Synthesis and Crystal Structure of(Z)-5-fluoro-3-(phenyl((5-(pyridin-3-ylmethyl)thiophen-2-yl)amino)methylene)Indolin-2-one

The crystal structure of the title compound （Z）-5-fluoro-3-（phenyl（（5-（pyridin-3- ylmethyl）thiophen-2-yl）amino）methylene） indolin-2-one （C25H18FN3OS, Mr = 427.50） has been prepared and determined by single-crystal X-ray diffraction. The crystal is of orthorhombic, space group P212121 with a = 5.931（1）, b = 12.413（1）, c = 28.102（2） A, V= 2090.4（3） A3, Z = 4, Dc = 1.358 g/cm3, F（000） = 888, μ= 0.186 mm-1, MoKa radiation （2 = 0.71073）, R = 0.041 and wR = 0.105 for 4567 observed reflections with I 〉 2σ（I）. X-ray diffraction analysis reveals that the indole and thiophene rings are not coplanar with a dihedral angle of 46.26（5）°. Intramolecular and intermolecular N-H＇..O hydrogen bonds together with C-H...π interations can be observed in the lattice.

The Inhibitory Effect of Endostatin and Doxycycline Administration on B16 Melanoma Angiogenesis and Cellular Proliferation

OBJECTIVE To investigate the effect of endostatin and doxycycline on melanoma cellular proliferation and tumor angiogenesis.METHODS The effects of endostatin and doxycycline were studied in mice transplanted with B16 melanoma cells. The mice were divided into 4 groups that were treated as follows： endostatin treatment （E group）, doxycycline treatment （D group）, endostatin plus doxycycline trearment （DE group）, controls （C group） received no treatment. Following 9 days of treatment the tumor tissue was removed to compare the differences in the tumor necrotic rate and micro-vessel density （MVD） among the different groups. Immunohistochemical staining was conducted to detect the expression of proliferating cell nuclear antigen （PCNA） in the different groups.RESULTS The MVD of the 3 experimental groups was significantly less than the control group, （F = 10.888, P 〈 0.05）, indicating that doxycycline and endostatin can inhibit tumor angiogenesis by decreasing the tumor blood supply. This effect results in inhibition of tumor cellular proliferation and promotion of tumor cell necrosis. The tumor cell necrotic rate of the 3 experimental groups were all significantly higher than the C group （F = 7.229, P 〈 0.05） and the difference between the DE and C groups also was statistically significant. PCNA expression in all 3 experimental groups was statistically less than the C group （F = 17.729, P 〈 0.05）.CONCLUSION The combined use of endostatin and doxycycline in vivo can influence PCNA expression and angiogenesis in melanoma, and significantly inhibit melanoma cellular proliferation.

Generation of Hepatitis B virus PreS2-S antigen in Hansenula polymorpha

Despite the long availability of a traditional prophylactic vaccine containing the HBV surface antigen(HBsA g) and aluminum adjuvant, nearly 10% of the population remains unable to generate an effective immune response. Previous studies have indicated that hepatitis B virus(HBV) PreS 2-S is abundant in T/B cell epitopes, which induces a stronger immune response than HBsA g, particularly in terms of cytotoxic T lymphocyte(CTL) reaction. In the current study, the HBV PreS 2-S gene encoding an extra26 amino acids(PreS 2 C-terminus) located at the N-terminus of HBsA g was cloned into the pV CH1300 expression vector. Pre S2-S expressed in the methylotrophic yeast, Hansenula polymorpha, was produced at a yield of up to 250 mg/L. Subsequent purification steps involved hydrophobic adsorption to colloidal silica, ion-exchange chromatography and density ultracentrifugation. The final product was obtained with a total yield of ~15% and purity of ~99%. In keeping with previous studies, ~22 nm viruslike particles were detected using electron microscopy. The generated PreS 2-S antigen will be further studied for efficacy and safty in animals.

Novel Method for Selective Debenzylation Under Maintenance of Fluoro Atom Substituted on β-Amino Acids

tert-Butyl （R）-3-amino-3-（3-fluorophenyl）propanoate（5） was prepared with conventional debenzylation method. However, the tert-butyl （R）-3-[（S）-1-phenylethyl-amino]-3-（3-fluorophenyl） propanoate（6） and tert-butyl （R）-3-amino-3-phenylpropanoate（7） were generated as the byproducts under the general catalytic hydrogenation Pd（OH）2/C-H2 conditions. So a series of experiments was performed to optimize the reaction conditions so that product 5 could be obtained with high purity and yield. Finally an effective catalytic system, Pd/C-HCOOH-CH3OH, was discovered.

Synthesis, Crystal Structure and Antiproliferative Activity of 2,2-Dimethyl-4-oxochroman-3-ylmorpholine-4-carbodithioate

The crystal structure of the new title compound 2,2-dimethyl-4-oxochroman-3-ylmorpholine-4-carbodithioate（C16H19NO3S2,Mr = 337.44） has been prepared and determined by single-crystal X-ray diffraction.The crystal is of triclinic,space group P1 with a = 9.5518（7）,b = 9.7172（7）,c = 11.0220（8）,α = 67.08（1）,β = 74.66（1）,= 61.31（1）°,V = 822.72（10）3,Z = 2,Dc = 1.362 g/cm3,F（000） = 356,μ = 0.092 mm-1,MoKa radiation（λ = 0.71073）,R = 0.0515 and wR = 0.1389 for 2623 observed reflections with I 2（I）.X-ray diffraction analysis reveals that the chroman ring adopts a half-chair conformation while the morpholine ring shows a chair conformation.Intramolecular and intermolecular C–H···S and C–H···O hydrogen bonds together with π-π interations are found in the structure.The result of MTT assay shows the title compound displays good antiproliferative activity against two human cancer cell lines.

Synthesis,Crystal Structure and Biological Activity of 8-((4-((2,3-diaminopyridin-4-yl)oxy)-3-fluorophenyl)-amino)-2-(4-fluorophenyl)-3-methyl-2,7-naphthyridin-1(2H)-one

The new title compound 8-（（4-（（2,3-diaminopyridin-4-yl）-oxy）-3-fluorophenyl）-amino）-2-（4-fluorophenyl）-3-methyl-2,7-naphthyridin-1（2H）-one（C26H20F2N6O2, Mr = 486.48） has been prepared and determined by single-crystal X-ray diffraction. The crystal is of monoclinic, space group P21/c with a = 15.365（3）, b = 13.144（2）, c = 11.863（2）, β= 108.882（3）°, Z = 4, V = 2267.0（7）3, Dc = 1.425 g/cm3, F（000） = 1008, μ = 0.105 mm-1, MoKa radiation（λ = 0.71073）, R = 0.0480 and wR = 0.1294 for 3197 observed reflections with I 〉 2σ（I）. X-ray diffraction analysis reveals that the region C（substituents of 8-amino group and 3-methyl group on the 2,7-naphthyridin-1（2H）-one ring） of compound 6 are effectively planar. Intramolecular and intermolecular hydrogen bonds together with π···π interations are found in the structure. In addition, compound 6 shows potent c-Met and c-Kit kinase inhibition activities.

Studies on tissue distribution of scutellarin and methyl polyethylene glycol (mPEG)-scutellarin prodrug in mice

This study was to determine tissue distribution and pharmacokinetics of mPEG-scutellarin prodrug(7e),a chemical entity previously shown to have a beneficial effect in cerebral ischemia/reperfusion(I/R)injury.After injecting scutellarin or prodrug 7e,the concentrations of scutellarin and 7e in tissues were determined and the pharmacokinetic parameters were calculated.The results showed that the distribution of scutellarin in tissues was enhanced by PEGylation.The distribution of 7e in brain was approximately 2.1-fold higher than that of scutellarin,indicating that PEGylation increased the brain penetration of scutellarin.We conclude that 7e could exert more effective protection on cerebral I/R injury in mice.This study also provided a simple and convenient strategy to identify novel drugs with potential protective function for I/R injury in mice.

Endostatin derivative angiogenesis inhibitors

Objective To throw light on the superiority of the anti-angiogenesis activity of endostatin （ES） derivatives by reviewing the recent progress in the field of ES molecular structure modification. Data sources The data used in this article were mainly from PubMed with relevant English articles published from 1971 to May 2008. The search terms were ＂endostatin＂ and ＂angiothesis＂. Study selection Articles involved in the ES molecular structure modification and the original milestone articles were selected. Results A number of ES derivatives were designed and studied to improve its clinical relevance. The modified ES with polyethylene glycol （PEG）, low molecular weight heparin （LMWH） and IgG Fc domain extended the circulation half-life. Meanwhile the recombinant ESs showed more potent anti-tumor activity than native ES in mouse xenografts. Mutated ES also changed its anti-angiogenesis activity. Conclusions The anti-angiogenesis treatment remains a promising tumor therapeutic strategy. New ES derivatives would be a good choice to meet the future challenge on clinical application of ES.

Synthesis and biological evaluation of 8-substituted and deglucuronidated scutellarin and baicalin analogues as antioxidant responsive element activators

Flavonoids are important bioactive dietary compounds, which are proved to be antioxidant responsive element (ARE) activators to defend against electrophilic toxicants and oxidative stress. The activators induce ARE gene transcription through Nrf2 factor, a major transcriptional stimulator of cytoprotective genes, relieved from a Keap1 complex. In this report, based on the structures of two flavonoids, scutellarin and baicalin, which are extracted from two common Chinese plants Dengzhanhua (Erigeron breviscapus (vant) Hand-Mazz) and Huangqin (Scutellaria baicalensis Georigi), respectively, we synthesized several 8-substituted and deglucuronidated analogues and identified the ARE activation effects of these flavonoids. We found that the Baicalin, deglucurnonidated Baicalin and diaza cyclopenta derivative were more active. Their dose-dependent upregulation activities of ARE and NQO1 and induction effects of Nrf2 were testified. The results presented that these three analogues had good upregulation effects on ARE, and they could be potentially utilized in relieving oxidative stress, upon further neuroprotective tests.