Synthesis and Characterization of Novel Stilbene Derivatives with 1,3,4‐Oxadiazole Unit

Four novel stilbene derivatives containing 1,3,4‐oxadiazole unit have been synthesized in four steps with overall yields (27～35%). The synthetic route involved one‐step installation of 2,5‐di‐p‐tolyl‐1,3,4‐oxadiazol via the direct coupling of p‐toluic acid with hydrazine hydrate promoted by PPA , benzylic bromination, conventional phosphonate formation, and Wittig‐Horner olefination.     

A Novel Approach for Determining the Orientation of 3-Hydroxyl Group of Some Steroids by CIMS

Stereochemicalanalysisisanimportantsubjectinorganicstructureelucidation,andmassspectrometryprovestobeapromisingtoolforthisproposeduetoitshighsensitivity(thelimitofdetectionisabout10-14mole),rapidity,etcl.Inourpreviouswork,aseriesofstudiesonthestereochemicaleffectsinmassspectrometryhavebeendiscussed2-6.Inthiscommunicationwereportanovelapproachfordeterminationtheeoraorientationof3hydroxylgroupofsomesteroidsdirectlybychemicalionizationmassspectrometryusingtrimethylchlorosilaneasastereoselectivere…     

1,2-苯并噻嗪类化合物的设计、合成及抗肿瘤活性研究

依据生物电子等排原理,设计合成了13个全新结构的1,2-苯并噻嗪类化合物,其结构均经IR,1H NMR,13C NMR和MS确证.以A431,A549,MDA-MB-468和HL60 4种细胞株为活性筛选对象,采用四甲基偶氮唑盐(MTT)法进行初步的体外抗肿瘤活性研究.结果表明,部分化合物对肿瘤细胞有一定的抑制活性,其中化合物5b对A431具有显著的抑制活性,IC50值为1.57μmol/L,化合物9a对A431,A549和MDA-MB-468 3种细胞株的抑制活性均强于阳性对照药gefitinib.并采用Moe软件对所合成的化合物与表皮生长因子受体(EGFR)结合位点进行对接,以进一步阐释所合成化合物的作用靶标.     

1,2-苯并噻嗪类化合物的合成及抗肿瘤活性研究

根据拼合原理,设计合成了一系列全新的具有拉帕替尼和诺拉替尼分子片段的1,2-苯并噻嗪类化合物,其结构均经IR、1H NMR、13C NMR和MS确证。考察所合成化合物的体外抗肿瘤细胞(A549,MCF-7)活性,结果表明,所合成的化合物对肿瘤细胞增殖均有一定的抑制活性,并强于阳性对照药吉非替尼和美洛昔康。     

Conducting Organic Frameworks Based on a Main‐Group Metal and Organocyanide Radicals

Reactions of the main‐group cation Tl^I with anions of 2,5‐derivatives of TCNQ (TCNQ=7,7,8,8‐tetracyanoquinodimethane) have led to the isolation of a family of unprecedented semiconducting main‐group‐metal–organic frameworks, namely, [Tl(TCNQX₂)], (X=H, Cl, Br, I). A comparison of single‐crystal and powder X‐ray diffraction data revealed the existence of a third polymorph of the previously reported material Tl(TCNQ)] and two distinct polymorphs of [Tl(TCNQCl₂)], whereas only one phase was identified for [Tl(TCNQBr₂)] and [Tl(TCNQI₂)]. These new results are described in the context of the structures of other known binary metal–TCNQ frameworks that display a variety of coordination environments for the central cation, namely, four‐, six‐, and eight‐coordinate, and different arrangements of the adjacent TCNQ radicals—parallel versus perpendicular—in the stacked columns. The halogen substituents affect the structures and the properties of these compounds, owing to both steric and electronic effects as evidenced by the semiconducting properties of crystals of [Tl(TCNQCl₂)] phase I, [Tl(TCNQBr₂)], and [Tl(TCNQI₂)], which correlate well with the distances of adjacent TCNQ radicals in the columns. 1D infinite Hückel model simulations of the band structures of [Tl(TCNQCl₂)] phase I, [Tl(TCNQBr₂)], and [Tl(TCNQI₂)] were conducted with and without consideration of the Tl^I cations, the results of which indicate that the charge mobility does not strictly occur in one dimension. The modulations of the band structures with various assumptions of the energy difference (Δ) between the Tl^I 6s orbital and the TCNQ LUMO orbital were calculated and are discussed in light of the observed properties.     

Identification of Vinyl Sulfone Derivatives as EGFR Tyrosine Kinase Inhibitor: In Vitro and In Silico Studies

Epidermal growth factor receptor (EGFR), overexpressed in many types of cancer, has been proved as a high potential target for targeted cancer therapy due to its role in regulating proliferation and survival of cancer cells. In the present study, a series of designed vinyl sulfone derivatives was screened against EGFR tyrosine kinase (EGFR-TK) using in silico and in vitro studies. The molecular docking results suggested that, among 78 vinyl sulfones, there were eight compounds that could interact well with the EGFR-TK at the ATP-binding site. Afterwards, these screened compounds were tested for the inhibitory activity towards EGFR-TK using ADP-Glo™ kinase assay, and we found that only VF16 compound exhibited promising inhibitory activity against EGFR-TK with the IC₅₀ value of 7.85 ± 0.88 nM. In addition, VF16 showed a high cytotoxicity with IC₅₀ values of 33.52 ± 2.57, 54.63 ± 0.09, and 30.38 ± 1.37 µM against the A431, A549, and H1975 cancer cell lines, respectively. From 500-ns MD simulation, the structural stability of VF16 in complex with EGFR-TK was quite stable, suggesting that this compound could be a novel small molecule inhibitor targeting EGFR-TK.     

Synthesis of 6- and 7-propargyloxy derivatives of 4-(3-fluoroanilino)-quinazoline

The preparation of the novel isomeric 6- and 7-propargyloxy derivatives of 4-(3-fluoroanilino)-quinazoline was achieved using a six-step process. An alternate method to the 7-propargyloxy derivative and analogous 7-propargyloxy containing compounds is also described.     

Improved Synthesis of Indirubin Derivatives by Sequential Build‐Up of the Indoxyl Unit: First Preparation of Fluorescent Indirubins

Indirubin, present in extracts of Isatis tinctoria and some other plant species, has promising cytotoxicity against a variety of cell lines by inhibition of cyclin‐dependent kinases. Chemical synthesis of its derivatives relies on the combination of isatins and 2,3‐dihydro‐1H‐indol‐3‐one (‘indoxyl’) derivatives and usually yields indigo as well as other by‐products. Inspection of the hydrolysis of the long‐known condensation products of 2‐thioxothiazolidin‐4‐one with isatins gave useful hints for an improved synthesis of indirubins: this reaction does not yield quinoline derivatives but 2‐(2,3‐dihydro‐2‐oxo‐1H‐indol‐3‐ylidene)‐2‐sulfanyl acetic acids. By substitution of the sulfanyl group in this oxindoles with anilines and straightforward cyclization under Nazarov conditions, a broad variety of indirubins substituted in the indoxyl ring system are thus available, usually in very good purity and yield. Use of naphthylamines in this reaction sequence yields various fluorescent substances with λ_fl at ca. 630 nm.     

C5,5—取代基对海因质子亲合能的影响

文章对５种碳五位（Ｃ５）的不同取代基海因的质子北合能（ＰＡ）,在亚稳状态下采用“动能法”进行了研究。以５,５－甲基海因作为参照,确定了５种样品亲质子能的顺序。     

Reversed-phase high-performance liquid chromatographic/mass spectrometric method for separation of 4-methylimidazole and 2-acetyl-4-(1,2,3,4-tetrahydroxybutyl)imidazole at pg levels

A high-performance liquid chromatographic/mass spectrometric method (HPLC/MS) has been developed to determine both 4-methylimidazole (4MeI) and 2-acetyl-4-(1,2,3,4-tetrahydroxybutyl)imidazole (THI) in one run. Among three sorbents tested, the best peak shape of 4MeI was achieved on a reversed-phase MetaChem Polaris C18-A at pH 9.5. The sensitivity and the range of UV detection at 215 and 290 nm for 4MeI and THI, respectively, were compared to the parameters achieved by the electrospray ionization mass spectrometric (ESI/MS) detection in the presence of 5 mmol l⁻¹ ammonium hydroxide using selected ion-monitoring (SIM) mode. The on-column limits of detection were 0.147 ng of 4MeI and 0.084 ng of THI using UV detection and 1 pg of 4MeI and 3 pg of THI using ESI/MS detection, respectively. The effect of both ammonium ion concentration and energy of fragmentation on 4MeI and THI ionization is discussed. The method could be applied for a fast and sensitive determination of 4MeI and THI in different biological materials as well as in Class III Caramels.     

Diversity in the Interaction of Amino Acid- and Peptide-Based Hydroxamic Acids with Some Platinum Group Metals in Solution

Complexes that incorporate both ligand(s) and metal(s) exhibiting cytotoxic activity can especially be interesting to develop multifunctional drug molecules with desired activities. In this review, the limited number of solution results collected in our laboratory on the complexes of Pd(II) and two other platinum group metals—the half-sandwich type, [(η⁶-p-cym)Ru(H₂O)₃]²⁺, and [(η⁵-Cp*)Rh(H₂O)₃]²⁺—with hydroxamic acid derivatives of three amino acids, two imidazole analogues, and four small peptides are summarized and evaluated. Unlike the limited number of coordination sites of these metal ions (four and three for Pd(II) and the organometallic cations, respectively), the ligands discussed here offer a relatively high number of donor atoms as well as variation in their position within the ligands, resulting in a large versatility of the likely coordination modes. The review, besides presenting the solution equilibrium results, also discusses the main factors, such as (N,N) versus (O,O) chelate; size of chelate; amino-N versus imidazole-N; primary versus secondary hydroxamic function; differences between hydrolytic ability of the metal ions studied; and hydrolysis of the coordinated peptide hydroxamic acids in their Pd(II) complexes, which all determine the coordination modes present in the complexes formed in measurable concentrations in these systems. The options for the quantitative evaluation of metal binding effectivity and selectivity of the various ligands and the comparison with each other by using solution equilibrium data are also discussed.     

Method development and validation for the quantification of dasatinib,erlotinib, gefitinib,imatinib, lapatinib,nilotinib, sorafenib and sunitinib in human plasma by liquid chromatography coupled with tandem mass spectrometry

To support pharmacokinetic‐guided dosing in individual patients, a fast and accurate method for simultaneous determination of anticancer tyrosine kinase inhibitors (TKIs) dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, sorafenib and sunitinib in human plasma was developed using high‐performance liquid chromatography and detection with tandem mass spectrometry (HPLC‐MS/MS). Stable isotopically labeled compounds of the eight different TKIs were used as internal standards. Plasma proteins were precipitated and an aliquot of supernatant was directly injected onto a reversed phase chromatography system consisting of a Gemini C₁₈ column (50 × 2.0 mm i.d., 5.0 µm particle size) and then compounds were eluted with a gradient. The outlet of the column was connected to a triple quadrupole mass spectrometer with electrospray interface. Ions were detected in the positive multiple reaction monitoring mode. This method was validated over a linear range from 20.0 to 10,000 ng/mL for erlotinib, gefitinib, imatinib, lapatinib, nilotinib and sorafenib, and from 5.00 to 2500 ng/mL for dasatinib and sunitinib. Results from the validation study demonstrated good intra‐ and inter‐assay accuracy (<13.1%) and precision (10.0%) for all analytes. This method was successfully applied for routine therapeutic drug monitoring purposes in patients treated with the investigated TKIs. Copyright © 2012 John Wiley & Sons, Ltd.     

Affinity capillary electrophoresis and quantum mechanical calculations applied to the investigation of hexaarylbenzene-based receptor binding with lithium ion

In this study, two complementary approaches, affinity capillary electrophoresis (ACE) and quantum mechanical density functional theory (DFT) calculations, have been employed for quantitative characterization and structure elucidation of the complex between hexaarylbenzene (HAB)‐based receptor R and lithium ion Li⁺. First, by means of ACE, the apparent binding constant of Li R ⁺ complex (K) in methanol was determined from the dependence of the effective electrophoretic mobilities of Li R ⁺ complex on the concentration of lithium ions in the 25 mM Tris/50 mM chloroacetate background electrolyte (BGE) using non‐linear regression analysis. Prior to regression analysis, the effective electrophoretic mobilities of the Li R ⁺ complex were corrected to reference temperature 25°C and constant ionic strength 25 mM. The apparent binding constant of the Li R ⁺ complex in the above methanolic BGE was evaluated as logK = 1.15±0.09. Second, the most probable structures of nonhydrated Li R ⁺ and hydrated Li R ⁺·3H₂O complexes were derived by DFT calculations. The optimized structure of the hydrated Li R ⁺·3H₂O complex was found to be more realistic than the nonhydrated Li R ⁺ complex because of the considerably higher binding energy of Li R ⁺·3H₂O complex (500.4 kJ/mol) as compared with Li R ⁺ complex (427.5 kJ/mol).     

A rapid and sensitive LC‐MS/MS method for evaluation of the absolute oral bioavailability of a novel c‐Met tyrosine kinase inhibitor QBH‐196 in rats

A sensitive, selective and high‐throughput UPLC‐MS/MS method was developed and validated for the determination of a novel c‐Met tyrosine kinase inhibitor, QBH‐196, in rat plasma. QBH‐196 and its analog BH357 (IS) were extracted from rat plasma using a mixture of dichloromethane and N‐hexane (2:3, v/v). The chromatographic separation was carried out on Phenomenex C₁₈ column (50 × 2.1 mm, 2.6 µm particle size) with a gradient mobile phase of methanol (A) and water containing 0.05% formic acid (B) at a flow rate of 0.2 mL/min. The assay was performed by positive electrospray ionization in multiple reaction monitoring mode using transitions of m/z 622.68 → 140.41 for QBH‐196 and m/z 591.19 →126.21 for the IS, respectively. Good linearity was obtained over the concentration range of 8.0–4000 ng/mL (r² > 0.99) for QBH‐196 and the lower limit of quantification was 8.0 ng/mL in rat plasma. Validations of the method, including its sensitivity, extraction recovery, matrix effect, intra‐ and inter‐day precision, accuracy and stability, were all within acceptable limits. The established method was successfully applied to determine absolute oral bioavailability of QBH‐196 in rats for the first time. The mean oral absolute bioavailability of QBH‐196 was found to be about 40.8% and the elimination half‐life was 40.0 ± 13.1 h. This result suggested that QBH‐196 exhibits good oral absorption in vivo, which is very important for the further development of QBH‐196 as a new oral anticancer drug. Copyright © 2015 John Wiley & Sons, Ltd.     

Affinity capillary electrophoresis for the assessment of binding affinity of carbohydrate‐based cholera toxin inhibitors

Developing tools for the study of protein carbohydrate interactions is an important goal in glycobiology. Cholera toxin inhibition is an interesting target in this context, as its inhibition may help to fight against cholera. For the study of novel ligands an affinity capillary electrophoresis (ACE) method was optimized and applied. The method uses unlabeled cholera toxin B‐subunit (CTB) and unlabeled carbohydrate ligands based on ganglioside GM1‐oligosaccharides (GM1os). In an optimized method at pH 4, adsorption of the protein to the capillary walls was prevented by a polybrene‐dextran sulfate‐polybrene coating. Different concentrations of the ligands were added to the BGE. CTB binding was observed by a mobility shift that could be used for dissociation constant (K_d) determination. The K_d values of two GM1 derivatives differed by close to an order of magnitude (600 ± 20 nM and 90 ± 50 nM) which was in good agreement with the differences in their reported nanomolar IC₅₀ values of an ELISA‐type assay. Moreover, the selectivity of GM1os towards CTB was demonstrated using Influenza hemagglutinin (H5) as a binding competitor. The developed method can be an important platform for preclinical development of drugs targeting pathogen‐induced secretory diarrhea.