BZD9L1 benzimidazole analogue hampers colorectal tumor progression by impeding angiogenesis

BACKGROUND The development of new vasculatures(angiogenesis)is indispensable in supplying oxygen and nutrients to fuel tumor growth.Epigenetic dysregulation in the tumor vasculature is critical to colorectal cancer(CRC)progression.Sirtuin(SIRT)enzymes are highly expressed in blood vessels.BZD9L1 benzimidazole analogue is a SIRT 1 and 2 inhibitor with reported anticancer activities in CRC.However,its role has yet to be explored in CRC tumor angiogenesis.AIM To investigate the anti-angiogenic potential of BZD9L1 on endothelial cells(EC)in vitro,ex vivo and in HCT116 CRC xenograft in vivo models.METHODS EA.hy926 EC were treated with half inhibitory concentration(IC50)(2.5μM),IC50(5.0μM),and double IC50(10.0μM)of BZD9L1 and assessed for cell proliferation,adhesion and SIRT 1 and 2 protein expression.Next,2.5μM and 5.0μM of BZD9L1 were employed in downstream in vitro assays,including cell cycle,cell death and sprouting in EC.The effect of BZD9L1 on cell adhesion molecules and SIRT 1 and 2 were assessed via real-time quantitative polymerase chain reaction(qPCR).The growth factors secreted by EC post-treatment were evaluated using the Quantibody Human Angiogenesis Array.Indirect co-culture with HCT116 CRC cells was performed to investigate the impact of growth factors modulated by BZD9L1-treated EC on CRC.The effect of BZD9L1 on sprouting impediment and vessel regression was determined using mouse choroids.HCT116 cells were also injected subcutaneously into nude mice and analyzed for the outcome of BZD9L1 on tumor necrosis,Ki67 protein expression indicative of proliferation,cluster of differentiation 31(CD31)and CD34 EC markers,and SIRT 1 and 2 genes via hematoxylin and eosin,immunohistochemistry and qPCR,respectively.RESULTS BZD9L1 impeded EC proliferation,adhesion,and spheroid sprouting through the downregulation of intercellular adhesion molecule 1,vascular endothelial cadherin,integrin-alpha V,SIRT1 and SIRT2 genes.The compound also arrested the cells at G1 phase and induced apoptosis in the EC.In mouse choroids,BZD9L1 inhibited sprouting and regressed sprouting vessels compared to the negative control.Compared to the negative control,the compound also reduced the protein levels of angiogenin,basic fibroblast growth factor,platelet-derived growth factor and placental growth factor,which then inhibited HCT116 CRC spheroid invasion in co-culture.In addition,a significant reduction in CRC tumor growth was noted alongside the downregulation of human SIRT1(hSIRT1),hSIRT2,CD31,and CD34 EC markers and murine SIRT2 gene,while the murine SIRT1 gene remained unaffected,compared to vehicle control.Histology analyses revealed that BZD9L1 at low(50 mg/kg)and high(250 mg/kg)doses reduced Ki-67 protein expression,while BZD9L1 at the high dose diminished tumor necrosis compared to vehicle control.CONCLUSION These results highlighted the anti-angiogenic potential of BZD9L1 to reduce CRC tumor progression.Furthermore,together with previous anticancer findings,this study provides valuable insights into the potential of BZD9L1 to co-target CRC tumor vasculatures and cancer cells via SIRT1 and/or SIRT2 down-regulation to improve the therapeutic outcome.

三维超分子化合物[2-(3-pyridyl)benzimidazoleH_2]_2^(4+)·[Cd_2Cl_8]^(4-)的水热合成、晶体结构及发光性质

将邻苯二胺、3-吡啶甲酸与二氯化镉在1∶1的盐酸溶液中经水热反应,合成了一种超分子化合物[2-(3-pyridyl)benzimidazoleH2]24+.[Cd2Cl8]4-。通过元素分析、红外光谱、热重对其结构和性质进行了表征,用X-射线单晶衍射测定了该化合物的晶体结构。化合物晶体为单斜晶系,P21/c空间群。超分子化合物中的Cd2+与其周围4个氯离子配位,构成畸变三角锥构型的离子[CdCl4]2-,2个配阴离子[CdCl4]2-之间通过双氯桥键[Cd-Cl-Cd]构成五配位双核镉髤四元环状结构,并与2个2-(3-吡啶基)苯并咪唑两价阳离子,通过静电引力、氢键及π-π堆积作用形成三维网状超分子化合物。荧光测试表明该化合物具有较好的光致发光性能。

离子化合物｛[2-(3′-pyridyl)benzimidazoleH_2]^(2+)·[SbCl_4]^-·Cl^-｝_4的水热合成、晶体结构及抑菌活性

A new ionic compound ｛[2-(3′-pyridyl)benzimidazoleH2]2+·[SbCl4]-·Cl-｝4 was synthesized by the hy- drothermal reaction of o-diaminobenzene, nicotinic acid with SbCl3 in 1∶1 HCl solution. The structure was charac- terized by chemical analysis, elemental analysis and IR patterns. The single crystal structure was determined by X-ray single crystal diffraction. It crystallizes in monoclinic system, space group P21/n with a=2.107 9(4) nm, b= 1.482 0(3) nm, c=2.113 4(4) nm, β=93.44(3)°, Z=4, V=6.590(2) nm3, Dc=2.001 g·cm-3, μ=2.480 mm-1, F(000)= 3840, R1=0.0468, wR2=0.1163. The single crystal structure indicates that the four chlorines coordinated to the antimony atom forms a distorted triangle bipyramid configuration together with the lone electron pair on the Sb atom. The [SbCl4]- to 2-(3′-pyridyl)benzimidazole cation and Cl- by weak interaction forms the ionic crystal. It has been proved that the title compound has antibacterial activity. CCDC: 283824.

Binding Mechanism and Molecular Design of Benzimidazole/Benzothiazole Derivatives as Potent Abl T3151 Mutant Inhibitors

Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of drug-resistant Abl mutants, especially the most difficult overcoming T3151 mutant, makes the search for new Abl T3151 inhibitors a very interesting challenge in medicinal chem- istry. In this work, a multistep computational framework combining the three dimensional quantitative structure-activity relationship （3D-QSAR）, molecular docking, molecular dy- namics （MD） simulation and binding free energy calculation, was performed to explore the structural requirements for the Abl T315I activities of benzimidazole/benzothiazole derivatives and the binding mechanism between the inhibitors and Abl T315I. The established 3D-QSAR models exhibited satisfactory internal and external predictability. Docking study elucidated the comformations of compounds and the key amino acid residues at the binding pocket, which were confirmed by MD simulation. The binding free energies correlated well with the experimental activities. The MM-GBSA energy decomposition revealed that the van der Waals interaction was the major driving force for the interaction between the ligands and Abl T3151. The hydrogen bond interactions between the inhibitors and Met318 also played an important role in stablizing the binding of compounds to Abl T315I. Finally, four new compounds with rather high Abl T3151 activities were designed and presented to experimenters for reference.

Synthesis of Cycloundecanone from Benzimidazole Methiodide Salt

The intra-molecular addition reaction of Grignard reagent with quaternary C=N bond of benzimidazole methiodide salt is reported, and a novel method for the synthesis of cycloundecanone is provided.

Ammonium metavanadate:A novel catalyst for synthesis of 2-substituted benzimidazole derivatives

Ammonium metavanadate （10 mol%） was found to be a useful catalyst for the synthesis of various 2-substituted aryl benzimidazoles. It was used as an oxidizing agent for the condensation of o-phenylenediamine with different substituted aryl aldehydes at room temperature in ethanol. The method was proved to be simple, convenient and the product was isolated with good yields （79-91%）.

Lithium bromide catalyzed solvent free method for synthesis of 2-substituted benzimidazoles and imidazopyridines

The first successful lithium bromide mediated solvent free condensation of arylenediamine and esters to obtain 2-substituted benzimidazole and imidazopyridine in good to excellent yields is described.

Hydrothermal Synthesis,Crystal Structure and Fluorescence Spectrum Studies of a Supramolecular Compound {[2-(2-Pyridyl)benzimidazoleH_2]^(2+)·[SbCl_5]^(2-)}_2

A new supramolecular compound, { [2-（2-pyridyl）benzimidazoleH2]2＋.[SBC15]2-}2, was synthesized by the hydrothermal reaction of o-diaminobenzene, 2-pyridinecarboxylie acid and SbCl3 in 1：1 HC1 solution, and characterized by chemical analysis, elemental analysis, IR spectra, thermogravimetfic analysis and fluorescence spectra. The crystal structure was deter- mined by X-ray single-crystal diffraction. The crystal belongs to the monoclinic system, space group P211c, with a = 16.0397（13）, b = 14.3189（12）, c = 15.6370（13） A, β = 105.8980（10）°, V = 3454.0（5） A3, Z = 4, C24H22Cl10N6Sb2, Mr = 992.48, Dc = 1.909 g/cm3,/z = 2.366 mm-1, S = 1.010, F（000） = 1920, R = 0.0254 and wR = 0.0555. The coordination anion, [SbCl5]2- which is a distorted tetragonal pyramid, is composed by coordinating action with Sb3＋ ion and five adjacent chloride ions. Every four coordination anions of [SbCl5]2- form a biquaternion ring structure through the secondary bonding of Sb...Cl. Moreover, the compound adopts a three-dimensional network supramolecular structure because of the hydrogen bonds and π-π stacking between the rings and the 2-（2-pyridyl）benzimidazole divalent cations. The title compound also shows good fluorescent behaviors.

BF_3·OEt_2 Promoted Solvent-free Synthesis of Benzimidazole Derivatives

Differently substituted benzimidazoles have been synthesized in very good yields in solvent-free conditions from o-phenylenediamine and aldehydes in the presence of BF3·OEt2 as a catalyst. The method is applicable to aromatic, unsaturated and aliphatic aldehydes and to substituted o-phenylenediamines without significant differences.

Synthesis and Characterization of Novel N-Ferrocenesulfonyl Benzimidazole

A new series of ferrocenesulfonyl benzimidazle has been synthesized and characterized by 1H NMR, FT-IR and elemental analysis. They are expected to have special bio-activity.

Glyoxylic acid as catalyst:A simple selective synthesis of 1,2-disubstituted benzimidazoles in aqueous media

Glyoxylic acid （5 mol%） performs as a novel highly water-soluble catalyst for the synthesis of 2-aryl-l-arylmethyl-lH- benzimidazoles from a wide range of substituted o-phenylenediamines and various substituted aldehydes in good to excellent isolated yields （85-95%） using water as solvent at ambient temperature. The remarkable advantages offered by this method are easily and inexpensive available catalyst, simple procedure, mild conditions, much faster （20--40 rain） reactions and excellent yields of products.

Efficient Syntheses of 2-Substituted Benzimidazoles and Benzoxazoles from β-Keto Esters

An efficient synthetic method was developed to synthesize 2-substituted benzimidazoles and benzo- xazoles with β-keto esters as starting materials under mild reaction conditions, during which other functional groups are bearable from reactants to products.

Eco-friendly synthesis of benzimidazole derivatives using solid acid scolecite catalyst

A series of benzimidazole derivatives were synthesized expeditiously in good yields by condensation of 1,2-diaminobenzene and aromatic aldehydes in the presence of modified scolecite catalyst.The world wide availability,easy handling and reusability of catalyst,higher yields and shorter reaction times are the advantages of the present method.

Microwave-assisted Syntheses and Crystal Structures of Benzimidazole Thiazolinone Derivatives

A rapid and efficient microwave-assisted synthesis method for the preparation of 3-（lH-benzo[d]imidazol-2-yl）-2-substituted phenyl thiazolidin-4-one （4a, 4b） was described. The structures of 4a and 4b were determined by elemental analyses, IR, 1H NMR and X-ray diffraction. In the crystals of compounds 4a and 4b, the imidazole ring and two benzene rings are planar. Interestingly, the dihedral angle between two benzene rings is 71.5° in 4a, while it is almost perpendicular in 4b due to the different benzene substituents. Meanwhile, the thiazolidinone ring is planar in 4a while slightly distorted with an r.m.s deviation of 0.1494（2） A in 4b. The hydrogen bonding interactions observed link the molecules to form a dimeric unit, which may be effective in the stabilization of the structure.

Synthesis and Crystal Structure of 4-Oxo-1,2,4-triazino[4,5-a]benzimidazole

The title compound 4-oxo-1,2,4-triazino[4,5-a]benzimidazole（C9H6N4O,Mr = 186.18） has been synthesized and structurally characterized by IR,NMR and single-crystal X-ray diffraction. The crystal belongs to monoclinic,space group P21/c,with a = 9.1530（18） ,b = 7.2260（14）,c = 12.604（3） ,β = 106.92（3） ,V = 797.5（3）A^3,Z = 4,Dc = 1.551 g/cm^3,λ（MoKa） = 0.71073,F（000） = 384,μ（MoKa） = 0.109 mm^-1,the final R = 0.0632 and wR = 0.1095. A total of 1444 unique reflections were collected,of which 767 with I 〉 2σ（I） were observed. The structure of the title compound is planar. In packing,the molecules are intersected to each other to form chains along three dimensions,together by intermolecular N-H…O and C-H…N hydrogen bonds. The whole structure is further stabilized by π…π interaction between two adjacent tricyclic ring systems,with the centroid-to-centroid distance of 3.369（4） A.

Solventless synthesis of 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles catalyzed by Fe(ClO_4)_3 at room temperature

A series of 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles was synthesized expeditiously in good yields from o-phenylenediamines and aldehydes in the presence of Fe（ClO4）3 without solvent at room temperature.

Hydrothermal Syntheses,Crystal Structures,and Characterization of Two Zinc(Ⅱ)Complexes Containing Flexible Bis(benzimidazole)Ligands

Two zinc（II） complexes, namely, [Zn（L1）Cl2]2 （1） and {[Zn（L2）（tbta）]·3H2O}n （2） （L1 = 1,3-bis（2-methylbenzimidazol-1-ylmethyl）benzene, H2tbta = tetrabromoterephthalic acid, L2 = 1,3-bis（2-methylbenzimidazol-1-yl）-2-propanol） have been successfully obtained under hydrothermal conditions. Complex 1 displays binuclear structure which is further extended into a 1D supramolecular chain through π–π stacking. Complex 2 features 2D （4,4） network based on L2/tbta2– double linker. The thermal stability, fluorescence properties and catalytic activities of two complexes for degradation of Methyl orange in a Fenton-like process were discussed.

SYNTHESIS, CHARACTERIZATION, METAL-UPTAKE BEHAVIOR OF BIS(BENZIMIDAZOLE) RESIN SUPPORTED ON EPOXIDE POLYMER

The new chelate resins, abbreviated as PNBMZs and PBBMZs based on epoxide polymer, were synthesized by polycondensation of N,N-diglycidyl-4-glycidyloxyaniline or 1,4-bis（2,3-epoxypropyl）benzene with the primary amine group of 1,3-bis（benzimidazol-2yl）propylamine （BBPAH）. The ion exchangers contain 2.71-3.23 mmol of the ligand contents per gram of the resin. Batch extraction capacities were determined for the metal chloride salts in buffer solutions in the pH range from -1 to 6.0. The chelate resins were very selective for Cu^2＋, Zn^2＋, Cd^2＋ in the presence of other divalent transition metal ions. The maximum uptake capacities of PNBMZ （synthetic molar ratio = 1：1.5） under non-competitive condition were found to be 0.94 mmol/g for Cu^2＋ at pH = 2, 1.3 mmol/g for Cd^2＋ at pH = 1 and 1.75 mmol/g for Zn^2＋ at pH = -1 respectively. While in the case of PBBMZ, it was 1.39 mmol/g for Cd〉 at pH = 1. The metal-uptake behaviors for both of them showed strong pH dependence, and their extraction capacities increase with decreasing pH. The uptake of Cu^2＋ by the resin PNBMZs at pH = 1 was found to be rather fast with t1/2 = 18 min. Metal-uptake experiments under competitive conditions also confirm that the chelate resins have a high selectivity for Cu^2＋, Zn^2＋, Cd^2＋ and the contrary pH dependence.

Crystal Structure and Electronic Structure of a Luminescent Compound 2-(2-Pyridyl) Benzimidazole

The crystal structure of 2-(2-pyridyl) benzimidazole was determined by single- crystal X-ray diffraction at 193(2) K. It crystallizes in orthorhombic system, space group Pbca with unit cell constants a = 10.6204(7), b = 10.1407(4), c = 18.6327(8) , Z = 8, V = 2006.7(2) 3, Dc = 1.292 g/cm3, F(000) = 816 and m(MoK) = 0.081 mm-1. The structure was refined to R = 0.0317 and wR = 0.0454 for 795 observed reflections with I > 2s(I). In the solid state, it has an emission maximum at 369 nm, while in solution (DMSO), the maximum excitation is at 372 nm. Quantum chemistry calculation was performed by the method of density functional theory. Theoretical results show that atom N is the reactive site when coordinating with a metal, and the electronic structure of the title compound presents excellent carrier transport properties.

A Benzimidazole-pyridine-2,3-dicarboxylic Acid Bridged Zinc(Ⅱ)Coordination Complex–crystal Structure,Quantum Chemistry and Luminescence

The structure of a zinc（Ⅱ） coordination complex（1）, [C14 H10 N3 O5 Zn1.5]n or [Zn1.5（bzim）（pydc）（H2 O）]n（H2 pydc = pyridine-2,3-dicarboxylic acid, Hbzim = benzimidazole）, has been determined by X-ray crystallography and characterized by elemental analysis, IR spectrum and luminescence. Chemical formula： C14 H10 N3 O5 Zn1.5. It crystallizes in the monoclinic system, space group P21/c with a = 12.303（4）, b = 12.052（4）, c = 10.212（3） ？, β = 104.147（4）, V = 1468.3（8） ？3, Z = 4, Mr = 398.30, Dc = 1.802 g/cm3, F（000） = 800, μ = 2.501 mm-1 and S = 1.000. The 2-D network architecture of 1 is constructed from benzimidazole, zinc and pyridine-2,3-dicarboxylic acid. The quantum-chemical calculations have been performed on ‘molecular fragments’ extracted from the crystal structure using the B3 LYP method in Gaussian 09. The luminescence spectrum shows that complex 1 emits blue luminescence.