Investigation of the solid phase synthesis of tyrosine‐derived diphenol monomers with resin‐bound carbodiimide coupling reagents

Tyrosine‐derived pseudo‐polypeptides have recently been established as potential biomaterials. The bulk production of these polymers is dependant upon the convenient synthesis of tyrosine‐derived diphenolic monomers. Suitable solution phase methods for the synthesis of such monomers, with transient activated esters, have been reported previously by Kohn, J.; Langer, R. In Biomaterials Science: An Introduction to Materials in Medicine; Ratner, B. D.; Hoffman, A. S.; Schoen, F. J.; Lemons, J. E., Eds.; Academic Press: New York, 1996; pp 64–72. However, for all the methods reported by them, purification and isolation of the diphenol monomer involves rigorous extraction, column purification, or an extensive aqueous workup. These may lead to the incorporation of solvent‐based as well as inorganic impurities and also may lead to difficulties in the process scale‐up. In this article, an alternate and relatively more convenient method for the synthesis of tyrosine‐based diphenol monomers is reported. This involved the investigation of polymer resin‐bound carbodiimide in the solid‐phase synthesis of L‐tyrosine‐based diphenolic monomers. This method was found to eliminate the need for rigorous purification processes and was found to maintain reasonable yield as well as maintain purity of the final monomer product. The monomer was able to produce polymers of a reasonably high‐molecular‐weight and a narrow polydispersity. The amide bond formation by such a polymer‐tethered reagent can be described to follow a reverse‐Merrifield sense and the method is relatively convenient to scale up. The L‐tyrosine‐based diphenolic monomeric compound formed by this method was analyzed by NMR, Fourier transform infrared, and elemental microanalysis techniques for chemical structure and composition. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 4906–4915, 2004     

Heterogeneous Catalytic Transformations of Natural Camphene

Reactions of the natural terpene camphene with various reagents on zeolitic catalysts are reviewed.     

Comparison of Intermolecular Interactions of Irreversible and Reversible Inhibitors with Bruton’s Tyrosine Kinase via Molecular Dynamics Simulations

Bruton’s tyrosine kinase (BTK) is a key protein from the TEC family and is involved in B-cell lymphoma occurrence and development. Targeting BTK is therefore an effective strategy for B-cell lymphoma treatment. Since previous studies on BTK have been limited to structure-function analyses of static protein structures, the dynamics of conformational change of BTK upon inhibitor binding remain unclear. Here, molecular dynamics simulations were conducted to investigate the molecular mechanisms of association and dissociation of a reversible (ARQ531) and irreversible (ibrutinib) small-molecule inhibitor to/from BTK. The results indicated that the BTK kinase domain was found to be locked in an inactive state through local conformational changes in the DFG motif, and P-, A-, and gatekeeper loops. The binding of the inhibitors drove the outward rotation of the C-helix, resulting in the upfolded state of Trp395 and the formation of the salt bridge of Glu445-Arg544, which maintained the inactive conformation state. Met477 and Glu475 in the hinge region were found to be the key residues for inhibitor binding. These findings can be used to evaluate the inhibitory activity of the pharmacophore and applied to the design of effective BTK inhibitors. In addition, the drug resistance to the irreversible inhibitor Ibrutinib was mainly from the strong interaction of Cys481, which was evidenced by the mutational experiment, and further confirmed by the measurement of rupture force and rupture times from steered molecular dynamics simulation. Our results provide mechanistic insights into resistance against BTK-targeting drugs and the key interaction sites for the development of high-quality BTK inhibitors. The steered dynamics simulation also offers a means to rapidly assess the binding capacity of newly designed inhibitors.     

表皮生长因子受体酪氨酸激酶抑制剂的药效团研究

根据一系列表皮生长因子受体酪氨酸激酶抑制剂的三维定量构效关系研究，得 到了该类抑制剂的药效团，研究结果与Novartis的药效团模型相当类似．药效团包 括一个氢键受体，一个氢键给体，一个疏水区和一个带有氯或溴原子药效团对于研 究表皮生长因子受体酪氨酸激酶抑制剂结构与活性的关系具有重要的意义．通过三 维数据库搜索可能会得到新的先导化合物．     

1,3,4-(口恶)二唑硫醚酰胺为核心骨架的新型多杂环分子的合成及对Cdc25B与PTP1B的抑制活性

首先利用含有三嗪的芳香酰肼(3)构筑了1,3,4-噁二唑衍生物(5), 然后将化合物5与含有1,3,4-噻二唑的衍生物(6)拼合合成了18个目标分子. 利用红外光谱(IR)、 核磁共振波谱(NMR)和高分辨质谱(HRMS)等技术对其结构进行了表征. 考察了目标分子对细胞分裂周期25磷酸酯酶B(Cdc25B)和蛋白酪氨酸磷酸酯酶1B(PTP1B)的抑制活性. 结果表明, 有8个目标分子的抑制活性优于其阳性对照物, 有望成为潜在的Cdc25B抑制剂; 有12个目标分子的抑制活性优于其对照物, 有望成为潜在的PTP1B抑制剂.     

Kinetics and mechanism of trichloroisocyanuric acid/NaNO2-triggered nitration of aromatic compounds under acid-free and Vilsmeier-Haack conditions

Kinetics and mechanism of nitration of aromatic compounds using trichloroisocyanuric acid (TCCA)/NaNO₂, TCCA-N,N-dimethyl formamide (TCCA-DMF)/NaNO₂, and TCCA-N,N-dimethyl acetamide (TCCA-DMA)/NaNO₂ under acid-free and Vilsmeier-Haack conditions. Reactions followed second-order kinetics with a first-order dependence on [Phenol] and [Nitrating agent] ([TCCA], [(TCCA-DMF)], or [(TCCA-DMA)] >> [NaNO₂]). Reaction rates accelerated with the introduction of electron-donating groups and retarded with electron-withdrawing groups, but did not fit well into the Hammett's theory of linear free energy relationship or its modified forms like Brown-Okamoto or Yukawa-Tsuno equations. Rate data were analyzed by Charton's multiple linear regression analysis. Isokinetic temperature (β) values, obtained from Exner's theory for different protocols, are 403.7 K (TCCA-NaNO₂), 365.8 K (TCCA-DMF)/NaNO₂, and 358 K (TCCA-DMA)/NaNO₂. These values are far above the experimental temperature range (303-323 K), indicating that the enthalpy factors are probably more important in controlling the reaction.     

Alkaloid production by callous tissue cultures of Cereus peruvianus (Cactaceae)

The morphologically undifferentiated cells of nonregenerant callous tissue of Cereus peruvianus cultured in the original medium and in medium supplemented with tyrosine were used as an alkaloid source. Comparison of alkaloid production by C. peruvianus plants and by callous tissues indicated that alkaloid levels were almost twice as high in callous tissues as in shoots of C. peruvianus plants. The ratio of alkaloid concentration between mature plant and morphologically und ifferentiated cells of callous tissue was 1∶1.7. A relationship between culture medium containing tyrosine and alkaloid production was also observed in the callous tissues of C. peruvianus. Since increased alkaloid production may be induced by additional factors such as tyrosine, increasing levels of tyrosine or other conditions of the culture medium may be considered factors for inducing higher alkaloid production by C. peruvianus callous tissues.     

Production of l-DOPA by tyrosinase immobilized on modified polystyrene

Mushroom tyrosinase was immobilized on modified polystyrene—polyaminostyrene (PSNH) and polymethylchloridestyrene (PSCL)—to produce l-DOPA from l-tyrosine. Glutaraldehyde was used as an activating agent for the PSNH to immobilize the tyrosinase and 10% (w/v) glutaraldehyde was optimal in conferring the highest specific activity (11.96 U/g) to the PSNH. Methylchloride on the PSCL was directly linked with the tyrosinase, and 1.5 mmol of Cl/g was optimal in attaining the specific activity of 17.0 U/g. The temperature and optimal acidity were, respectively, 60°C and pH 5.5 for the PSNH, and 70°C and pH 3.0 for the PSCL. In a 50-mL batch reactor working over 36 h, the l-DOPA production rate at 30°C was 1.44 mg/(L·h) for the PSNH and 2.33 mg/(L·h) for the PSCL. The production rate over 36 h was 3.86 mg/(L·h) for the PSNH at 60°C and 5.54 mg/(L·h) for the PSCL at 70°C. Both of the immobilized enzymes showed a remarkable stability with almost no change in activity after being stored wet. The operational stability study indicated a 22.4% reduction in l-DOPA production for the PSNH and an 8.63% reduction for the PSCL over seven runs (each run was for 144h at 30°C) when the immobilized enzymes were used under turnover conditions. The immobilized tyrosinase was more stable on the PSCL than on the PSNH.     

甲苯定向硝化的理论研究

运用密度泛函理论(DFT)B3LYP方法，在6-31G~(* *)基组水平上，全优化计算 了硝酰阳离子NO_2~+对苯和从0-，m-,p-位进攻甲苯亲电取代硝化后应，求得4条反 应途径上包括反应物、过渡态和Wheland中间体共(4×3)12个反应驻点σ络合物的 分子几何、电子结构、能量和IR光谱等性质，阐明了反应中无同位素效应的实验事 实，求得各反应途径的活化能排序：p-＞o-＞PhH＞m-和σ络合物(R,TSak或INT)的 相对稳定化能排序：p-ArCH_3-NO_2~+＞o-ArCH_3-NO_2~+＞m-ArCH_3-NO_2~+＞ PhH-NO_2~+，从而阐明了甲基对苯环致活(或致钝)以及增加甲苯硝化络合物稳定性 的双重功能，对甲苯定向硝化的理论预示与实验结果相吻合。     

Mass spectrometric methods for the analysis of chlorinated and nitrated isoflavonoids: a novel class of biological metabolites

Electrospray ionization combined with tandem mass spectrometry was applied to a study of some representative chlorinated and nitrated isoflavones-potential metabolites of isoflavones in inflammatory cells. Upon collision-induced dissociation of deprotonated [M - H](-) ions of these compounds, a number of structurally characteristic product ions were produced. The product ion analysis of 3'- and 8-chlorodaidzein in the tandom mass spectra led to ready differentiation of these isomers. 3-Nitro derivatives of both genistein and daidzein have product ions due to the losses of HNO(2) and two OH groups. Chlorinated derivatives of isoflavones were detected in cell-based experiments and their structures were proposed by comparing the tandem mass spectra of their product ions with those of standards. This work provides a suitable analytical basis to aid the characterization of chlorinated and nitrated metabolites in studies in vivo and in vitro.