Synthesis and Dynamic Behavior of Chiral NNO-Scorpionate Zinc Initiators for the Ring-Opening Polymerization of Cyclic Esters

Abstract

The reaction of chiral alcohol–scorpionate compounds bpzbeH [bpzbeH = 1,1-bis(3,5-dimethylpyrazol-1-yl)-3,3-dimethyl-2-butanol] or bpzteH [bpzteH = 2,2-bis(3,5-dimethylpyrazol-1-yl)-1-para-tolylethanol] with [ZnR₂] (R = Me, Et, CH₂SiMe₃) in a 1:2 molar ratio afforded the dinuclear chiral zinc alkyls [Zn(R)(κ²-NNµ-O)Zn(R)₂] (1–4) [κ²-NNµ-O = bpzbe, R = Me (1), Et (2), CH₂SiMe₃ (3); bpzte, R = Et (4)]. Subsequent alcoholysis or thioalcoholysis reaction with ArEH (1 equiv.; E = O, S; Ar = 2,6-C₆H₃Me₂) yielded the chiral dinuclear mixed alkyl–alryl oxides/thioaryl oxides [(ZnR)₂(κN:κN-µ-O)(µ-EAr)] (5–12) [κN:κN-µ-O = bpzbe, E = O, R = Me (5), Et (6), CH₂SiMe₃ (7); bpzte, E = O, R = Et (8); bpzbe, E = S, R = Me (9), Et (10), CH₂SiMe₃ (11); bpzte, E = S, R = Et (12)]. The alcoholysis reaction of the previously reported monoalkyls [Zn(Me)(κ³-NNO)] or [Zn(R)(κ-NNµ-O)]₂ with ArOH (1 equiv., Ar = 2,6-C₆H₃Me₂) afforded the chiral aryl oxides [Zn(OAr)(κ²-NNµ-O)]₂ (13–14) [κ²-NNµ-O = bpzbe (13); bpzte (14)]. The X-ray crystal structures of 3, 5, 6, and 14 confirmed a dinuclear structure in all cases with the alkoxide of the heteroscorpionates in a µ-bridging mode between the Zn^II centers. Variable-temperature NMR spectroscopic studies were carried out to study their dynamic behavior in solution. Complexes 1–9 and 12 can act as single-component initiators for the ROP of ϵ-CL and L-/rac-LA, and afforded materials with low molecular weights and narrow monomodal molecular weight distributions. MALDI-TOF mass spectra confirmed that for 5–8 the initiation occurred through nucleophilic attack by the alkoxide group, rather than the alkyl group, on the lactide monomer. Furthermore, inspection of the kinetic parameters showed propagations with a pseudo-first-order dependence on monomer and catalyst concentrations. Microstructural analysis of poly(rac-lactide) revealed that the mixed alkyl/aryl oxide-substituted initiators exert a moderate level of heteroselectivity (P_s = 0.66).

A new series of chiral dinuclear trisalkyl- and alkyl–aryl oxide-containing zinc heteroscorpionates complexes, namely, [Zn(R)(κ²-NNµ-O)Zn(R)₂] and [(ZnR)₂(κN:κN-µ-O)(µ-OAr)], respectively, has been synthesized. Their dynamic behavior has been studied. Both families act as single-component living initiators for the ring-opening polymerization of ϵ-CL and L-/rac-LA.

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Controlled Synthesis of Pnicogen–Chalcogen Polycations in Ionic Li­quids

Abstract

Three new pnicogen–chalcogen polycations were synthesized under specific conditions in the Lewis-acidic ionic liquids (ILs) [EMIm]X·nAlX₃ and [BMIm]X·nAlX₃ (X = Cl, Br; [EMIm]: 1-ethyl-3-methylimidazolium, [BMIm]: 1-butyl-3-methylimidazolium) and crystallized as their tetrahalogenidoaluminate salts. Single-crystal X-ray diffraction revealed the new polycation [Bi₆Te₄Br₂]⁴⁺ in triclinic [Bi₆Te₄Br₂](AlBr₄)₄ as the reaction product of bismuth, tellurium, and bismuth tribromide. Substitution of the elements with Bi₂Te₃ yielded the heterocubane [Bi₄Te₄]⁴⁺ in tetragonal [Bi₄Te₄](AlBr₄)₄, which crystallizes isotypically to its known chlorine counterpart. The latter is also accessible from ILs. The interactions between cations and anions were evaluated by quantum-chemical calculations. Bi₂S₃, which is insoluble in most media, readily dissolves in the employed IL and forms the new augmented heterocubane [Bi₃S₄AlCl]³⁺, which crystallizes with the complex anion [S(AlCl₃)₃]^2– as triclinic [Bi₃S₄AlCl][S(AlCl₃)₃]AlCl₄. Quantum-chemical calculations support the assignment of elements in this compound. The monoclinic crystal structure of [Sb₁₃Se₁₆](AlCl₄)₆(Al₂Cl₇) contains a new member of the small family of pnicogen–chalcogen spiro-heterocubanes.

Heteropolycations: Three new pnicogen–chalcogen polycations were synthesized in imidazolium-based Lewis-acidic ionic liquids (IL) at moderate temperatures. Bi₂S₃, usually soluble only under harsh conditions, readily dissolves and reacts in the employed IL to give a quaternary polycation. The choice of starting materials and the reaction temperature were identified as important control parameters.

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Rare-Earth Metal Oxo/Hydroxo Clusters – Synthesis, Structures, and Applications

Abstract

Multinuclear rare-earth metal coordination clusters bridged by oxo/hydroxo units have emerged from being lab curiosities to become a readily accessible class of compounds. New synthetic strategies for accessing these compounds on reasonable scales have been established. Clusters of different sizes have been investigated in terms of their magnetic and photophysical properties. Some preliminary biological applications have also been established.

The synthesis and the structures of rare-earth metal oxo/hydroxo clusters are reviewed. The clusters are very robust, which makes them ideal materials for further chemical, physical, and biological studies.

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Abnormal N-Heterocyclic-Carbene-Mediated Fixation of CO2 and N2O, and the Activation of Tetrahydro­furan and Tetrahydrothiophene under Ambient Conditions

Abstract

A strong σ-donor abnormal N-heterocyclic carbene (aNHC), 1,3-bis(2,6-diisopropylphenyl)-2,4-diphenylimidazol-5-ylidene (L1), reacted with B(C₆F₅)₃ in the presence of CO₂ and N₂O to form the adducts [aNHC·CO₂·B(C₆F₅)₃] (1) and [aNHC·N₂O·B(C₆F₅)₃] (2), respectively, in high yields at room temperature within a very short period of time. Furthermore, this aNHC/B(C₆F₅)₃ reagent system was found to be very efficient for the ring-opening of tetrahydrofuran (thf) and tetrahydrothiophene (tht), affording 3 and 4, respectively, within 5–10 min at room temperature in good yields. Interestingly, this aNHC forms the air-stable Lewis acid/base adduct [aNHC·B(C₆F₅)₃] (5) with B(C₆F₅)₃ in the absence of any suitable substrate upon keeping this mixture in solution. DFT calculations showed that the Lewis acid/base adduct 5 is energetically less stable than compounds 1–4, and this may be the driving force for the formation of compounds 1–4 in the presence of small molecules such as CO₂, N₂O, thf and tht. All the new compounds were characterized spectroscopically (¹H, ¹³C, ¹⁹F and ¹¹B NMR, IR spectroscopy) in solution and the solid-state structures were unambiguously established by single-crystal X-ray diffraction analysis.

The abnormal N-heterocyclic carbene, 1,3-bis(2,6-diisopropylphenyl)-2,4-diphenylimidazole-5-ylidene, reacts with B(C₆F₅)₃ in the presence of CO₂ or N₂O to form [aNHC·CO₂·B(C₆F₅)₃] or [aNHC·N₂O·B(C₆F₅)₃], respectively, in high yields at room temperature within a very short period of time.

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Neuropilin-1 is associated with clinicopathology of gastric cancer and contributes to cell proliferation and migration as multifunctional co-receptors

Abstract

Background

Neuropilin-1 (NRP-1) is a transmembrane glycoprotein participating in the growth and metastasis of cancer cells as multifunctional co-receptors by interacting with the signaling pathways. However, its role in gastric cancer has not yet been clarified. This study aims to investigate whether NRP-1 expression is associated with the clinicopathology of gastric cancer, and involved in the growth and metastasis of gastric cancer cells.

Methods

NRP-1 expression in clinical gastric cancer specimens was examined by immunohistochemistry and its association with clinicopathology analyzed. The expression of NRP-1 in a panel of human gastric cancer cells was examined by real-time RT-PCR and immunoblotting. Stable transfectants depleted of NRP-1, termed MGC-803-NRP^low, were generated from MGC-803 cells. Cell proliferation was analyzed by the Cell Counting Kit-8 and Bromodeoxyuridine incorporation assays, and migrating ability analyzed by migration assays. The xenograft model was used to assess the effects of NRP-1 depletion on tumorigenesis, growth, metastasis and therapeutic potentials. The role of NRP-1 as co-receptors in the signaling pathways stimulated by ligands was examined. The key molecules involved in cell proliferation, migration and related signaling pathways were detected by immunoblotting.

Results

Gastric cancer tissues expressed higher levels of NRP-1 compared to normal gastric mucosa. Its expression correlated with clinical staging, tumor differentiation and pathological types. NRP-1 depletion inhibited cell proliferation by inducing cell cycle arrest in the G1/S phase by upregulating p27, and downregulating cyclin E and cyclin-dependent kinase 2. NRP-1 depletion reduced the ability of cells to migrate by inhibiting the phosphorylation of focal adhesion kinase. NRP-1 depletion suppressed tumorigenesis, tumor growth and lung metastasis by inhibiting cell proliferation and tumor angiogenesis in situ. Therapeutic NRP-1 shRNA inhibited the growth of established BGC823 tumors. Depletion of NRP-1 inhibited the activation of VEGF/VEGFR2, EGF/EGFR and HGF/c-Met pathways stimulated by respective recombinant human VEGF-165, EGF and HGF proteins.

Conclusions

The present results indicate that NRP-1 may be a potentially valuable biomarker and therapeutic target for gastric cancer.

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Eliciting cytotoxic T lymphocytes against human laryngeal cancer-derived antigens: evaluation of dendritic cells pulsed with a heat-treated tumor lysate and other antigen-loading strategies for dendritic-cell-based vaccination

Abstract

Background

Dendritic cells (DCs) have been used successfully in clinical pilot studies. However, tumor-specific immunity and clinical responses were only induced in certain cancer patients. It has been well documented that immunotherapy efficacy can be optimized for responses using antigen pulsing.

Methods

The human laryngeal squamous cell cancer (LSCC) cell line SNU899 was used to evaluate the in vitro anti-tumor efficacy of three different preparations of dendritic cell (DC) vaccines consisting of either whole tumor cells or their derivatives including: i) DCs pulsed with a tumor cell supernatant (DC-TCS), ii) DCs pulsed with whole-cell tumor stressed lysate (DC-TSL), and iii) DCs pulsed with irradiated tumor cells (DC-ITC).

Results

Our results showed that DC-TSL is an effective source of tumor-associated antigens (TAAs) for pulsing DCs. DC-TSL induced the highest expansion of TAA-specific T cells, the strongest Th1 cytokine response, and the most potent cytotoxic T lymphocyte (CTL) activity. DC-TCS and DC-ITC inhibited T cell activation but induced a certain extent of CTL activity.

Conclusions

These data suggest that DC-TSL is a more potent inducer of antitumor immunity against laryngeal cancer than other antigen-loading strategies using whole tumor cell materials. This strategy provides an alternative approach for DC-based immunotherapy for laryngeal cancer.

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Integrated analysis of microRNA regulatory network in nasopharyngeal carcinoma with deep sequencing

Abstract

Background

MicroRNAs (miRNAs) have been shown to play a critical role in the development and progression of nasopharyngeal carcinoma (NPC). Although accumulating studies have been performed on the molecular mechanisms of NPC, the miRNA regulatory networks in cancer progression remain largely unknown. Laser capture microdissection (LCM) and deep sequencing are powerful tools that can help us to detect the integrated view of miRNA-target network.

Methods

Illumina Hiseq2000 deep sequencing was used to screen differentially expressed miRNAs in laser-microdessected biopsies between 12 NPC and 8 chronic nasopharyngitis patients. The result was validated by real-time PCR on 201 NPC and 25 chronic nasopharyngitis patients. The potential candidate target genes of the miRNAs were predicted using published target prediction softwares (RNAhybrid, TargetScan, Miranda, PITA), and the overlay part was analyzed in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological process. The miRNA regulatory network analysis was performed using the Ingenuity Pathway Analysis (IPA) software.

Results

Eight differentially expressed miRNAs were identified between NPC and chronic nasopharyngitis patients by deep sequencing. Further qRT-PCR assays confirmed 3 down-regulated miRNAs (miR-34c-5p, miR-375 and miR-449c-5p), 4 up-regulated miRNAs (miR-205-5p, miR-92a-3p, miR-193b-3p and miR-27a-5p). Additionally, the low level of miR-34c-5p (miR-34c) was significantly correlated with advanced TNM stage. GO and KEGG enrichment analyses showed that 914 target genes were involved in cell cycle, cytokine secretion and tumor immunology, and so on. IPA revealed that cancer was the top disease associated with those dysregulated miRNAs, and the genes regulated by miR-34c were in the center of miRNA-mRNA regulatory network, including TP53, CCND1, CDK6, MET and BCL2, and the PI3K/AKT/ mTOR signaling was regarded as a significant function pathway in this network.

Conclusion

Our study presents the current knowledge of miRNA regulatory network in NPC with combination of bioinformatics analysis and literature research. The hypothesis of miR-34c regulatory pathway may be beneficial in guiding further studies on the molecular mechanism of NPC tumorigenesis.

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