Calamitic metallomesogens derived from unsymmetric pyrazoles

Three series of copper(II) complexes 1a-1c derived from unsymmetric pyrazoles 2a-2c were prepared and their mesomorphic properties investigated. The mesomorphic behavior of compounds was studied by differential scanning calorimetry, polarizing optical microscopy, and powder X-ray diffractometry. The crystal and molecular structures of mesogenic copper complex (2a; n=10) of 3-[4-decyloxyphenyl]-1H-pyrazole were determined by means of X-ray structural analysis. It crystallizes in the triclinic space group P-1, with a=4.0890(1) Å, b=18.0167(2) Å, c=25.5015(5) Å, and Z=2. The geometry at copper center was not perfectly square planar. A weak intermolecular H-bond (d=2.36 Å) between Cl1 and H2 atoms and π-π interaction (ca. 3.45-3.55 Å) was also observed. All their precursors 2a-2c were not mesogenic. In contrast, copper complexes 1a formed nematic or smectic C phases and complexes 1b-1c formed crystalline phases. Powder X-ray diffraction experiments confirmed the presence of SmC phase.     

H-Bonded metallomesogens: preparation, characterization, and mesomorphic studies of (3-hydroxypropylimino)propan-1,2-diols

Two series of new Schiff bases 2 (n=8, 12, 16) derived from (3-hydroxypropyl imino)propan-1, 2-diol with a hydroxyl group at C₁₉/C₂₀-position and their palladium complexes 1 were prepared and their mesomorphic properties investigated by DSC, POM, and XRD. The presence of both hydroxyl groups was found to be crucial in forming the liquid crystalline behavior. All compounds 2a exhibited smectic A or and C phases, in contrast, all compounds 2b formed hexagonal columnar phases. The formation of mesophases in both compounds 1-2 was probably induced by inter-molecular H-bonds. Single crystallographic data in mesogenic compound 2a (n=8) indicated that a dimeric structure with a better linear or rod-like molecular shape was formed by an inter-molecular H-bond (O4-O1′, ∼1.854 Å). Another inter-molecular H-bond (∼1.903 Å) between two dimeric structures was also observed. It crystallizes in a monoclinic space group P2(1)/c. On the other hand, all palladium complexes 1 formed enantiotropic smectic A phases. Single crystallographic data in mesogenic compound 1a (n=8) indicated that the geometry at Pd²⁺ center was coordinated as slightly twisted square planar. It crystallizes in a monoclinic space group P2(1)/n. An inter-molecular H-bond (∼1.799 Å) between neighboring molecules were observed, which might have facilitated the formation of mesophases. Variable-temperature powder XRD experiments confirmed their mesophase structures.     

H-Bonded metallomesogens derived from salicyladiminates

A series of new mesogenic compounds 1a-b (n=8, 10, 12, 14, 16) derived from salicyladimines and their palladium 2a, 2b, vanadyl 2a, and copper complexes 3a, 3b were prepared and their mesomorphic properties investigated by optical microscopy, differential scanning calorimetry and powder X-ray diffractometry. Pd²⁺ and VO²⁺ ions formed mononuclear complexes, whereas, Cu²⁺ ion formed binuclear complexes due to the relative acidic strength of Schiff base. Single crystallographic analysis of non-mesogenic compound 2a (n=8) confirmed its coordination geometry at Pd²⁺ as square plane. It crystallizes in a triclinic space group P−1 with a Z=1. As expected, the Pd²⁺ was coordinated via a trans-N₂O₂ donor set of phenolic-O and imine-N atoms, leaving two hydroxyl groups intact and uncoordinated. The two alkoxy chains, pointing to the opposite direction were parallel, and the molecule was considered as twisted Z-shaped. Both hydroxyl-OH groups attached on C₁₇ and C₁₈-Schiff imines participate in the H-bonds in the lattice. Interestingly, a pseudo polymeric structure was observed, in which H-bonded dimer was continuously extended by another H-bonded dimer in the lattice. Compounds 1 exhibited smectic A phases, and Pd and VO complexes and Cu complexes 3b exhibited smectic A or/and smectic X phases, however, Cu complexes 3a formed crystal phases. Intermolecular H-bonds might be attributed to the difference observed on the mesomorphic properties in these compounds. Copper complexes 2b were not active on ESR spectroscopy.     

Design,synthesis, and biological evaluation of the novel glycyrrhetinic acid-cinnamoyl hybrids as anti-tumor agents

Background

Glycyrrhetinic acid (GA) derivatives had shown not only cytotoxicity but also could trigger apoptosis in various human cancer cell lines. Moreover, cinnamic acid (CA) and its phenolic analogues as potent antitumor agents were employed in the design of anti-tumor drugs. To further improve the anti-tumor activity of GA and CA derivatives, a series of novel compounds were designed and synthesized using GA and CA derivatives fragments.

Results

The result showed that all the novel glycyrrhetinic acid-cinnamoyl (GA–CA) hybrids presented higher antitumor activity on the tumor cell lines of HepG2, HT-29, Hela and lower cytotoxicity on three non-tumor cells lines MDCK, HY926, H9C2 than the parent compounds (IC₅₀ > 50 μM). It was worth noting that 8a had a superior cytotoxicity effect on Hela cells (IC₅₀ = 8.54 μM) than on other cancer cell lines (IC₅₀ > 15 μM). And it also indicated that 8a showed lower cytotoxicity (IC₅₀ > 27 μM) towards MDCK, HY926 and H9C2 cells than cisplatin (DDP, IC₅₀ < 10 μM). Moreover, according to the acute toxicity, it could be indicated that the LD₅₀ of 8a exceeded 3.0 g/kg by oral administration in mice. The further research using Giemsa, H33342 staining, flow cytometric analysis and caspase-3 assay showed that 8a could cause Hela cell damage, nuclei lysis and apoptosis. In addition, the structure–activity relationships of these hybrids were briefly discussed.

Conclusions

Compared with GA, target compounds demonstrated better anti-tumor activity, among which 8a was the most active one. What’s more, structure–activity relationship analysis also revealed that hybrids with trans olefinic bond group show higher antitumor activity than those without olefinic bond, such as 1a > 1b, 6a > 2b, 8a > 3b, 9a > 4b. In addition, it was found that the methoxy substituent might enhance selectivity of GA–CA hybrids towards regular non-cancerous cells MDCK, HY926 and H9C2, such as 4a, 6a, 7a, 8a. However, there might be less relationship between the cytotoxicity and the quantity, position of methoxy moiety. Hence, it is urgent need to synthesize efficient, low toxicity and multi-target anti-tumor compounds based on the structure combination principle.

     

Columnar/smectic metallomesogens derived from heterocyclic benzoxazoles

The synthesis, mesomorphic behavior, and optical properties of two new series of metal complexes 1a,b-M (M=Pd, Cu, Zn) derived from benzoxazoles 2a,b are reported. The crystal and molecular structures of mesogenic 5-decyloxy-2-(6-decyloxybenzooxazol-2-yl)phenol and nonmesogenic bis[5-octyloxy-2-(6-octyloxybenzooxazol-2-yl) phenol]Pd(II) were determined by means of X-ray structural analysis. Two benzoxazoles 2a exhibited monotropic SmA phases, and all benzoxazoles 2b were nonmesogenic. On the other hand, metal complexes 1a-M exhibited distinctly different mesomorphism from complexes 1b-M. Complexes 1a-Pd formed SmC phases; complexes 1a-Cu and 1a-Zn formed crystal phases. In contrast, complexes 1b-Zn exhibited columnar phases, and complexes 1b-Cu and 1b-Pd were nonmesogenic. The difference of the mesomorphism in 1a-M and 1b-M was probably attributed to the geometry and/or the overall molecular shape created by 2a and 2b. The electronic configuration of metal ion might play an important role in forming the mesophases. The fluorescent properties of these compounds were also examined.     

Unsymmetric 1,3,4-oxa(thia)diazoles of quinoxaline–naphthalene conjugates

Two new series of unsymmetric 1,3,4-oxa(thia)diazoles 1a,b containing both quinoxaline and naphthalene moieties were prepared and their mesomorphic properties were investigated. The mesomorphic behavior of compounds 1a,b and 2 was studied by DSC analysis and polarized optical microscopy. All compounds 1a and 2 exhibited hexagonal columnar phases (Col_h), which were also confirmed by powder XRD diffractometer. N_cell and R_ar values equal to 5.23 and 22.73 Å² within a slice of 9.0 Å thick were also obtained for 1a (n=16), indicating that a more disc-like structure constructed by two molecules lying side-by-side was correlated in Col_h phases. In contrast, all compounds 1b were not mesogenic, and the lack of mesomorphic properties in 1b might be due to their unfavorable conformations. The PL spectra of all compounds 1a,b showed one intense peak at λ_max=509–512 nm, and these photoluminescent emissions originated from quinoxaline moiety.     

Design,modification, and bio-evaluation of salazinic acid derivatives

Data on synthesized derivatives of salazinic acid are scarce, with existing reports addressing only derivative hexaacetyl salazinic acid. This study investigated a set of novel potential antidiabetic agents. Analogs of salazinic acid were designed and synthesized using bromination, nucleophilic addition, Friedel-Crafts alkylation, and esterification. Ten synthetic compounds were prepared and structurally elucidated, including eight new compounds (1a-1c, 2a, 3a, 3b, 4a, 4b) and two known analogs. Under bromination, salazinic acid (1) enabled the following reaction chain: oxidation, decarboxylation, and substitution. This yielded products 1a-1c, which were found to have unprecedented scaffolds. Parmosidone F (5) was prepared from 1 with orsellinic acid via Friedel-Crafts alkylation, confirming a previously reported biosynthesis route. These analogs were evaluated for enzyme inhibition of α-glucosidase, and all showed more potent activity than that of acarbose, a positive control (IC₅₀ 332 μM), with IC₅₀ values in the range 9.32–39.96 μM. An in silico molecular docking model confirmed that, in terms of enzyme inhibition, the compounds ranked as follows: 3b > 4b > 4a > 1c > 2a > 1b > 1a > 3a. The kinetics of enzyme inhibition showed 4a and 5 to be a non-competitive-type and mixed-type inhibitors, respectively.     

Synthesis of quinoxaline-benzoxale conjugates and mesomorphic properties

A new series of non-discotic heterocyclic compounds 1a-e derived from quinoxaline was prepared and their mesomorphic properties investigated. The crystal and molecular structures of nonmesogenic 2,3-bis(3,4-didodecyloxyphenyl)quinoxaline-6-carboxylic acid 4-[(4-butoxy2-hydroxyphenylimino)methyl]phenyl ester 2a (n=4, m=12) were determined by means of X-ray structural analysis. It crystallizes in a monoclinic space group P2(1)/c, with a=21.9193(13) Å, b=8.3693(4) Å, c=30.896(2) Å, and Z=4. The molecule was considered as an elongated or tapered triangle. Both inter- and intra-molecular H-bonds were observed in the crystal lattice, which was attributed to the formation of columnar mesophase in compounds 2. The mesomorphic behavior of compounds 1-2 was studied by thermal analysis and polarized optical microscopy. All compounds 1-2 exhibited hexagonal columnar phases (Col_h), which were also confirmed by powder XRD diffractometer. A N_cell and R_ar value equal to 4.74 and 4.34 within a slice of 9.0 Å thick were obtained for 1b and 2b, indicating that a more disc-like correlated structure by two molecules lying side-by-side was formed in Col_h phases. The fluorescent properties of the compounds 1-4 in CH₃Cl were also examined.     

New star-shaped triarylamines: synthesis, mesomorphic behavior, and photophysical properties

A total of 18 compounds 1-6 derived from triphenylamine as core group were prepared and characterized, and their mesomorphic properties were also investigated. Compounds 1-4 and 5,6 were prepared from p,p′,p″-triformyltriphenylamine and p,p′-diformyltriphenylamine with appropriate alkoxyphenylamines. The phase behavior of these mesogenic compounds was characterized and studied by differential scanning calorimetry, polarized optical microscopy, and powder XRD diffraction. Compounds 1-3 exhibited columnar mesophase, however, compounds 4-6 were nonmesogenic. The mesophases observed in compounds 1-3 were found to be side dependent. Compounds 1a, 2a, and 3a appended with one, two, or three side chains exhibited lamellar columnar (Col_L) phases, and compounds 2b and 3b with four or six side chains formed hexagonal columnar (Col_h) phases. The formation of the mesophases, lamellar or columnar mesophases, was probably induced by H-bonding formed between -CH₂NH groups. The oxidation process determined by cyclic voltammetry showed two redox waves, one appeared at 220-255 mV and the other one at 503-677 mV, which gave energy to HOMOs range of 5.02-5.36 eV. The fluorescent properties of the compounds were examined. All λ_max peaks of the absorption and photoluminescence spectra of compounds occurred at ca. 307-392 nm and 368-456 nm, respectively. Compound 4a has a larger red shift due to a better conjugation linked by CC double bonds instead of -CH₂NH in other compounds.     

Synthesis of p-tert-butylcalix[4]arene semitubes and their binding studies with C60

The synthesis of p-tert-butylcalix[4]arene semitubes in one step reaction with fairly good yields is described. The structures of these compounds were confirmed by ¹H NMR, ¹³CNMR and mass spectrometry. The complexation ability of these compounds with C₆₀ was investigated and found that they are able to form 1:1 complexes. The stability constants of these complexes were determined and found to be 15, 203 and 525 dm³ mol^?1 for the semitubes 3a, 3b, 3c respectively. The binding energies of each of C₆₀, the semitubes and the complexes are calculated using PM6 (Semiempirical quantum chemical) and DFT (Density Functional Theory) methods and found in the order m > p > o. On the other hand, the calculated binding energies using DFT method showed that the stabilities of both centered and side complexes are in the order p > m > o.     

Monosubstituted thermotropic ferrocenomesogens containing heterocyclic pyrazole

The synthesis and mesomorphic properties of two series of ferrocenyl derivatives, 5-[4-(4-alkoxylbenzyloxy)phenyl]-3-(4-ferrocenylphenyl)-1H-pyrazoles 1a and 3-[4-(4-ferrocenylbenzyloxy)phenyl]-5-(4-alkoxylphenyl)-1H-pyrazoles 1b are reported. Compounds 1a exhibited either nematic (N) or smectic A (SmA) phases, whereas compounds 1b formed N/SmC or SmA/SmC phases depending on the terminal carbon length. The formation of SmC phases in compounds 1b was attributed to better molecular interaction between layers since the ferrocenyl unit was remotely located one phenyl ring away from pyrazole core. In contrast, their precursors, ferrocenyl β-diketonates, were in fact non-mesogenic. A less bent shape formed by ferrocenyl pyrazoles than ferrocenyl β-diketones was believed to be responsible for the formation of observed mesophases. The crystal and molecular structure of 3-[4-(4-ferrocenylbenzyloxy)phenyl]-5-(4-hexyloxyphenyl)-1H-pyrazole (1b; n=6) was determined by means of X-ray structural analysis. It crystallizes in the triclinic space group p-1, with a=11.0725(5) Å, b=12.5514(5) Å, c=14.2085(6) Å, and Z=2. The molecular arrangement was quite consistent with the layer structure observed by powder X-ray diffractometer. The cyclic voltammogram measured for 1 and 2 (n=16) indicated that incorporation of pyrazole group hardly influenced the electrochemical behavior of the ferrocenyl moiety.     

Symmetrical dimer liquid crystals derived from benzoxazoles

A series of dimeric twin liquid crystals derived from symmetric heterocyclic benzoxazoles 1a-1f exhibiting single smectic C phase are reported. All benzoxazoles were prepared by condensation of 2-aminophenols with benzaldehydes and then followed by subsequent intramolecular cyclization. The mesomorphic properties were investigated by DSC and POM, and the structure of the mesophases was confirmed as smectic C phases by powder XRD. The formation of mesophases was attributed to the weak dipole force induced by donor-acceptor interaction (D→A). A monolayer conformation was proposed based on the powder XRD data. A value of aspect ratio d/l=0.80-0.92 was calculated from d-spacings and the molecular lengths. By contrast, the odd-even effects by a value of entropy changes ΔS_SmC→I/R=2.00-6.50 showing odd-even effect for the transition of SmC→I phases were also associated in twin system.     

Synthesis and antimicrobial activities of novel quinazolin-4(3H)-one derivatives containing a 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole moiety

A series of novel quinazolin-4(3H)-one derivatives (6a–6y) containing a 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole moiety were designed and synthesized, and their structures were fully characterized by ¹H NMR, ¹³C NMR, HRMS and IR spectra. Among them, the structure of compound 6u was unambiguously confirmed via single crystal X-ray diffraction analysis. The obtained bioassay results showed that compounds 6h, 6k, 6l and 6y had the EC₅₀ (half-maximal effective concentration) values of 34.8, 28.2, 41.5 and 42.5 μg/mL against the phytopathogenic bacterium Xanthomonas oryzae pv. oryzae (Xoo), respectively, which were significantly better than commercial bactericide Bismerthiazol (EC₅₀ = 95.8 μg/mL). Additionally, compounds 6a and 6b exhibited the strong inhibition activity against the pathogen Xanthomonas axonopodis pv. citri (Xac).     

Theoretical investigation on conformational preferences and structural properties of 2-lithio-1,3-diphosphinane and 2-lithio-1,3-dimethyl-1,3-diphosphinane

A new family of dialphosphacyclohexane is introduced which has three nucleophilic centers. The conformational stabilities and structural properties of 2-lithio-1,3-diphosphinane and 2-lithio-1,3-dimethyl-1,3-diphosphinane were investigated computationally by DFT calculations and NBO analyses at B3LYP/6-31+G(d,p). Relative energy trend in 1,3-diphosphinane and 1,3-dimethyl-1,3-diphosphinane conformations explored from steric and hyperconjugative point of view. The stability trend of 2-lithio derivatives based on calculated relative energies in 1,3-diphosphinane is 1d > 1f > 1b > 1a > 1c > 1e and for 1,3-dimethyl-1,3-diphosphinane derivatives is 2f > 2d > 2b > 2a > 2c > 2e. Calculated NBO atomic charges indicate that high positive charge at lithium and small C–Li Wiberg bond indexes in these derivatives are demonstrators of ionic nature of the C–Li bonds. Stereoelectronic interactions, polarizability of phosphorus, and chelate formation between each of phosphorous and lithium are determining factors in stability trend observed in these derivatives. Ease of lithiation in bis(dimethylphosphino)methane, 1,3-diphosphinane, and 1,3-dimethyl-1,3-diphosphinane derivatives was estimated and compared by isodesmic reaction.     

Hydrogen-bond-assisted supramolecular 1-D tape-like structures of mesogenic bis-pyrazoles

Two new series of isomeric bis-pyrazoles 1a–b are prepared, characterized, and their mesomorphic properties investigated. These pyrazoyl derivatives were obtained from the condensation of α,β-diketones 2a–b with hydrazine monohydrate in refluxing THF. Two single crystallographic structures of compounds mesogenic 1a (n=14) and nonmesogenic 1b (n=8) were determined by X-ray analysis. Both 1a–14 and 1b–8 crystallize in a triclinic space group P?1 and monoclinic C2/c group, respectively. An extended H-bonded structure was formed in both crystal lattices, giving a pseudo 1D-polymeric tape-like structure. Derivatives 1a exhibited smectic A/C mesophases, in contrast, derivatives 1b were all nonmesogenic. The difference in mesomorphic behavior was attributed to the between linear conformation and the coplanarity of the five rings over than in 1a. The correlation between the molecular structures and the mesomorphic properties is discussed.     

Polarization effects in mesogenic isoxazoles and 1,3,4-oxadiazoles

Four new series of unsymmetric isoxazoles and 1,3,4-oxadiazoles were prepared, characterized and their mesomorphic properties investigated. Isoxazoles were obtained by condensation–cyclization of β-diketones with hydroxylamine hydrochloride in refluxing THF, while 1,3,4-oxadiazoles were obtained from hydrazine-carboxylate in refluxing POCl₃. Two single crystallographic structures were determined by X-ray crystallographic analysis. A correlated dimeric structure was formed by H-bonds in isoxazoles 1a (n=6), leading to a more elongated structure required for the formation of mesophases. All compounds 1a–c formed N, SmA or/and SmC phases. In contrast, compounds 1d exhibited columnar phases, and an N_cell=14.6 obtained from powder XRD data indicated that a correlated structure formed by four molecules was probably induced in Col_h phases. The better mesomorphic behavior formed in 1a than 1b might be attributed to stronger intermolecular interactions and higher polarization induced in isoxazoles 1a.     

Polar effect in columnar unsymmetric 1,3,4-oxa(thia)diazoles

Three new series of heterocyclic 1,3,4-oxa(thia)diazoles 1a–c were prepared and their mesomorphic behavior studied. All compounds 1a exhibited monotropic columnar phases, which were confirmed by powder XRD diffractometer. Compounds 1b were not mesogenic. The formation of columnar phases was sensitive to the substituent groups attached on the phenyl moiety; those with electron-donating groups (R=H, OCH₃) were not liquid crystals, in contrast, other derivatives with electron-withdrawing groups (R=F, NO₂) formed enantiotropic columnar phases. A N_cell and R_ar value equal to 4.73 and 20.20 Å² of compound 1a (n=16) within a slice of 9.0 Å thick were obtained, indicating that two molecules was correlated to give a supplemental more disc-like molecule within columns. This is the first example, showing that the formation of columnar phases could be controlled by polar groups. The PL spectra of two compounds 1a–c showed one intense peak at λ_max=505–511 nm, and these photoluminescent emissions originated from quinoxaline moiety.     

Columnar catenar bisoxazoles and bisthiazoles

Three new series of catenar liquid crystals 1a–c derived from heterocyclic bisoxazoles and bisthiazoles exhibiting columnar phases were reported. All compounds 1a–c exhibited hexagonal columnar phases, which were confirmed by powder XRD diffractometer. Compounds 1a have a slightly wider temperature range of columnar phases than that of compounds 1b, which might be attributed to higher dipole polarized in 1a. A N_cell and R_ar value equal to 2.54–2.76 and 19.99–20.45 Å² within a slice of 9.0 Å thick were obtained for three derivatives 1a–c (all ns=12), indicating that a single molecule was packed within columns in Col_h phases. All derivatives showed good stabilities at temperature below T=408 °C on TGA. The PL spectra of all compounds 1a–c showed one intense peak at λ_max=505–510 nm, and these photoluminescent emissions originated from quinoxaline moiety.     

Symmetrical mesogenic 2,5-bis(6-naphthalen-2-yl)-1,3,4-thiadiazoles

Two series of new symmetrical 1,3,4-oxadiazoles 1a-n and 1,3,4-thiadiazoles 1b-n were prepared and their mesomorphic properties investigated by optical microscopy, differential scanning calorimetry, and powder X-ray diffractometry. Compounds 1b-n are kinetically more stable than compounds 1a-n. Compounds 1a-n exhibited monotropic nematic or smectic C phases, whereas, compounds 1b-n exhibited enantiotropic nematic or smectic A/smectic C phases. Compounds 1b-n have higher clearing temperatures and the larger temperature ranges of mesophases, which might be attributed to the better linearity and/or larger dipole, resulted from a more polarized sulfur atom than oxygen atom incorporated. The fluorescent properties of these two series of 1,3,4-thiadiazole/oxadiazole-based derivatives were also examined. The λ_max peaks of the photoluminescence spectra for compounds 1a-6 and 1b-6 measured in THF occurred at ca. 385 nm and 423 nm, respectively. Both series were blue emitters.     

Preparation of (1R,8S)- and (1S,8R)-9-azabicyclo[6.2.0]dec-4-en-10-one: potential starting compounds for the synthesis of anatoxin-a

9-Azabicyclo[6.2.0]dec-4-en-10-one (±)-2, obtained from cyclooctadiene by addition of chlorosulfonyl isocyanate, was N-hydroxymethylated to (±)-3 and then resolved by lipase-catalysed asymmetric acylation of the primary OH group at the (S)-stereogenic centre. High enantioselectivity (E=94) was observed when lipase PS and vinyl butyrate were used in di-iso-propyl ether at −15°C, resulting in the enantiomerically enriched ester 3a and alcohol 3b (e.e. ≥92%). Treatment of 3a and 3b with NH₄OH/MeOH afforded the corresponding β-lactams (1R,8S)-2a and (1S,8R)-2b (e.e. ≥93%), potential starting compounds in anatoxin-a synthesis. The ring opening of lactams (±)-2, (±)-7, 3a and 3b, followed by reduction, resulted in racemic 4–6 and 8 and enantiomeric 4a, 4b, 5a and 5b eight-membered cyclic β-amino acid derivatives.