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991.
The absolute configurations of three synthesized anthracycline analogues have been determined using vibrational circular dichroism (VCD) spectroscopy and the density functional theory (DFT) calculations. The experimental VCD spectra of the three compounds have been measured for the first time in the film state, prepared from their CDCl3 solutions. Conformational searches for the monomers and some dimers of the three compounds have been performed at the DFT level using the B3LYP functional and the 6‐311G** and 6‐311++G** basis sets. The corresponding vibrational absorption and VCD spectra have been calculated. The good agreement between the experimental and the calculated spectra allows one to assign the absolute configurations of the three compounds with high confidence. In addition, the dominant conformers of the three compounds have also been identified. Chirality, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
992.
The SurePath liquid-based Pap test (LPT) is successfully and widely used to assess sputum cytology. This study aimed to compare
the cytological findings and diagnostic sensitivity of LPT with those of the conventional Pap smear (CPS) method for diagnosing
lung cancer. Bronchial brushing specimens from 204 patients diagnosed with lung cancer were studied. LPT slides showed decreased
areas of cell monolayers, a clearer background and distinct, stereoscopic cytological features. The LPT had a significantly
higher diagnostic sensitivity for lung cancer (71.6%) than the CPS method (57.8%, p < 0.05), particularly for small cell lung carcinoma and >2 cm lesions (p < 0.05). Combination of the LPT with the CPS method showed obviously higher diagnostic sensitivity for the detection of adenocarcinoma
(63.6%), central lesions (85.0%) and >2 cm lesions (81.4%) compared with the CPS method alone (p < 0.05, p < 0.01). Thus, LPT is a useful and easily performed technique that can be widely applied, and is suitable for the early diagnosis
of lung cancer. 相似文献
993.
994.
Perera MA Qin W Yandeau-Nelson M Fan L Dixon P Nikolau BJ 《The Plant journal : for cell and molecular biology》2010,64(4):618-632
Long-chain normal hydrocarbons (e.g. alkanes, alkenes and dienes) are rare biological molecules and their biosynthetic origins are obscure. Detailed analyses of the surface lipids that accumulate on maize silks have revealed that these hydrocarbons constitute a large portion (>90%) of the cuticular waxes that coat this organ, which contrasts with the situation on maize seedling leaves, where the cuticular waxes are primary alcohols and aldehydes. The normal hydrocarbons that occur on silks are part of a homologous series of alkanes, alkenes and dienes of odd-number carbon atoms, ranging between 19 and 33 in number. The alkenes and dienes consist of a homologous series, each of which has double bonds situated at defined positions of the alkyl chains: alkenes have double bonds situated at the sixth, ninth or 12th positions, and dienes have double bonds situated at the sixth and ninth, or ninth and twelfth positions. Finding a homologous series of unsaturated aldehydes and fatty acids suggests that these alkenes and dienes are biosynthesized by a series of parallel pathways of fatty-acid elongation and desaturation reactions, which are followed by sequential reduction and decarbonylation. In addition, the silk cuticular waxes contain metabolically related unsaturated long-chain methylketones, which probably arise via a decarboxylation mechanism. Finally, metabolite profiling analyses of the cuticular waxes of two maize inbred lines (B73 and Mo17), and their genetic hybrids, have provided insights into the genetic control network of these biosynthetic pathways, and that the genetic regulation of these pathways display best-parent heterotic effects. 相似文献
995.
Malamas MS Robichaud A Erdei J Quagliato D Solvibile W Zhou P Morris K Turner J Wagner E Fan K Olland A Jacobsen S Reinhart P Riddell D Pangalos M 《Bioorganic & medicinal chemistry letters》2010,20(22):6597-6605
The identification of small molecule aminohydantoins as potent and selective human β-secretase inhibitors is reported. These analogs exhibit good brain permeability (40-70%), low nanomolar potency for BACE1, and demonstrate >100-fold selectivity for the structurally related aspartyl proteases cathepsin D, renin and pepsin. Alkyl and alkoxy groups at the meta-position of the P1 phenyl, which extend toward the S3 region of the enzyme, have contributed to the ligand's reduced affinity for the efflux transporter protein P-gp, and decreased topological polar surface area, thus resulting in enhanced brain permeability. A fluorine substitution at the para-position of the P1 phenyl has contributed to 100-fold decrease of CYP3A4 inhibition and enhancement of compound metabolic stability. The plasma and brain protein binding properties of these new analogs are affected by substitutions at the P1 phenyl moiety. Higher compound protein binding was observed in the brain than in the plasma. Two structurally diverse potent BACE1 inhibitors (84 and 89) reduced 30% plasma Aβ40 in the Tg2576 mice in vivo model at 30 mg/kg p.o.. 相似文献
996.
Pawel Nowak Derek C. Cole Ann Aulabaugh Jonathan Bard Rajiv Chopra Rebecca Cowling Kristi Y. Fan Baihua Hu Steve Jacobsen Minakshi Jani Guixan Jin Mei-Chu Lo Michael S. Malamas Eric S. Manas Rani Narasimhan Peter Reinhart Albert J. Robichaud Joseph R. Stock Joan Subrath Kristine Svenson John W. Ellingboe 《Bioorganic & medicinal chemistry letters》2010,20(2):632-635
8,8-Diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibitor of BACE1. X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S1 to the S3 pocket. 相似文献
997.
Mark R. Herbert Dana L. Siegel Lena Staszewski Charmagne Cayanan Urmi Banerjee Sangeeta Dhamija Jennifer Anderson Amy Fan Li Wang Peter Rix Andrew K. Shiau Tadimeti S. Rao Stewart A. Noble Richard A. Heyman Eric Bischoff Mausumee Guha Ayman Kabakibi Anthony B. Pinkerton 《Bioorganic & medicinal chemistry letters》2010,20(19):5718-5721
Optimization of a screening hit from uHTS led to the discovery of TGR5 agonist 32, which was shown to have activity in a rodent model for diabetes. 相似文献
998.
Matthew G. Stanton Jed Hubbs David Sloman Christopher Hamblett Paula Andrade Minilik Angagaw Grace Bi Regina M. Black Jamie Crispino Jonathan C. Cruz Eric Fan Georgia Farris Bethany L. Hughes Candia M. Kenific Richard E. Middleton George Nikov Peter Sajonz Sanjiv Shah Nirah Shomer Alexander A. Szewczak Benito Munoz 《Bioorganic & medicinal chemistry letters》2010,20(2):755-758
We report herein a novel series of difluoropiperidine acetic acids as modulators of γ-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective β-difluorination with Selectfluor®. Compounds 1f and 2c were selected for in vivo assessment and demonstrated selective lowering of Aβ42 in a genetically engineered mouse model of APP processing. Moreover, in a 7-day safety study, rats treated orally with compound 1f (250 mg/kg per day, AUC0–24 = 2100 μM h) did not exhibit Notch-related effects. 相似文献
999.
Lin He Fan He Huichang Bi Jiankang Li Su Zeng Hai-Bin Luo Min Huang 《Bioorganic & medicinal chemistry letters》2010,20(20):6008-6012
Our kinetics studies demonstrated that the nature product chrysin exhibited a high inhibitory affinity of 54 nM towards human cytochrome P450 1A2 and was comparable to α-naphthoflavone (49 nM), whereas it represented a moderate affinity of 5225 nM against human cytochrome P450 2C9. However, it remains unclear how this inhibitor selectively binds 1A2. To better understand the isoform selectivity of chrysin, molecular docking and molecular dynamics simulations were performed. Chrysin formed a strong H-bond with Asp313 of 1A2. The stacking interactions with Phe226 also contributed to its tight binding to 1A2. The larger and much more open active site architectures of 2C9 may explain the weaker inhibitory affinity of chrysin towards 2C9. The predicted binding free energies suggest that chrysin preferred 1A2 (ΔGbind, pred = ?23.11 kcal/mol) to 2C9 (?20.41 kcal/mol). Additionally, the present work revealed that 7-hydroxy-flavone bound to 1A2 in a similar pattern as chrysin and represented a slightly less negative predicted binding free energy, which was further validated by our kinetics analysis (IC50 = 240 nM). Results of the study can provide insight for designing novel isoform-selective 1A2 inhibitors. 相似文献
1000.
Menghua Wang Yi Xia Yuting Fan Palma Rocchi Fanqi Qu Juan L. Iovanna Ling Peng 《Bioorganic & medicinal chemistry letters》2010,20(20):5979-5983
Novel arylethynyltriazole acyclonucleosides were synthesized and assessed for their anticancer activity on drug-resistant pancreatic cancer MiaPaCa-2 cells. One lead compound was found to have much more potent apoptosis-related antiproliferative effects than gemcitabine, the current first-line treatment for pancreatic cancer. Further investigations showed that this active compound did not inhibit DNA synthesis, which means that it does not resemble gemcitabine and may involve a different mechanism of action. 相似文献