom duration, lower preoperative JOA score, smaller △Cobb angle and larger △SVA were identified as risk factors of poor clinical outcomes.Fifty-four patients (60.67%) were divided into group GO, while 35 patients (39.33%) were divided into group PO. Cobb angle, SVA and T1S was corrected from preoperative average 11.80° ± 9.63°, 23.69 mm ± 11.69 mm and 24.43° ± 11.78° to postoperative average 15.08° ± 9.05°, 18.79 mm ± 10.78 mm and 26.92° ± 11.94° respectively (Multi-level ACDF is an effective surgical method to treat patients with MCSM. However, long duration of preoperative symptoms, lower preoperative JOA score, smaller △Cobb angle and larger △SVA are risk factors for poor outcomes in patients with MCSM after ACDF. Sagittal parameters should be paid attention to in surgery. Cervical spondylotic myelopathy (CSM) is caused by spinal cord compression as a result of multiple pathological changes such as disc herniation, degeneration and/or osteophyte formation at the posterior margin of the vertebral body . Multi-lAs an anterior procedure surgery, multi-level ACDF was widely used in treating MCSM . AlthougAll protocols of the study were approved by the Ethics Committee of the Third Hospital of Hebei Medical University and informed consent was obtained from all individual participants for using their imaging data and questionnaire scores.From January 2010 to December 2015, 89 patients, including 40 men and 49 women, diagnosed as MCSM according to clinical manifestations and imaging scans underwent multi-level ACDF at the Department of Spinal Surgery, the Third Hospital of Hebei Medical University, were enrolled in this retrospective study. The inclusion criteria were the following: (1) MCSM required surgical treatment for equal to or more than three levels; (2) ineffective conservative treatment for more than 3 months or acute aggravated neurological deficit; (3) complete imaging and clinical date; (4) follow-up for at least 2 years. Exclusion criteria were the following: (1) history of operation involving with cervical spine; (2) combined with trauma, spinal tumours, spinal tuberculosis or infections; (3) ossification of posterior longitudinal ligament; (4) combined with severe osteoporosis; (5) combined with neurological diseases, such as vitamin B deficiency or motor neuron diseases. The average age of all patients at operation was 58.97 ± 5.79 years, range from 37 to 78 years. Three-level ACDF (C3-C6 in 34 cases and C4-C7 in 41 cases) was performed in 75 patients and four-level ACDF (C3-C7) in 14 patients. The patients were followed up for an average of 2.57 ± 0.78 years.Japanese Orthopaedic Association (JOA) scoring system (0–17 scores) was used for neurological function assessment before surgery and at last follow-up visit. Neurological function recovery rate was calculated on the basis of JOA scoring system: (postoperative score-preoperative score)/(17-preoperative score) × 100%. According to average JOA scores, patients were divided into two groups: good-outcome group  and poor-outcome group .Cervical magnetic resonance imaging (MRI), CT (Computed Tomography) and posterior-anterior and lateral X-rays were taken preoperatively to diagnose and evaluate the disease and make surgical planning. Cervical posterior-anterior and lateral X-rays were also taken postoperatively and at each follow-up visit. Cervical sagittal parameters were measured on lateral radiographs on synapse system  with patients in a neutral position. The measurement methods of cervical sagittal parameters were as follows , duration of symptoms, follow-up period, preoperative JOA scores, number of operative segments, △Cobb angle, △SVA, △T1S, △cranial tilt and △cervical tilt were collected for potential risk factors of poor clinical outcomes in patients with MCSM after ACDF. Duration of symptoms was defined as the period from appearance of primary neurological clinical symptoms to surgery.p value < 0.05 was considered statistically significant. Quantitative dates were first tested its normality and homogeneity of variance and according to different situations, they were tested by Student’s t test or Mann–Whitney U test. Qualitative date was tested by chi-square test. The potential risk factors were tested by univariate analysis and if p < 0.05, the factor was selected into multivariate logistic model. Then, multivariate logistic regression analysis was used to identify the risk factors of poor clinical outcomes in patients with MCSM after ACDF with adjusted odds ratios (ORs) and 95% confidence intervals (CIs).Clinical and imaging date was evaluated by SPSS program . p < 0.001). The average recovery rate was 61.13% ± 21.48%. Fifty-four patients (60.67%) whose recovery rate higher than the average were divided into group GO and their average recovery rate was 75.00% ± 9.52%, while 35 patients (39.33%) whose recovery rate lower than the average were divided into group PO and their average recovery rate was 39.73% ± 16.62%. There was significantly statistical difference in recovery rate between two groups (p < 0.001).For all patients, the mean duration of symptoms was 14.64 ± 8.02 months. All the operations were completed successfully Fig. . JOA scop = 0.114), sex (p = 0.450), BMI (p = 0.582), follow-up time (p = 0.159) and operative segment (p = 0.768) between two groups. The JOA scores were significantly improved at last follow-up visit comparing with the preoperative scores in both groups (p < 0.001). No matter preoperative JOA scores (p = 0.014) or last follow-up JOA scores (p < 0.001), group GO got significantly higher scores than group PO. In addition, patients in group PO complained of syndromes for a significantly longer period before surgery than patients in group GO (p < 0.001).The clinical dates between group GO and group PO were showed in Table p < 0. 001) and the average △Cobb angle was 3.28° ± 3.88°. The average last follow-up SVA (18.79 mm ± 10.78 mm) was significantly lower than the preoperative (23.69 mm ± 11.69 mm) (p < 0.001) and the average △SVA was − 4.90 mm ± 6.30 mm. Meanwhile, significantly significant difference was also found between preoperative T1S (24.43° ± 11.78°) and last follow-up T1S (26.92° ± 11.94°) (p < 0.001) and the average △T1S was 2.49° ± 4.19°. Significantly statistical difference (p < 0.001) was found between preoperative (5.16° ± 6.47°) and last follow-up cranial tilt (7.52° ± 6.27°) and the average △cranial tilt was 2.36° ± 2.25°.There was no significantly statistical difference (p = 0.132) between preoperative (17.71° ± 6.28°) and last follow-up cervical tilt (17.46° ± 6.54°) and the average △cervical tilt was − 0.25° ± 1.53°.For all patients, Cobb angle was corrected from preoperative average 11.80° ± 9.63° to postoperative average 15.08 ± 9.05° (p = 0.467), preoperative SVA (p = 0.868) and preoperative T1S (p = 0.740) between two groups. However, last follow-up Cobb angle in group GO was greater than that in group PO (p = 0.025) and significantly statistical difference was also found when comparing △Cobb angle (p = 0.008). Last follow-up SVA showed the opposite result than the value in group PO was greater than that in group GO (p = 0.030). △SVA in group PO was also greater than that in group GO (p = 0.009). There was no significantly statistical difference in both last follow-up T1S (p = 0.814) and △T1S (p = 0. 826) between two groups. No significantly statistical difference was found in preoperative cranial tilt (p = 0.740), last follow-up cranial tilt (p = 0.653), △cranial tilt (p = 0.952), preoperative cervical tilt (p = 0.590), last follow-up cervical tilt (p = 0.585) and △cervical tilt (p = 0.946) between two groups.The comparison of cervical sagittal parameters between group GO and group PO is shown in Table p < 0.001), preoperative JOA score (p = 0.009), △Cobb angle (p = 0.013) and △SVA (p = 0.001) showed significantly statistical difference in univariate analysis and the four factors were selected into multivariate logistic model (Table p < 0.001), lower preoperative JOA score , smaller △Cobb angle  and larger △SVA  were identified as four risk factors of poor clinical outcomes in patients with MCSM after ACDF  is one of the most common diseases in orthopaedics and is one of the most harmful diseases, mostly in the elderly . It has The clinical outcomes of ACDF were limited by a variety of factors involving with preoperative condition and postoperative complications. Pumberger et al.  found thCervical sagittal parameters had been proved to be important in clinical recovery of patients with CMS after cervical surgery and preoperative cervical sagittal parameters had been proved to be predictors for clinical outcomes –24. CervThe similar result showed in the study of Basques et al.  that ACDMulti-level ACDF is an effective surgical method to treat patients with MCSM. Cervical sagittal parameters were changed after multi-level ACDF with larger Cobb angle, smaller SVA and greater T1S. However, long duration of preoperative symptoms, lower preoperative JOA score, smaller △Cobb angle and larger △SVA is risk factors for poor outcomes in patients with MCSM after ACDF. Sagittal parameters should be paid attention to in design of surgical plan for better clinical outcomes.


In the crystal, [010] polymeric chains are crosslinked by N—H⋯O hydrogen bonds to form sheets lying parallel to the (001) plane.The title compound is one-dimensional coordination polymer built up of tetragonally distorted CuN catena-poly[[[(perchlorato-κO)copper(II)]-μ-3-(3-carboxypropyl)-1,5,8,12-tetraaza-3-azoniacyclotetradecane-κ4N1,N5,N8,N12] bis(perchlorate)], {[Cu(C13H30N5O2)(ClO4)](ClO4)2}n, (I), consists of a macrocyclic cation, one coordinated perchlorate anion and two perchlorate ions as counter-anions. The metal ion is coordinated in a tetragonally distorted octahedral geometry by the four secondary N atoms of the macrocyclic ligand, the mutually trans O atoms of the perchlorate anion and the carbonyl O atom of the protonated carboxylic acid group of a neighbouring cation. The average equatorial Cu—N bond lengths [2.01 (6) Å] are significantly shorter than the axial Cu—O bond lengths [2.379 (8) Å for carboxylate and average 2.62 (7) Å for disordered perchlorate]. The coordinated macrocyclic ligand in (I) adopts the most energetically favourable trans-III conformation with an equatorial orientation of the substituent at the protonated distal 3-position N atom in a six-membered chelate ring. The coordination of the carboxylic acid group of the cation to a neighbouring complex unit results in the formation of infinite chains running along the b-axis direction, which are crosslinked by N—H⋯O hydrogen bonds between the secondary amine groups of the macrocycle and O atoms of the perchlorate counter-anions to form sheets lying parallel to the (001) plane. Additionally, the extended structure of (I) is consolidated by numerous intra- and interchain C—H⋯O contacts.The asymmetric unit of the title compound,  N3,N10-disubstituted 1,3,5,8,10,12-hexaazacyclotetradecane (diazacyclam) and, to a lesser extent, N3-substituted 1,3,5,8,12-pentaazacyclotetradecane (azacyclam) are popular building units for the assembly of metal–organic frameworks (MOFs), demonstrating many promising applications  or 3,7-diazanonane-1,9-diamine complexes, respectively, with formaldehyde and primary amines catena-poly[[[(perchlorato-κO)copper(II)]-μ-3-(3-carboxypropyl)-1,5,8,12-tetraaza-3-azoniacyclotetradecane-κ4N1,N5,N8,N12] bis(perchlorate)], {[Cu(H2L)(ClO4)](ClO4)2}n, which is the first example of azacyclam ligand with a carboxylic acid group.Herein, we describe the synthesis and the crystal structure of the title CuII ion in the complex cation in (I)II ion is displaced by 0.075 Å from the mean plane of the N4 donor atoms (r.m.s. deviation = 0.005 Å) towards the O2 atom of the carboxylate group. The equatorial Cu—N bond lengths are significantly shorter than the axial Cu—O bond lengths  conformation °] and the six-membered chelate rings in chair [average bite angle = 93.6 (2)°] conformations. The methylene group of the substituent at the noncoordinated N3 atom in the six-membered chelate ring is oriented equatorially. Such an arrangement of the substituent, in contrast to an axial orientation, is relatively uncommon and only a few examples of such CuII complexes with aza- and diazacyclam ligands have been described so far + group in (I)sp3-hybridized N atom (ca 327°), thus indicating their partial sp2 character -substituted diazacyclam polymeric complex  and 1.198 (13) Å for C13—O1 and C13—O2, respectively], thus confirming its protonated form and the lack of delocalization. Interestingly, it is coordinated to the Cu4 anion is completely disordered over two positions with site occupancies of 50% and is weakly coordinated to the metal ion (Table 14) and 78% (Cl3O4). Because of the low partial population, the minor components of these perchlorate anions were not considered further in the analysis of the hydrogen-bonding network.Three disordered perchlorate anions in the title compound counterbalance the charge of the complex cations. The Cl1On Table 1. Two remb-axis direction ,O12(Cl3)], so that each perchlorate anion is fixed in a chain in a ditopic manner ], as well as between secondary amine groups of the macrocycle and an O atom of the carboxylic acid group as the proton acceptor [N2—H2(N4—H4)⋯O1]. Hydrogen bonding of the secondary amine groups of the macrocycle and the O atoms of perchlorate anions not involved in above-mentioned intrachain interactions [N1—H1⋯O7(Cl2)(x − y + z) and N5—H5⋯O14(Cl3)(x − y + z)] results in the formation of sheets lying parallel to the (001) plane  and many of them were investigated as building blocks for the construction of MOFs by using additional carboxylate or metalocyanide linkers. At the same time, there are only two examples demonstrating self-polymerization , namely, those with diazacyclam ligands containing 2-propionitrile ](ClO4)2 , was prepared according to a published method ](ClO4)2 , 4-aminobutanoic acid  and 30% aqueous formaldehyde  in methanol (40 ml) was refluxed for 24 h. After cooling and filtration, the solution was kept in a refrigerator overnight. The violet crystalline precipitate was filtered off, washed with methanol (5 ml) and recrystallized from a 1:1 (v/v) water–ethanol solvent mixture (10 ml) containing 0.5 M perchloric acid . Analysis calculated (%) for C13H30Cl3CuN5O14: C 24.01, H 4.65, N 10.76; found: C 24.17, H 4.51, N 10.92. Violet blocks of (I)All chemicals and solvents used in this work were purchased from Sigma–Aldrich and were used without further purification. The starting CuSafety note: perchlorate salts of metal complexes are potentially explosive and should be handled with care.Uiso(H) values of 1.2 or 1.5Ueq of the parent atoms. The crystal of (I)Crystal data, data collection and structure refinement details are summarized in Table 310.1107/S205698901901377X/hb7857sup1.cifCrystal structure: contains datablock(s) I, global. DOI: 10.1107/S205698901901377X/hb7857Isup2.hklStructure factors: contains datablock(s) I. DOI: 1958285, 1958285CCDC references:  crystallographic information; 3D view; checkCIF reportAdditional supporting information:


H-imidazol-3-ium) heptamolybdate 2-methyl-1H-imidazole disolvate dihydrate,(C4H7N2)6[Mo7O24]·2C4H6N2·2H2O, [Mo7O24]6− heptamolybdate anions, 2-methylimidazolium cations, neutral 2-methylimidazole molecules and water molecules are linked through hydrogen bonds into a three-dimensional network.In the crystal structure of hexakis(2-methyl-1 H-imidazol-3-ium) heptamolybdate 2-methyl-1H-imidazole disolvate dihydrate, (C4H7N2)6[Mo7O24]·2C4H6N2·2H2O, was prepared from 2-methylimidazole and ammonium heptamolybdate tetrahydrate in acid solution. The [Mo7O24]6− heptamolybdate cluster anion is accompanied by six protonated (C4H7N2)+ 2-methylimidazolium cations, two neutral C4H6N2 2-methylimidazole molecules and two water molecules of crystallization. The cluster consists of seven distorted MoO6 octahedra sharing edges or vertices. In the crystal, the components are linked by N—H⋯N, N—H⋯O, O—H⋯O, N—H⋯ and O—H⋯ hydrogen bonds, generating a three-dimensional network. Weak C—H⋯O interactions consolidate the packing.The title compound, hexakis(2-methyl-1 M = V, Nb, Ta, Mo, W, ⋯) and oxygen atoms with a structural and compositional diversity that lead to numerous applications because of their electrochemical, optical, catalytic and photochromic properties as well as their antiviral and antitumor activities  are clusters of transition metals , μ2-O (oxygen atoms bridging two molybdenum atoms), μ3-O (oxygen atoms bridging three molybdenum atoms) and μ4-O (oxygen atoms bridging four molybdenum atoms). All of the Mo atoms are bound to two terminal oxygen atoms except for Mo7, which is located in the ‘core’ of the cluster. The geometrical data for the cluster in (I)et al., 1992et al., 2008t, 1.754 (2)—2.453 (2) Å for μ2-O, 1.8945 (19)–2.3057 (19) Å for μ3-O and 2.1329 (19)–2.3011 (18) Å for μ4-O. The variations of Mo—O bond lengths and O—Mo—O angles indicate that all seven octahedra (MoO6) within the cluster are highly distorted. As in the compound (H3dien)2[Mo7O24]·4H2O . As well as the [Mo7O24]6− anion, six (C4H7N2)+ cations, two neutral C4H6N2 molecules and two water molecules of crystallization are present in the asymmetric unit + cations and/or neutral 2-methylimidazole molecules + cations to neutral molecules. The packing is consolidated by weak C—H⋯O links , 2-methylimidazole  and ammonium heptamolybdate tetrahydrate  in a ratio of 1:2:1/12 were dissolved in water (60 ml). The solution was stirred for one h and evaporated in the oven at 333 K to yield a whitish precipitate. The precipitate was recrystallized from methanol solution: after two weeks at room temperature, colourless prisms of (I)supporting information. The absorption bands at 3400 and 3395 cm−1 correspond to ν(O—H) stretches and indicate the presence of water molecules and those at 1621 and 1564 cm−1 to the deformation vibrations δ(O—H). The bands centered at 3132 and 1431 cm−1 with shoulders are respectively attributed to the stretching and deformation vibrations of the N—H bonds of the protonated and/or non-protonated entities of 2-methylimidazole  deformation vibration  stretching vibrations while the bands between 838 and 650 cm−1 are typical for the vibrations of ν(Mo—O—Mo) and ν[Mo—(μ-O)] groupings Uiso (H) = 1.2Ueq or 1.5Ueq(C-methyl).Crystal data, data collection and structure refinement details are summarized in Table 210.1107/S2056989019008454/hb7831sup1.cifCrystal structure: contains datablock(s) global, I. DOI: 10.1107/S2056989019008454/hb7831Isup2.hklStructure factors: contains datablock(s) I. DOI: Click here for additional data file.10.1107/S2056989019008454/hb7831sup3.tifThe IR spectrum of compound (I). DOI: 1922927CCDC reference:  crystallographic information; 3D view; checkCIF reportAdditional supporting information:


The structure of the pseudopolymorph of 3-(triphenylphosphoranylidene)-2,5-dihydrofuran-2,5-dione with a THF solvent molecule is described. The compound has a hydrogen-bonded layer structure, and displays C—H⋯O hydrogen bonds connecting molecules of the dihydrofuran-2,5-dione derivative into chains. viz. C22H17O3P·C4H8O. The succinic anhydride ring is approximately planar (r.m.s. deviation = 0.032 Å). The tetrahydrofuran molecule is disordered over two orientations about a pseudo-twofold axis with refined occupancy ratio 0.718 (4):0.282 (4). In the crystal, C—H⋯O hydrogen bonds link molecules of the dihydrofuran-2,5-dione derivative into chains parallel to the b axis and arranged into layers stacked along [100] alternating with hydrogen-bonded tetrahydrofuran layers.The title pseudo-polymorph of 3-(triphenylphosphoranylidene)-2,5-dihydrofuran-2,5-dione crystallizes with a tetrahydrofuran solvent molecule,  The distribution histogram of the P=C distance [with a mean value of 1.729 Å and a standard deviation of 0.030 Å] is shown in Fig. 3et al., 19932Cl2 solvate : 1.78 , 3.14 , 3.67 , 7.44–7.72 . 31P{1H} NMR : +13.6 (s).To a stirred solution maleic anhydride  in tetrahydrofuran THF (5 mL) was added triphenylphosphine  at room temperature. The reaction mixture was stirred at room temperature for 24 h, then the solution was filtered and concentrated under reduced pressure. The reaction mixture was allowed to cool in the freezer  and yellowish crystals precipitated. The crystals were separated from solvent and dried to give 0.56 g (90%) of the title compound. Uiso(H) = 1.2Ueq(C).Crystal data, data collection and structure refinement details are summarized in Table 210.1107/S2056989018011775/rz5234sup1.cifCrystal structure: contains datablock(s) I. DOI: 10.1107/S2056989018011775/rz5234Isup2.hklStructure factors: contains datablock(s) I. DOI: Click here for additional data file.10.1107/S2056989018011775/rz5234Isup3.cdxSupporting information file. DOI: 1862873CCDC reference:  crystallographic information; 3D view; checkCIF reportAdditional supporting information:


Both molecules feature an intramolecular N—H⋯N hydrogen bond. In the crystal, weak aromatic π–π stacking interactions [centroid–centroid separation = 3.830 (2) Å] link the molecules into dimers.In each of the two independent molecules in the asymmetric unit of the title compound, [CdI For A, the Cd1—I1 and Cd1—I2 bond lengths are 2.7509 (4) and 2.6917 (4) Å, respectively, and the Cd1—N2 bond length is 2.342 (3) Å. For B, the Cd2—I3 and Cd2—I4 bond lengths are 2.7530 (4) and 2.6732 (4) Å, respectively, and the Cd2—N6 bond length is 2.344 (3) Å. Both molecules feature an intramolecular N—H⋯N hydrogen bond with the pyridine-ring N atom as the acceptor ° for r Table 2.A + B associations by aromatic π–π stacking interactions  y] Fig. 3.CrystalExplorer3.1 , H⋯H (29.5%), C⋯H / H⋯C (13.3%), H⋯O / O⋯H (5.6%) and C⋯I / I⋯C (4.9%) are shown in Figs. 4b–f, respectively. The full list of percentage surface contributions in given in Table 3The Hirshfeld surface analysis -4-hydroxybenzylidene]-pyridine-4-carbohydrazide-κN1}diiodidocadmium methanol disolvate ethylidene]picolinohydrazide-κ2N′,O}cadmium methylidene]pyridine-2-carbohydrazide-κ2N′,O}cadmium) cadmium -4-(2-hydroxybenzylideneamino)benzoato-κ2O,O′]cadmium methylidene]picolinohydrazide-κ2N′,O}cadmium N′-[(E)-(pyridin-2-yl)methylidene]pyridine-2-carbohydrazide ligand was synthesized according to the literature method  = 1.2Ueq.Crystal data, data collection and structure refinement details are summarized in Table 410.1107/S2056989019008831/hb7823sup1.cifCrystal structure: contains datablock(s) I, global. DOI: 10.1107/S2056989019008831/hb7823Isup2.hklStructure factors: contains datablock(s) I. DOI: 1935658CCDC reference:  crystallographic information; 3D view; checkCIF reportAdditional supporting information:


The title Schiff base compound, consisting of a cyclohexane and a 2-hydroxy-3-methylbenzylidene ring bridged by a hydrazinecarbothioamine moiety, crystallizes with two independent molecules in the asymmetric unit. In the crystal, the molecules are linked by N—H⋯S hydrogen bonds and C—H⋯π interactions, forming ribbons along the [010] direction. 15H21N3OS, comprises of two crystallographically independent molecules (A and B). Each molecule consists of a cyclohexane ring and a 2-hydroxy-3-methylbenzylidene ring bridged by a hydrazinecarbothioamine unit. Both molecules exhibit an E configuration with respect to the azomethine C=N bond. There is an intramolecular O—H⋯N hydrogen bond in each molecule forming an S(6) ring motif. The cyclohexane ring in each molecule has a chair conformation. The benzene ring is inclined to the mean plane of the cyclohexane ring by 47.75 (9)° in molecule A and 66.99 (9)° in molecule B. The mean plane of the cyclohexane ring is inclined to the mean plane of the thiourea moiety [N—C(=S)—N] by 55.69 (9) and 58.50 (8)° in molecules A and B, respectively. In the crystal, the A and B molecules are linked by N—H⋯S hydrogen bonds, forming ‘dimers’. The A molecules are further linked by a C—H⋯π interaction, hence linking the A–B units to form ribbons propagating along the b-axis direction. The conformation of a number of related cyclohexanehydrazinecarbothioamides are compared to that of the title compound.The asymmetric unit of the title compound, C The benzene ring is inclined to the mean plane of the thiourea moiety by 10.95 (8)° in molecule A and 9.80 (8)° in molecule B.The cyclohexane ring (C9–C14) in each molecule has a chair conformation. The mean plane of the four central C atoms (C10/C11/C13/C14) is inclined to the mean plane of the thiourea moiety [N2—C8(=S1)—N3] by 54.83 (11) and 55.64 (10)° in molecules i.e. τ1 (C1—C6—C7—N1), τ2 (C7—N1—N2—C8), τ3 (N1—N2—C8—N3), τ4 (N2—C8—N3—C9) and τ5 (C8—N3—C9—C10), as illustrated in Fig. 3τ1 between the benzylidine ring and the azomethine double bond for both molecules are approximately 0° [3.0 (2)° in molecule A and 1.9 (2)° in molecule B], signifying the coplanarity between benzylidine ring and the azomethine double bond (C7=N1). In molecule B, the azomethine double bond is close to planar with the hydrazine moiety [τ2 = 177.23 (14)°], whereas τ2 in molecule A is slightly twisted [τ2 = 171.68 (14)°]. In both molecules, the torsion angle between the hydrazine moiety and the carbothio group are also slight twisted with τ3 values in molecules A and B of 7.4 (2) and −10.2 (2)°, respectively. Similarly to τ1, the carbothio group is almost coplanar with the thioamide group for both molecules, as implied by torsion angle τ4 [178.07 (14)° in molecule A and 175.59 (14)° in molecule B], which are approximately 180°. The thioamide group and the cyclohexane ring are almost perpendicular to each other with τ5 torsion angles of 85.3 (2) and −81.6 (2)° in molecules A and B, respectively. This may arise from the steric repulsion between the cyclohexane ring and adjacent sulfur atom.The unique molecular conformations of the two molecules can be characterized by five torsion angles, A and B molecules are connected into ‘dimers’ with an via N2A—H1N2⋯S1Bi and N2B—H2N2⋯S1Ai hydrogen bonds -2-benzylidene-N-cyclohexylhydrazine-1-carbothioamide as the reference moiety resulted in nine structures containing a cyclohexylhydrazinecarbothioamide moiety with different substituents (R). The different substituents (R) together with the torsion angles of the hydrazinecarbothioamide connecting bridge are compiled in Table 2cf. Fig. 3τ2, τ3 and τ4 are in, respectively, anti-periplanar (153.5 to 179.3°), syn-periplanar (0.8 to 14.7°) and anti-periplanar (from 171.8 to 180.0°) conformations. The attached cyclohexane ring is always close to perpendicular to the thioamide group and with a syn/anti-clinal (τ5 = 78.3 to 94.5°) conformation. Furthermore, torsion angle τ1 for most of these structures exists in a syn-periplanar conformation, ranging from 0 to 25.8°, but there is one outlier  conformation. The cyclohexylhydrazinecarbothioamide moiety of this structure is substituted with an anthracen-9-ylmethylene ring system.A search of the Cambridge Structural Database  in 20 ml methanol was added dropwise with stirring to the aldehyde solution. The resulting colourless solution was refluxed for 4 h with stirring. A colourless precipitate was obtained on evaporation of the solvent. The crude product was washed with n-hexane (5 ml). The recovered product was dissolved in acetonitrile and purified by recrystallization. Colourless block-like crystals suitable for X-ray diffraction analysis were obtained on slow evaporation of the acetonitrile solvent .2-Hydroxy-3-methylbenzaldehyde  was dissolved in 20 ml of methanol. Glacial acetic acid (0.20 ml) was added and the mixture was refluxed for 30 min. A solution of Spectroscopic and analytical data: 1H NMR : δ 11.27 , δ 9.51 , δ 8.34 , δ 8.05 , δ 7.39–6.81 , δ 2.20 , δ 1.87–1.14  ppm. 13C NMR : δ 175.79 (C=S), δ 154.29 (C=N), δ 143.76-119.17 (C-aromatic), δ 15.93 (CH3), δ 52.87–24.90 (C-cyclohexyl) ppm. IR : 3364 (NH), 3148 (OH), 2989(CH3), 2931 and 2854 , 1620 (C=N), 1540 , 1268 (C=S), 1218 , 1122 (C—O). 1075 (C—N). Elemental analysis calculated for C15H21N3OS (Mr = 291.41 g mol−1); C, 61.77; H, 7.21; N, 14.42%; found: C, 61.81; H, 7.19; N, 14.42%.Uiso(H) = 1.5Ueq(C-methyl) and 1.2Ueq(C) for other H atoms.Crystal data, data collection and structure refinement details are summarized in Table 310.1107/S2056989019008946/su5501sup1.cifCrystal structure: contains datablock(s) I, Global. DOI: 10.1107/S2056989019008946/su5501Isup2.hklStructure factors: contains datablock(s) I. DOI: 1480651CCDC reference:  crystallographic information; 3D view; checkCIF reportAdditional supporting information:


In the molecular packing, methylene-C—H⋯O(ring carbonyl) and N(pyridazinyl) interactions result in the formation of a supramolecular tape along the  16H18N2O3, is constructed about a central oxopyridazinyl ring (r.m.s. deviation = 0.0047 Å), which is connected to an ethylacetate group at the N atom closest to the carbonyl group, and benzyl and methyl groups second furthest and furthest from the carbonyl group, respectively. An approximately orthogonal relationship exists between the oxopyridazinyl ring and the best plane through the ethylacetate group [dihedral angle = 77.48 (3)°]; the latter lies to one side of the central plane [the Nr—Nr—Cm—Cc  torsion angle being 104.34 (9)°]. In the crystal, both H atoms of the N-bound methylene group form methylene-C—H⋯O(ring carbonyl) or N(pyridazinyl) interactions, resulting in the formation of a supramolecular tape along the a-axis direction. The tapes are assembled into a three-dimensional architecture by methyl- and phenyl-C—H⋯O(ring carbonyl) and phenyl-C—H⋯O(ester carbonyl) interactions. The analysis of the calculated Hirshfeld surface indicates the dominance of H⋯H contacts to the overall surface (i.e. 52.2%). Reflecting other identified points of contact between molecules noted above, O⋯H/H⋯O (23.3%), C⋯H/H⋯C (14.7%) and N⋯H/H⋯N (6.6%) contacts also make significant contributions to the surface.The title compound, C H)-ones are pyridazine derivatives, being constructed about a six-membered ring which contains two adjacent nitrogen atoms, at positions one and two, and with a carbonyl group at position three. The interest in these nitrogen-rich heterocyclic derivatives arises from the fact that they exhibit a number of promising pharmacological and biological activities. These include anti-oxidant , the crystal and molecular structures of the the title pyridazin-3(2H)-one derivative, (I)Pyridazin-3(2The molecular structure of (I)2 and eight-membered {⋯NNCH}2 synthons, respectively. The result is the formation of a supramolecular tape orientated along the a-axis direction, Fig. 2a). Globally, the tapes assemble into layers in the ab plane and these stack along the c-axis direction as shown in Fig. 2b). Weak interactions contributing to the formation of the layers include methyl-C16—H⋯O1(ring carbonyl) contacts s Table 2. Betweenet al., 2019dnorm in Fig. 3a), the C—H⋯N contact involving the methylene-H13A and pyridazinyl-N2 atoms are represented as bright-red spots on the surface. The diminutive red spots appearing near the methylene-H13B and carbonyl-O1 atoms indicate the weak C—H⋯O contact, Fig. 3a) and (b). The intense blue and red regions corresponding to positive and negative electrostatic potentials on the Hirshfeld surfaces mapped over electrostatic potential in Fig. 4dnorm-mapped Hirshfeld surfaces in Fig. 3dnorm mapped Hirshfeld surface illustrating weak intermolecular interactions are shown in the views of Fig. 5The Hirshfeld surfaces calculated for (I)a), and those delineated into H⋯H, O⋯H/H⋯O, N⋯H/H⋯N and C⋯H/H⋯C and C⋯C contacts –(f); the percentage contribution from different interatomic contacts to the Hirshfeld surfaces of (I)b), having the greatest contribution, i.e. 52.2%, to the Hirshfeld surface, a pair of beak-shaped tips at de + di ∼2.3 Å reflect the short interatomic contact between the methyl-H5C and H16C atoms, Table 2c) demonstrates two pairs of adjoining short tips at de + di ∼2.5 and 2.6 Å, together with the green aligned points in the central region, which are indicative of weak C—H⋯O contacts present in the crystal. The pair of long spikes at de + di ∼2.5 Å in the fingerprint plot delineated into N⋯H/H⋯N contacts of Fig. 6d), are the result of a potential C—H⋯N interaction involving the methylene-C13—H13A and pyridazinyl-N2 atoms. The short interatomic C⋯H/H⋯C contacts as summarized in Table 2de + di ∼2.7 and 2.8 Å, respectively in Fig. 6e). The presence of a weak π–π contact between the oxopyridazinyl and phenyl rings is reflected in the thick arrow-like tip at de + di ∼3.4 Å in the fingerprint plot delineated into C⋯C contacts of Fig. 6f), specifically the short interatomic C2⋯C9 contact, Table 2i.e. 2.3%, contribution from C⋯N/N⋯C contacts to the Hirshfeld surface.The overall two-dimensional fingerprint plot, Fig. 6et al., 2007The most closely related structure to (I)H)-one precursor. To this pyridazine (0.05 mol) was added potassium carbonate (0.1 mmol), tetrabutylammonium bromide (0.01 mmol) and 2-ethyl bromoacetate (0.1 mol) in dimethylformamide (20 ml). The mixture was stirred for 24 h at room temperature. At the end of the reaction, the solution was filtered and the solvent evaporated under reduced pressure. The residue was washed with water and methylenechloride. The solvent was removed and colourless blocks of (I)A mixture of 3-benzylidene-4-oxopentanoic acid (0.05 mol) and hydrazine hydrate (0.1 mol) in ethanol (100 ml) was refluxed for 2 h. The precipitate formed was filtered off and recrystallized from acetone to obtain the 5-benzyl-6-methylpyridazin-3(2Uiso(H) set to 1.2–1.5Ueq(C).Crystal data, data collection and structure refinement details are summarized in Table 410.1107/S205698901900241X/hb7802sup1.cifCrystal structure: contains datablock(s) I, global. DOI: 10.1107/S205698901900241X/hb7802Isup2.hklStructure factors: contains datablock(s) I. DOI: Click here for additional data file.10.1107/S205698901900241X/hb7802Isup3.cmlSupporting information file. DOI: 1897511CCDC reference:  crystallographic information; 3D view; checkCIF reportAdditional supporting information:


Bnz⋯NPrpnit  hydrogen bonds, are linked into stepped ribbons extending parallel to [110] by C—HPrpnit⋯OThz (Thz = thiazine) hydrogen bonds. The ribbons are joined into pairs by inversion-related C=O⋯Cl interactions.In the title compound, the dihydrobenzothiazine moiety is folded about the S1⋯N1 axis. In the crystal, inversion dimers, generated by C—H 18H12Cl2N2OS, consists of a dihydrobenzothiazine unit linked by a –CH group to a 2,4-dichlorophenyl substituent, and to a propanenitrile unit is folded along the S⋯N axis and adopts a flattened-boat conformation. The propanenitrile moiety is nearly perpendicular to the mean plane of the dihydrobenzothiazine unit. In the crystal, C—HBnz⋯NPrpnit and C—HPrpnit⋯OThz  hydrogen bonds link the molecules into inversion dimers, enclosing R22(16) and R22(12) ring motifs, which are linked into stepped ribbons extending along [110]. The ribbons are linked in pairs by complementary C=O⋯Cl interactions. π–π contacts between the benzene and phenyl rings, [centroid–centroid distance = 3.974 (1) Å] may further stabilize the structure. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the crystal packing are from H⋯H (23.4%), H⋯Cl/Cl⋯H (19.5%), H⋯C/C⋯H (13.5%), H⋯N/N⋯H (13.3%), C⋯C (10.4%) and H⋯O/O⋯H (5.1%) interactions. Hydrogen bonding and van der Waals interactions are the dominant interactions in the crystal packing. Computational chemistry calculations indicate that the two independent C—HBnz⋯NPrpnit and C—HPrpnit⋯OThz hydrogen bonds in the crystal impart about the same energy (ca 43 kJ mol−1). Density functional theory (DFT) optimized structures at the B3LYP/6–311 G level are compared with the experimentally determined molecular structure in the solid state. The HOMO–LUMO behaviour was elucidated to determine the energy gap.The title compound, C These molecules exhibit a wide range of biological applications indicating that the 1,4-benzothiazine moiety is a potentially useful template in medicinal chemistry research and has therapeutic applications as anti-inflammatory (Trapani A (C1–C6), is oriented at a dihedral angle of 1.89 (6)° with respect to the phenyl ring, C (C10–C15). A puckering analysis of the heterocyclic ring B (S1/N1/C1/C6–C8) of the dihydrobenzothiazine unit gave the parameters QT = 0.1983 (15) Å, q2 = 0.1957 (17) Å, q3 = 0.0323 (19) Å, φ = 354.6 (6)° and θ = 80.8 (5)°, indicating it adopts a flattened-boat conformation. The propanenitrile moiety is essentially perpendicular to the dihydrobenzothiazine unit, as indicated by the C7—N1—C16—C17 torsion angle of 88.6 (2)°. In heterocyclic ring B, the C1—S1—C8 [103.69 (9)°], S1—C8—C7 [121.12 (14)°], C8—C7—N1 [120.59 (17)°], C7—N1—C6 [126.27 (16)°], C6—C1—S1 [123.84 (15)°] and N1—C6—C1 [121.46 (17)°] bond angles are enlarged when compared with the corresponding values in the closely related compounds, (2Z)-2-(4-chlorobenzylidene)-4-[2-(2-oxooxazoliden-3-yl) ethyl]-3,4-dihydro-2H-1,4-benzothiazin-3-one, (II), -2-[(4-fluorobenzylidene]-4-(prop-2-yn-1-yl)-3,4 -dihydro-2H-1,4-benzothiazin-3-one, (III), -4-[2-ethyl]-2(phenylmethylidene)-3,4-dihydro-2H-1,4-benzothiazin-3-one, (IV), -2-[methylidene]-4-[2-ethyl]3,4-dihydro-2H-1,4-benzothiazin-3-one, (V), Bnz⋯NPrpnit (Bnz = benzene and Prpnit = propanenitrile) hydrogen bonds (Table 1Prpnit⋯OThz (Thz = thiazine) hydrogen bonds Cg1) and 2,4-dichlorophenyl rings  [Cg1⋯Cg3 = 3.974 (1) Å] may further stabilize the structure.In the crystal, inversion dimers are formed by C—Hs Table 1, enclosis Table 1, enclosi)° Fig. 3. The conCrystalExplorer17.5  analysis  have a nearly symmetrical distribution of points, Fig. 7c, with the thin edges at de + di = 2.82 Å. In the absence of C—H⋯π interactions, the wings in the fingerprint plot delineated into H⋯C/C⋯H contacts (13.5%) also have a nearly symmetrical distribution of points, Fig. 7d, with the thick edges at de + di ∼2.90 Å. The wings in the fingerprint plot delineated into H⋯N/N⋯H contacts  have as pair of spikes with the tips at de + di = 2.30 Å. The C⋯C contacts  have an arrow-shaped distribution of points with the tip at de = di ∼1.78 Å. The H⋯O/O⋯H  and C⋯Cl/Cl⋯C  contacts  and C⋯S/S⋯C  contacts are seen as pairs of wide spikes with the tips at de + di ∼3.30 and 3.48 Å, respectively.The overall two-dimensional fingerprint plot, Fig. 7H Table 2, contribs Table 2 are viewdnorm plotted onto the surface are shown for the H⋯H, H⋯Cl/Cl⋯H, H⋯C/C⋯H, H ⋯ N/N⋯H, C⋯C and H⋯O/O⋯H interactions in Fig. 8a–f, respectively.The Hirshfeld surface representations with the function et al., 2015The Hirshfeld surface analysis confirms the importance of H-atom contacts in establishing the packing. The large number of H⋯H, H⋯Cl/Cl⋯H, H ⋯ C/C⋯H and H⋯N/N⋯H interactions suggest that van der Waals interactions and hydrogen bonding play the major roles in the crystal packing  is the sum of electrostatic (Eele), polarization (Epol), dispersion (Edis) and exchange-repulsion (Erep) energies  were calculated to be −13.0 (Eele), −1.8 (Epol), −68.0 (Edis), 48.3 (Erep) and −44.4 (Etot) for the C—HBnz⋯NPrpnit hydrogen-bonding interaction and −37.3 (Eele), −9.3 (Epol), −19.0 (Edis), 33.7 (Erep) and −42.0 (Etot) for C—HPrpnit⋯OThz.The intermolecular interaction energies were calculated using the CE–B3LYP/6–31G energy model available in via density functional theory (DFT) using standard B3LYP functional and 6–311 G basis-set calculations -2-[methylidene]-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-4-yl]propanenitrile ring. The energy band gap [ΔE = ELUMO − EHOMO] of the molecule is about 6.1979 eV, and the frontier molecular orbital energies, EHOMO and ELUMO are −7.1543 and −0.9564 eV, respectively.The optimized structure of the title compound in the gas phase was generated theoretically et al., 2016R1 = Ph, R2 = C), gave 14 hits. With R1 = Ph and R2 = CH2C≡CH IIa  to 36° (IIf). The other three  have the benzothiazine unit nearly planar with a corresponding dihedral angle of ca 3–4°.A search in the Cambridge Structural Database (Groom Z)-2--2H-1,4-benzothiazin-3(4H)-one (1.8 mmol), potassium carbonate (2.0 mmol) and tetra n-butyl ammonium bromide (0.15 mmol) in DMF (20 ml). Stirring was continued at room temperature for 12 h. The salts were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was separated by chromatography on a column of silica gel with ethyl acetate–hexane (1/9) as eluent. The solid product obtained was recrystallized from ethanol to afford colourless crystals (yield: 82%).3-Bromopropanenitrile (2.0 mmol) was added to a mixture of (Uiso(H) = 1.2Ueq(C).Crystal data, data collection and structure refinement details are summarized in Table 310.1107/S2056989019005966/lh5901sup1.cifCrystal structure: contains datablock(s) I, global. DOI: 10.1107/S2056989019005966/lh5901Isup2.hklStructure factors: contains datablock(s) I. DOI: Click here for additional data file.10.1107/S2056989019005966/lh5901Isup3.cdxSupporting information file. DOI: 1913051CCDC reference:  crystallographic information; 3D view; checkCIF reportAdditional supporting information:


E,1′E)-bis(methanylylidene)}bis[2-(trifluoromethoxy)phenol].In the title complex, the nickel(II) ion has a square-planar coordination sphere, being ligated by two N and two O atoms of the tetradentate Schiff base ligand 6,6′-{-bis(methanylylidene)}bis[2-(trifluoromethoxy)phenol]-κ4O,N,N′,O′)nickel(II), [Ni(C18H12F6N2O4)], the nickel(II) ion has a square-planar coordination sphere, being ligated by two N and two O atoms of the Schiff base ligand 6,6′-{-bis(methanylylidene)}bis[2-(trifluoromethoxy)phenol] (L). Inversion-related molecules are linked by a short Ni⋯Ni interaction of 3.2945 (6) Å forming a dimer. In the crystal, the dimers stack up the a axis, with a closest Ni⋯Ni separation of ca 3.791 Å. There are no other significant intermolecular interactions present. However, the Hirshfeld surface analysis and the two-dimensional fingerprint plots indicate that the packing is dominated by H⋯F/F⋯H, H⋯H, O⋯H/H⋯O and C⋯H/H⋯C contacts.In the title complex, (6,6′-{(1 Their —OH and C=N groups are involved in the formation of covalent bonding with the metal atom; besides, these molecules are known to be easy to synthesize giving a high yield under mild conditions by solvent or solvent-free methods  Å . The nickel ion Ni1 is coordinated by two imine N atoms, N6 and N7, and by two phenoxo O atoms, O2 and O3, of the tetradentate Schiff base ligand L. The bond lengths, Ni—O2 and Ni—O3 , and Ni—N6 and Ni—N7  are close to the values observed for nickel complexes of similar ligands (see section Database survey). The coordinating atoms, N6, N7, O2, O3, are essentially planar with no atom deviating from its mean plane by more than 0.0325 Å. The τ4 factor for four-coordinated metal atoms is = 0.04, indicating an almost perfect square-planar coordination sphere for atom Ni1 a-axis direction with a Ni1i⋯Ni1ii separation of ca. 3.791 Å . There are no other significant intermolecular interactions present; both C—H⋯F and C—H⋯O interactions exceed the sum of their van der Walls radii.In the crystal, the dimers stack up the et al., 2016et al. (1970supporting information files S1(H), S2(OMe) and S3(OEt)]. A common feature of these complexes is the dimer formation with an Ni⋯Ni separation of between ca 3.2 to 3.9 Å. The same dimeric arrangement is found in the title complex, where this separation is 3.2945 (6) Å. In the majority of these complexes, the Ni—Nimine bond lengths vary from ca 1.837 to 1.956 Å while the Ni—Ophenoxo bond lengths vary from ca 1.834 to 1.936 Å. In the title complex, the Ni—Nimine [1.839 (3) and 1.843 (3) Å] and Ni—Ophenoxo [1.840 (2) and 1.845 (2) Å] bond lengths fall within these limits.A search of the Cambridge Structural Database , O⋯H (12.4%) and C⋯H (11.3%) contacts. The electrostatic potential energy in the range −0.031 to 0.256 a.u., obtained using the STO-3G basis set at the Hartree–Fock level of theory, is illustrated in Fig. 6The Hirshfeld surface analysis , was synthesized by condensation of 2-hydroxy-3-trifluoromethoxybenzaldehyde (0.0095 mmol) and 1,2-ethanediamine (0.0095 mmol) in ethanol under reflux for ca 18 h. The yellow product obtained was washed with ether and dried at room temperature. Ni(CH3COO)2·4H2O (0.0080 mmol) dissolved in 20 ml of ethanol was added slowly to an ethanol (20 ml) solution of L (0.0080 mmol) and the mixture was refluxed for ca 6 h. The orange product obtained was filtered off and washed with toluene. Red rod-like crystals of the title complex were obtained by slow evaporation of a solution in ethanol at room temperature .The title Schiff base ligand (Uiso(H) = 1.2Ueq(C).Crystal data, data collection and structure refinement details are summarized in Table 110.1107/S2056989019001919/su5478sup1.cifCrystal structure: contains datablock(s) I, Global. DOI: 10.1107/S2056989019001919/su5478Isup2.hklStructure factors: contains datablock(s) I. DOI: 10.1107/S2056989019001919/su5478sup3.pdfCSD search S1. DOI: 10.1107/S2056989019001919/su5478sup4.pdfCSD search S2. DOI: 10.1107/S2056989019001919/su5478sup5.pdfCSD search S3. DOI: 1890705CCDC reference:  crystallographic information; 3D view; checkCIF reportAdditional supporting information:


A new quinoxalin-derived ene-dithiocarbonate was synthesized and structurally analysed. The synthetic procedure and the compound’s spectroscopic and analytical characterization are reported. I, C13H10N2O2S2, crystallizes in the monoclinic space group C2/c with eight molecules in the unit cell. Excluding for the ethyl substituent, the molecule of I adopts a nearly coplanar conformation (r.m.s. deviations is 0.058 Å), which is supported by the intramolecular C—H⋯O hydrogen-bonding interaction between the two ring systems [C⋯O = 2.859 (3) Å]. In the crystal, the molecules form dimeric associates via two bifurcated C—H⋯O hydrogen-bonding interactions between an ene hydrogen atom and a carbonyl functional group of an adjacent molecule [C⋯O = 3.133 (3) Å] and vice versa. The crystal structure is further stabilized by a three-dimensional network of weak hydrogen bonds between one molecule and six adjacent molecules as well as offset π–π stacking. The combination of the quinoxaline 2(1H)-one moiety with the dithiocarbonate moiety extends the aromaticity of the quinoxaline scaffold towards the substituent as well as influencing the π-system of the quinoxaline. The title compound is the direct precursor for a dithiolene ligand mimicking the natural cofactor ligand molybdopterin.The title compound  As a result of their unusual redox and structural characteristics and those of their metal complexes, they immediately attracted considerable scientific interest  Å for C5] and the dithiolene ring , which are connected by the C3—C4 bond [length = 1.465 (3) Å], are essentially coplanar, with an angle of only 4.89 (12)° between the two planes  Å; Table 1et al., 19952 bonds  and O2⋯H2—C2; D⋯A = 3.133 (3) Å]. Here, the exact same atoms are involved as in the intramolecular hydrogen bond mentioned above. The respective hydrogen atom H2 is therefore bound to the ene carbon atom C2 and hydrogen bonded to the carbonyl oxygen (O2) of the quinoxaline moiety of the same molecule as well as that of the adjacent molecule , the quinoxalin substituent of the present molecule is replaced by a coumarine , the ene-dithiocarbonate is replaced by an aminothiazole  an overall weaker resonance in A, in which the benzene ring C—C distances are all very similar (i.e. strongly resonant) whereas all other distances are of more pronounced single- and double-bond character and of less aromatic character.By bidirectional intermolecular hydrogen bonding, the title compound crystallizes as dimeric associate with the same donor and acceptor roles for both monomers , C7 [C7—H7⋯O1 Å], C9 , C12  and acceptor interactions involving S2 [S2⋯H9—C9(−x + y + z + 1)], O2  and O1 [O1⋯H7—C7 C—H⋯O and C—H⋯S hydrogen-bonding interactions, forming a three-dimensional network Fig. 2. In the H)-one was synthesized based on a reported literature procedure quinoxalin-2quinoxalin-2(1H)-one: To a solution of S-2--2-oxo-ethyl o-isopropyl carbonodithioate  in 250 ml DCM/Et2O 1:1 at ambient temperature, H2SO4 (25.50 ml) was added. The reaction mixture was stirred at room temperature for 2h. After that, the reaction was quenched by addition of 250 ml of ice and the mixture was stirred for 30 min. The organic phase was washed with brine and water 3 × 250 ml. The solvent was reduced to 10 ml in vacuo and the greenish precipitate was filtered off and washed on the filter with cold acetone 3 × 50 ml. The title compound was obtained as a greenish-white powder. Single crystals suitable for X-ray analysis were obtained by slow diffusion of solvents with chloroform and Et2O Yield: 1.85g (20%).1H NMR  δ 8.79 ppm , 7.87 ppm , 7.61 ppm , 7.4 ppm , 4.39 ppm , 1.42 ppm . 13C NMR  δ 152.54 ppm, 144.75 ppm, 133.25 ppm, 132.58 ppm, 131.14 ppm, 130.32 ppm, 126.98 ppm, 124.00 ppm, 113.47 ppm, 37.47 ppm, 12.20 ppm. IR (KBr pellet): (ν cm−1) = 3495 (br), 1734 (w), 1646 (sst), 1601 (st), 1579 (st), 1535 (st), 1463 (st), 1383 (w), 1280 (st), 1248 (w), 1216 (w), 1173 (st), 1128 (w), 1087 (w), 1045 (w), 950 (w), 892 (st), 868 (w), 825 (st), 785 (w), 758 (st), 631 (w), 554 (w), 529 (w), 467 (w), 432 (w). APCI–MS (m/s) = 291 (M+ + H+). Analysis calculated for C13H10N2O2S2: C, 53.78; H 3.47; N 9.65; S 22.09. Found: C, 53.41; H 3.25; N 9.86; S 22.32.Uiso(H) = 1.5Ueq(C) for the methyl group, C—H = 0.99 Å with Uiso(H) = 1.2Ueq(C) for the methylene group and C—H = 0.95 Å with Uiso(H) = 1.2Ueq(C) for the aromatic atoms.Crystal data, data collection and structure refinement details are summarized in Table 210.1107/S2056989018007892/kq2022sup1.cifCrystal structure: contains datablock(s) I. DOI: 10.1107/S2056989018007892/kq2022Isup2.hklStructure factors: contains datablock(s) I. DOI: Click here for additional data file.10.1107/S2056989018007892/kq2022Isup3.cmlSupporting information file. DOI: 1845671CCDC reference:  crystallographic information; 3D view; checkCIF reportAdditional supporting information:


The crystal structure of the title molecular solvate features O—H⋯O hydrogen bonds, Br⋯O and π–π interactions. Hirshfeld surface analysis and fingerprint plots helped to identify the major contributors to the intermolecular interactions. 8H4Br2O4·C2H6O2, crystallizes with one-half of a 2,5-dibromoterephthalic acid (H2Br2tp) molecule and one-half of an ethylene glycol (EG) molecule in the the asymmetric unit. The whole molecules are generated by application of inversion symmetry. The H2Br2tp molecule is not planar, with the dibromobenzene ring system inclined by a dihedral angle of 18.62 (3)° to the carboxylic group. In the crystal, the H2Br2tp and EG molecules are linked into sheets propagating parallel to (R44 (12) and R44 (28) graph-set motifs. Br⋯O and weak π–π stacking interactions are also observed. Hirshfeld surface analysis was used to confirm the existence of these interactions.The title compound, C As a result of symmetry restrictions, the EG molecule adopts an anti-conformation with an O3—C5—C5i—O3i torsion angle of 180° .The structures of the molecular components in the title compound are shown in Fig. 12Br2tp and EG molecules are linked by strong-to-medium O—H⋯O hydrogen bonds between carboxylic acid and alcohol OH functions  to 0.9385 a.u. (blue) and the two-dimensional fingerprint plots are illustrated in Fig. 4dnorm surface can be assigned to Br⋯O contacts. Analysis of the two-dimensional fingerprint plots reveals that the H⋯O/O⋯H (28.8%) contacts are the dominant contributors to the Hirshfeld surface. The contribution of the Br⋯H/H⋯Br contacts is 22.1%, whereas Br⋯Br contacts are negligible (0.9%). Other contacts viz. H⋯H (17.7%), H⋯C/C⋯H (7.7%), Br⋯C/C⋯Br (7.2%), Br⋯O/O⋯Br (5.8%), C⋯O/O⋯C (4.5%), C⋯C (3.3%) and O⋯O (2.2%) also make significant contributions to the Hirshfeld surface.Hirshfeld surfaces ethylidene]pyridine-4-carbohydrazonato-κ2N′,O}nickel(II)–2,5-dibromoterephthalic acid  in 5 ml of EG was heated (333 K) to reflux for 15 min. The reaction solution was held for 2–3 h and colourless block-shaped crystals suitable for single-crystal X-ray diffraction analysis were obtained.HUiso(H) = 1.2Ueq(C). The H atoms bound to O atoms were located from difference-Fourier maps but were refined with distance restraints of O—H = 0.82 ± 0.02 Å and Uiso(H) = 1.5Ueq(O).Crystal data, data collection and structure refinement details are summarized in Table 210.1107/S2056989019010260/wm5512sup1.cifCrystal structure: contains datablock(s) I. DOI: Click here for additional data file.10.1107/S2056989019010260/wm5512Isup3.cdxSupporting information file. DOI: 10.1107/S2056989019010260/wm5512Isup4.hklStructure factors: contains datablock(s) I. DOI: 1941436CCDC reference:  crystallographic information; 3D view; checkCIF reportAdditional supporting information:


ANCA)‐associated vasculitis (AAV), S1P participated in MPO‐ANCA‐positive IgG‐induced glomerular endothelial cell (GEnC) activation via a S1P receptor (S1PR)‐dependent way. However, the downstream signalling pathways are not fully clear yet. In this study, we demonstrated that Rho guanosine triphosphatases (GTPases) signalling pathways, RhoA and Rac1 in particular, were implicated in MPO‐ANCA‐positive IgG‐mediated GEnCs activation enhanced by pathophysiological concentration of S1P in AAV. These results provide mechanistic insights into vascular barrier dysfunction in AAV, which may facilitate the development of effective therapies.Sphingosine‐1‐phosphate (S1P) is a crucial regulator in vascular inflammation. Our recent study found that under pathophysiological concentration in active anti‐neutrophil cytoplasmic antibody ( S1P and its five G‐protein‐coupled receptors (GPCRs), S1PR1‐5, are implicated in diverse vascular inflammatory conditions.Rho guanosine triphosphatases (GTPases) mediate diverse biological responses including morphogenesis, chemotaxis and cell cycle progression.22.1See the “Supporting Information Data 2.2Primary human glomerular endothelial cells  were cultured according to the manufacturer's instructions.2.3MPO‐ANCA‐positive IgGs and normal IgGs were prepared as previously described2.4Rac1 and RhoA activation assays were performed following the manufacturer's instructions .2.5As biomarkers of endothelial cell activation, levels of soluble vascular cell adhesion molecule‐1(sVCAM‐1) and intercellular adhesion molecule‐1 (sICAM‐1) in the GEnC supernatants were tested with commercially available ELISA kits .2.6P < .05 . Differences were considered statistically significant if 33.1P < .001 by ANOVA; 140.1 ± 8.9% vs 100%, P < .001 by ANOVA)  Figure ,S3.3.2P < .001 by ANOVA; 113.9 ± 9.4% vs 147.9 ± 5.2%, P < .001 by ANOVA; 124.7 ± 4.4% vs 147.9 ± 5.2%, P < .001 by ANOVA, respectively), while the S1PR5 agonist A97 up‐regulated the RhoA activity  . By contrast, the ICAM‐1 and VCAM‐1 levels in the supernatants of GEnCs stimulated by S1P combined with MPO‐ANCA‐positive IgG increased significantly upon pre‐incubation with Rac1 antagonist NSC  (Figure Pre‐incubation of GEnCs with the RhoA antagonist CCG significantly decreased ICAM‐1 and VCAM‐1 levels in the supernatants of GEnCs stimulated by S1P plus MPO‐ANCA‐positive IgG (1352.33 ±  122.73 pg/mL vs 812.91 ± 25.12 pg/mL, 4In our present study, we demonstrated that under pathophysiological concentration in active AAV patients, S1P could activate both RhoA and Rac1 signalling pathways in MPO‐ANCA‐positive IgG‐treated GEnCs. According to Singleton et al, RhoA and Rac1 play opposing roles in regulating endothelial barrier function in response to differential activation of S1PRs.In conclusion, our current study demonstrated that Rho GTPases signalling pathways were involved in S1P‐enhanced GEnCs activation with MPO‐ANCA‐positive IgG. RhoA activated by S1PR2‐5 dominated the S1P‐induced GEnC activation in the presence of MPO‐ANCA‐positive IgG, while Rac1 activated by S1PR1 exerted opposite effect during this process. These findings provide us with more clues to determine the role of and Rho GTPases and S1P in the development of AAV.No conflict of interest to declare. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file.


The dihedral angles between the pyridine ring and its attached phenyl groups are 42.24 (8) and 6.37 (14)°. In the crystal, a system of classical O—H⋯O and O—H⋯ hydrogen bonds links the molecules to form tube-like assemblies propagating parallel to the  23H20N2O4S, the sulfur atom is attached equatorially to the sugar ring with unequal S—C bonds, viz.: S—Cs = 1.808 (2) and S—Cp = 1.770 (2) Å . The dihedral angles between the pyridine ring and its attached phenyl groups are 42.24 (8) and 6.37 (14)°. In the crystal, a system of classical O—H⋯O and O—H⋯ hydrogen bonds links the molecules to form tube-like assemblies propagating parallel to the c-axis direction. Weak C—H⋯N interactions are also observed.In the racemic title compound, C Thus, (1) reacted with (2) in KOH in acetone to give a product for which two isomeric N- or S-arabinoside structures were conceivable, corresponding to two possible modes of glycosylation. The final deprotected product (see Scheme4) or its regioisomer pyridine-2-thione-N-arabinoside (5). Spectroscopic data cannot differentiate between these two structures.Here we report a one-step synthesis of the pyridine-2-thioarabinoside (4) as the only product in the solid state. We suggest that the 2,3,4-tri-O-acetyl-α-d-arabinopranosyl bromide (2) interacts via a simple SN2 reaction to give the β-glycoside product (3), which after deprotection leads to the free 2-(β-d/l-arabinopyranosylthio)-pyridine-3-carbonitrile (4). This separates as a racemic mixture, presumably because of thermodynamic racemization during synthesis or crystallization  is shown in Fig. 1et al., 2017s 1.808 (2) and S—Cp 1.770 (2) Å . The phenyl ring at C31 is approximately coplanar with the pyridyl ring, but the ring at C21 is significantly rotated (interplanar angles = 6.4 (2) and 42.24 (8)°, respectively). The relative orientation of the pyridyl ring and the sugar moiety is defined by the torsion angles N1—C2—S1—C11 9.7 (2) and C2—S1—C11—C12 162.73 (12)°. The intramolecular contact O1—H01⋯S1, with H⋯S 2.79 (4) Å and an angle of 109 (3)°, is probably too long and has too narrow an angle to be considered a hydrogen bond.The molecular structure of  contact of 3.2374 (16) Å  may play a supporting role, but is not shown explicitly.In the crystal, the molecules are connected by two-centre O2—H02⋯O3d Table 1, via thes Figs. 2 and 3 ▸.et al., 1993There is one other structure involving arabinose with a sulfur substituent at the C2 position; the arabinose is triacetylated and the sulfur atom, which is axially bonded to the sugar ring, acts as a bridge to a pyranopyrimidine ring system (Tomas H)-thione (1)  in aqueous potassium hydroxide  was added a solution of 2,3,4-tri-O-acetyl-α-d-arabinopyranosyl bromide (2)  in acetone (30 ml). The reaction mixture was stirred at room temperature until the reaction was judged complete by TLC (30 min to 2 h). The mixture was evaporated under reduced pressure at 313 K and the residue was washed with distilled water to remove the potassium bromide. The solid was collected by filtration and crystallized from ethanol to give compound (3) in 70% yield (m. p. 440–442 K). Dry gaseous ammonia was then passed through a solution of the protected thioglycoside (3) (0.5 g) in dry methanol (20 ml) at 273 K for 15 min, and the mixture was stirred at 273 K until the reaction was complete . The mixture was evaporated at 313 K to give a solid residue, which was recrystallized from methanol solution to give compound (4) in 60% yield (m.p. 479–480 K), IR (KBr): 3370–3480 (OH); 2222 (CN) cm−1. 1H NMR : δ 3.10–3.70 ; 4.81–5.20 ; 5.52 , 7.05–7.78 , 7.99 . Analysis calculated for C23H20N2O4S (420.47): C, 65.60%; H, 4.76%; N, 6.66%. Found: C, 65.48%; H, 4.84%; N, 6.41%.To a solution of the pyridine-2- with Uiso(H) = 1.2–1.5Ueq(C).Crystal data, data collection and structure refinement details are summarized in Table 210.1107/S2056989018007284/hb7743sup1.cifCrystal structure: contains datablock(s) I, global. DOI: 10.1107/S2056989018007284/hb7743Isup2.hklStructure factors: contains datablock(s) I. DOI: 1843269CCDC reference:  crystallographic information; 3D view; checkCIF reportAdditional supporting information:


Protein‐polymer conjugates show improved pharmacokinetics but reduced bioactivity and tumor penetration as compared to native proteins, resulting in limited antitumor efficacy. To address this dilemma, genetic engineering of a body temperature‐responsive and matrix metalloproteinase (MMP)‐cleavable conjugate of interferon alpha (IFNα) and elastin‐like polypeptide (ELP) is reported with spatiotemporally programmed two‐step release kinetics for tumor therapy. Notably, the conjugate could phase separate to form a depot postsubcutaneous injection, leading to 1‐month zero‐order release kinetics. Furthermore, it could selectively be cleaved by MMPs that are overexpressed in tumors to release IFNα from ELP and thus to recover the bioactivity of IFNα. Consequently, it exhibits dramatically enhanced tumor accumulation, tumor penetration, and antitumor efficacy as compared to free IFNα in two mouse models of melanoma and ovarian tumor. These findings may provide an intelligent technology of thermoresponsive and protease‐cleavable protein‐polymer conjugates with spatiotemporally programmed two‐step release kinetics for tumor treatment. In this proof‐of‐concept study, a MMP substrate (MMPS) as a linker was genetically fused to the C‐terminal of IFNα and the N‐terminal of a body temperature‐responsive elastin‐like polypeptide (ELP(V)) to form a body temperature‐responsive and MMP‐cleavable IFNα‐MMPS‐ELP(V) conjugate Schemea. IFNα is Scheme b. Furthes Scheme c. Indeed22.1Tt values were genetically engineered (see Supporting Information). Simultaneously, two MMP‐noncleavable IFNα‐ELP conjugates of IFNα‐ELP(V) and IFNα‐ELP(A) with distinct Tt values were prepared as controls. Specifically, the sequence of MMPS was Pro‐Leu‐Gly‐Leu‐Ala‐Gly (PLGLAG). The A and V in ELP(A) and ELP(V) were the X in VPGXG repeat unit. The repeat unit number per ELP chain was 90. The conjugates were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS‐PAGE) and further confirmed by matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF‐MS) to have the expected molecular weights  of the conjugates were determined by dynamic light scattering (DLS) to be around 11 nm, which were 3.8‐fold larger than that of IFNα (2.9 nm)  and IFNα‐ELP(V) were below the body temperature of 37 °C when the concentrations were above 1 × 10−6m. These data suggested that IFNα‐MMPS‐ELP(V) and IFNα‐ELP(V) would in situ form depots upon subcutaneous injections at high concentrations and then would slowly liberate from the depots into circulatory system at low concentrations. By contrast, the Tt values of IFNα‐MMPS‐ELP(A) and IFNα‐ELP(A) were well above the body temperature even if the concentrations were as high as 1000 × 10−6m, suggesting that they could not in situ form depots upon subcutaneous injections. The antiproliferative activities of the conjugates , 53.8 pg mL−1 for IFNα‐MMPS‐ELP(A), 54.6 pg mL−1 for IFNα‐ELP(V), 56.9 pg mL−1 for IFNα‐ELP(A)) were nearly the same, which were around 37% of that of IFNα (IC50 = 20.2 pg mL−1)  and IFNα‐MMPS‐ELP(A) with distinct s Figurea,b. The 2.2−1, IC50) and IFNα‐MMPS‐ELP(A)  were increased from 37% to about 91% of that of IFNα   and IFNα‐MMPS‐ELP(A), the conjugates were treated with MMP‐2, followed by SDS‐PAGE analysis Figure g. As exp2.3Figuret1/2) of IFNα‐MMPS‐ELP(A) (8.9 ± 1.0 h) and IFNα‐ELP(A) (9.6 ± 2.7 h) were 6.4‐ and 6.9‐fold longer than that of free IFNα (1.4 ± 0.21 h), respectively. The area under the curves (AUCs) of IFNα‐MMPS‐ELP(A) (684.1 ± 12.1 µg L−1·h) and IFNα‐ELP(A) (707.3 ± 37.1 µg L−1 h) were 11.1‐ and 11.4‐fold larger than that of free IFNα (61.8 ± 1.7 µg L−1·h), respectively. Similarly, the biodistribution of IFNα‐MMPS‐ELP(A) was almost the same as that of IFNα‐ELP(A) but much superior to that of free IFNα , respectively. These data indicated that the introduction of the MMPS linker into IFNα‐ELP(A) did not change the pharmacokinetics and biodistribution significantly. However, IFNα‐MMPS‐ELP(A) showed significantly enhanced tumor penetration as compared to both IFNα‐ELP(A) and free IFNα, as indicated by the more intense fluorescence (yellow) observed in the area that was distant from the vessels (red) for IFNα‐MMPS‐ELP(A) than for IFNα‐ELP(A) and free IFNα  on its in vivo properties in a mouse model of C8161 melanoma Figure. The pha2.4−1 body weight) for IFNα‐MMPS‐ELP(V) was the same as that for IFNα‐ELP(V), which was 5.0‐ and 6.7‐fold higher than those for IFNα‐MMPS‐ELP(A) (20 mg kg−1 body weight) and free IFNα (15 mg kg−1 body weight), respectively . Interestingly, a bump in situ formed and gradually diminished over 40 d after subcutaneous injection of IFNα‐MMPS‐ELP(V) or IFNα‐ELP(V) at its MTD . This phenomenon suggested that both IFNα‐MMPS‐ELP(V) and IFNα‐ELP(V) could in situ form depots after subcutaneous injections at their MTDs because the Tt values of the two conjugates were far below the in vivo temperature  and IFNα rapidly increased to 5878.7 ± 187.1 µg L−1 at 4.0 h and 5456.9 ± 758.5 µg L−1 at 2.8 h, respectively, and then decreased quickly. Representative pharmacokinetic parameters were generated by fitting the data with a one‐compartment model . Notably, The t1/2 of IFNα‐MMPS‐ELP(V) (422.2 ± 13.7 h) was close to that of IFNα‐ELP(V) (491.8 ± 38.1 h), but was 46.9‐ and 222.2‐fold longer than those for IFNα‐MMPS‐ELP(A) (9.0 ± 0.87 h) and free IFNα (1.9 ± 0.08 h), respectively. The AUC of IFNα‐MMPS‐ELP(V) (2755.9 ± 16.8 mg L−1·h) was close to that of IFNα‐ELP(V) (3102.0 ± 269.8 mg L−1·h), but was 23.3‐ and 58.8‐fold larger than those for IFNα‐MMPS‐ELP(A) (118.3 ± 15.1 mg L−1 h) and free IFNα (46.9 ± 7.8 mg L−1·h), respectively. Furthermore, the AUCs of IFNα‐MMPS‐ELP(V) and IFNα‐ELP(V) were correlated to time linearly , we further studied the in vivo properties of IFNα‐MMPS‐ELP(V) postsubcutaneous administration at its maximum tolerated dose (MTD). The MTD (100 mg kg−1 tissue) was nearly equal to that of IFNα‐ELP(V) (555.7 ± 164.7 ng g−1 tissue), but was 18.0‐ and 317.2‐fold higher than those for IFNα‐MMPS‐ELP(A) (29.9 ± 1.8 ng g−1 tissue) and free IFNα (1.7 ± 0.05 ng g−1 tissue) at 3 d postinjection, respectively  was studied after subcutaneous administration at the MTD. The biodistribution of IFNα‐MMPS‐ELP(V) was similar to that of IFNα‐ELP(V), but was much better than those of IFNα‐MMPS‐ELP(A) and free IFNα . Notably, the tumor concentration of IFNα‐MMPS‐ELP(V)  was 3.5‐, 9.1‐, and 19.5‐fold smaller than those for IFNα‐ELP(V) (145.3 ± 49.1 mm3), IFNα‐MMPS‐ELP(A) (376.8 ± 121.7 mm3), and free IFNα (808.2 ± 226.1 mm3) at 30 d after the subcutaneous injections, respectively. Notably, 60% of the mice in the IFNα‐MMPS‐ELP(V) treatment group were tumor free, which was much higher than those for the treatments with IFNα‐ELP(V) (30%), IFNα‐MMPS‐ELP(A) (0%), and free IFNα (0%)  was 3.4‐, 6.0‐, and 11.6‐fold smaller than those for IFNα‐ELP(V) (250.4 ± 24.9 mm3), IFNα‐MMPS‐ELP(A) (434.9 ± 119.9 mm3), and free IFNα (847.9 ± 248.2 mm3) at 33 d after the subcutaneous injections, respectively. Notably, 37.5% of the mice in the IFNα‐MMPS‐ELP(V) treatment group were tumor free, whereas the tumor cure percentages for the treatments with IFNα‐ELP(V), IFNα‐MMPS‐ELP(A), and free IFNα were 0%  in a mouse model of melanoma. After subcutaneous injection at its MTD, IFNα‐MMPS‐ELP(V) suppressed melanoma growth more efficiently than IFNα‐ELP(V), IFNα‐MMPS‐ELP(A), and free IFNα Figurea. The av2.6FigureAll the treatments did not cause obvious loss of body weight . As indicated by hematoxylin and eosin (H&E) staining, a more extensive degree of kidney damage was observed in the IFNα treatment than in the other treatments, but no histological change in other major organs was observed in all the treatments Figure. This re3thuman = tmouse (Whuman/Wmouse)0.13 in which thuman and tmouse are the half‐lives of the conjugate in human and mouse, respectively, and Whuman and Whuman are the body weights of human and mouse, respectively.In conclusion, we have reported genetic engineering of a body‐temperature‐responsive and MMP‐cleavable protein‐polymer conjugate of IFNα‐MMPS‐ELP(V) with not only dramatically improved pharmacokinetics but also remarkably enhanced tumor accumulation and penetration, and antitumor efficacy. IFNα‐MMPS‐ELP(V) can be genetically engineered to own dual functions of body temperature responsiveness and MMP cleavability that enable spatiotemporally programmed two‐step release kinetics. The body temperature responsiveness can remarkably enhance the tolerability, pharmacokinetics, and tumor accumulation of the conjugate through the mechanism of body temperature‐responsive controlled release due to the concentration dependence of the phase transition temperature. Notably, in a mouse model, subcutaneous injection of the conjugate at its MTD offers an extremely prolonged circulation half‐life of 422.2 h. The half‐life of the conjugate in human is expected to be as long as 1195.5 h according to the empirical formulus of The authors declare no conflict of interest.SupplementaryClick here for additional data file.


The structure of a decaahydroacridine derivative with phenyl substituents at the 3- and 5-positions of the cyclohexenone rings is reported. An extensive range of O—H⋯O, C—H⋯O hydrogen bonds augmented by C—H⋯π(ring) hydrogen bonds an O⋯Br halogen bond and an unusual Br⋯π(ring) contact stabilizes the crystal packing. 33H29BrClNO4, (I), the hexahydro-2H-acridine ring system has a hydroxyethyl substituent on the N atom and a 3-bromo-6-chloro-2-hydroxyphenyl substituent on the central C atom at the 9-position. An unusual feature of the molecule is that the substituents at the 3- and 5-positions of the outer cyclohexenone rings are phenyl rings rather than the more common dimethyl substituents. C atoms on both of the cyclohexenone rings are disordered over two sites. In the crystal structure, O—H⋯O, C—H⋯O and C—H⋯π(ring) hydrogen bonds combine with an Br—O and unusual C—Br⋯π(ring) halogen bonds to generate a three dimensional network with molecules stacked along the a-axis direction.In the structure of the title compound C These include compounds that are used as anti-infammatory  ring. The C2 and C3 atoms of one cyclohexenone are disordered over two sites as is the C6 atom of the corresponding cyclohexenone. Their occupancy ratios refine to 0.521 (10):0.479 (10) for C2,C3 and 0.746 (9):0.254 (9) for C6. Only details of the major disorder components will be considered here. The central C9,N10,C11–C14 ring adopts a half-chair conformation and is inclined to the adjacent C1–C4,C11,C12 and C5–C8,C13,C14 rings at angles of 7.11 (18) and 21.64 (10)°, respectively, so the hexahydro-2H-acridine unit is far from planar. The 3-bromo-6-chloro-2-hydroxyphenyl ring subtends an angle of 84.39 (6)° to this central ring. The C1–C4,C11,C12 ring is best described as a severely flattened boat while the C5–C8,C13,C14 system is in a distorted half-chair conformation. The phenyl substituents on these outer cyclohexenone rings are inclined to their parent rings at angles of 76.87 (12)° for C31–C36 and 86.27 (8)° for C61–C66. The N-bound 2-hydroxyethyl substituent points away from the convex face of the hexahydro-2H-acridine system as does the 3-bromo-6-chloro-2-hydroxyphenyl substituent.The title compound (I)ly Fig. 1. The cenO⋯O8 hydrogen bonds, Table 1C(9) chains along the b-axis direction, linking the molecules in a head-to-tail fashion, Fig. 2a-axis direction through C65—H65⋯Cg7 contacts, Fig. 3A⋯O16 hydrogen bonds form inversion dimers that enclose Cg8 interactions. Adjacent dimers are linked by C34—H34⋯Cl5′ hydrogen bonds, forming double chains of molecules along the ab diagonal, Fig. 4v halogen bonds   Å, C3′—Br3′⋯Cg4 = 83.89 (7)°; Cg4 is the centroid of the C1′–C6′ benzene ring] et al. 2016H-acridine ring system, emphasizing the uniqueness of the structure reported here. Refining the search to structures with CH2CH substitution on the acridine N atom reduced the hits to seven, four of which have hydroxyethyl substituents on N10  = 0.95 Å for aromatic, 0.99 Å for methylene and 1.00 Å for methine H atoms, all with Uiso = 1.2Ueq(C). The C2 and C3 atoms in the C1–C4,C11,C12 cyclohexenone ring and atom, C6, in the corresponding C5–C8,C13,C14 ring are disordered over two positions. Their occupancies were refined to sum to unity with the disordered atoms of the different rings allowed to refine separately. The occupancies converged to ratios of 0.521 (10): 0.479 (10) for C2 and C3 and 0.746 (9): 0.254 (9) for C6. Positions of the hydrogen atoms on adjacent methylene groups and phenyl rings were assigned taking this disorder into account but a somewhat close H15A⋯H5C contact was still observed. One reflection with Fo >>> Fc, was omitted from the final refinement cycles.Crystal data, data collection and structure refinement details are summarized in Table 210.1107/S2056989018010873/ff2154sup1.cifCrystal structure: contains datablock(s) global, I. DOI: 10.1107/S2056989018010873/ff2154Isup2.hklStructure factors: contains datablock(s) I. DOI: Click here for additional data file.10.1107/S2056989018010873/ff2154Isup3.cmlSupporting information file. DOI: 1859007CCDC reference:  crystallographic information; 3D view; checkCIF reportAdditional supporting information:


C—H⋯O, C—F⋯π and F⋯F interactions are also observedThe title compound crystallizes with four molecules in the unit cell (Z = 4) and one formula unit in the asymmetric unit. In the crystal, molecules are linked in a head-to-tail fashion into dimers along the b-axis direction through weak C—H⋯Br and C—O⋯C 10H5BrF6O, synthesized via continuous stirring of 3,5-bis(trifluoromethyl) acetophenone with bromine in an acidic medium and concentrated under reduced pressure, crystallizes with four molecules in the unit cell (Z = 4) and one formula unit in the asymmetric unit. In the crystal, molecules are linked in a head-to-tail fashion into dimers along the b-axis direction through weak C—H⋯Br and C—O⋯Csp2 interactions. C—H⋯O, C—F⋯π and F⋯F interactions are also observed.The title compound, C N-bromosuccinimide . The torsion angle between the alkyl bromide unit and the phenyl ring (C3—C2—C1—Br1) is −179.6 (3)° whereas that between the alkyl bromide and carbonyl parts (O1—C2—C1—Br1) is 0.3 (5)°, which shows a preference for a syn orientation of the alkyl bromide unit with respect to the carbonyl group.A displacement ellipsoid plot of the title compound with the atom labelling is shown in Fig. 1c-axis direction by C—H⋯O and C—F⋯π interactions  [2.868 (4) Å] interactions, resulting in a bilayer which further packs in parallel fashion along the a-axis direction  (O⋯π = 3.252 Å) interactions. The dimers are linked along the s Table 1. The asson Fig. 3.et al., 2016et al., 2011et al., 1991Z = 4, features two prominent hydrogen bonds involving the oxygen atom while in the second, also Z = 4, the oxygen atom forms a complex with antimony pentachloride.There are more than 1000 crystal structure of phenyl ethanone derivatives in the Cambridge Structural Database (CSD) : 8.44 , 8.13 , 4.48 ; 13C NMR: : 188.81, 135.31, 133.06, 132.83, 132.60, 128.99, 127.08, 127.06, 125.42, 123.61, 121.80, 120.00, 29.46.A stirred solution of 3,5-bis(trifluoromethyl) acetophenone  in acetic acid (5 mL) was added dropwise to bromine  in acetic acid. The reaction medium was stirred at room temperature for 5 h. To the resulting mixture, water (5 mL) was added and the mixture was concentrated under reduced pressure. The residue obtained was diluted with ethylacetate (10 mL), the organic layer washed with water (10 mL) and a sodium bicarbonate solution (5 mL), and filtered through dried sodium sulfate and evaporated to obtain 1-phenyl)-2-bromoethanone as a light-yellow solid in 62% yield. m.p: 317–318 K. Uiso(H) = 1.2–1.5Ueq(C).Crystal data, data collection and structure refinement details are summarized in Table 210.1107/S2056989018007478/ds2250sup1.cifCrystal structure: contains datablock(s) global, I. DOI: 10.1107/S2056989018007478/ds2250Isup2.hklStructure factors: contains datablock(s) I. DOI: Click here for additional data file.10.1107/S2056989018007478/ds2250Isup3.cmlSupporting information file. DOI: 1843826CCDC reference:  crystallographic information; 3D view; checkCIF reportAdditional supporting information: