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Zhao Zhao Jiaxin Cui Yan Yin Heng Zhang Yecheng Liu Rui Zeng Chao Fang Zhenpeng Kai Zhonghua Wang Fanhong Wu 《中国化学》2016,34(8):801-808
HMG‐CoA reductase inhibitors were widely used as lipid‐lowing agents through effectively blocking the rate‐limiting step of cholesterol biosynthesis. 8 analogs of Rosuvastatin were firstly prepared with different distance and functional group between the O5‐hydroxyl group and terminal COOH group in the hydrophilic side‐chain. In primary and secondary screening of the inhibitory activities against human HMG‐CoA reductase, gem‐difluoromethylenated derivatives exhibited more than 50% inhibition rate. Then 4 compounds with gem‐difluoro group were further synthesized and evaluated in vitro, three compounds among them exhibited low single digital nmol/L IC50 values against HMG‐CoA reductase. Molecular docking also well explained the observed special contribution of the gem‐difluoro group. 相似文献
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Rational Control of Polyketide Extender Units by Structure‐Based Engineering of a Crotonyl‐CoA Carboxylase/Reductase in Antimycin Biosynthesis 下载免费PDF全文
Lihan Zhang Takahiro Mori Qingfei Zheng Dr. Takayoshi Awakawa Yan Yan Prof. Wen Liu Prof. Ikuro Abe 《Angewandte Chemie (International ed. in English)》2015,54(45):13462-13465
Bioengineering of natural product biosynthesis is a powerful approach to expand the structural diversity of bioactive molecules. However, in polyketide biosynthesis, the modification of polyketide extender units, which form the carbon skeletons, has remained challenging. Herein, we report the rational control of polyketide extender units by the structure‐based engineering of a crotonyl‐CoA carboxylase/reductase (CCR), in the biosynthesis of antimycin. Site‐directed mutagenesis of the CCR enzyme AntE, guided by the crystal structure solved at 1.5 Å resolution, expanded its substrate scope to afford indolylmethylmalonyl‐CoA by the V350G mutation. The mutant A182L selectively catalyzed carboxylation over the regular reduction. Furthermore, the combinatorial biosynthesis of heterocycle‐ and substituted arene‐bearing antimycins was achieved by an engineered Streptomyces strain bearing AntEV350G. These findings deepen our understanding of the molecular mechanisms of the CCRs, which will serve as versatile biocatalysts for the manipulation of building blocks, and set the stage for the rational design of polyketide biosynthesis. 相似文献
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In this paper, we develop a concise approach to (+)‐benzene diol epoxide and (+)‐conduramine A‐1 based upon the utilization of the C2‐symmetric L‐tartaric acid as a chiral building block. 相似文献
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Fast Efficient and General PASE Approach to Medicinally Relevant 4H,5H‐Pyrano‐[4,3‐b]pyran‐5‐one and 4,6‐Dihydro‐5H‐pyrano‐[3,2‐c]pyridine‐5‐one Scaffolds 下载免费PDF全文
Michail N. Elinson Fedor V. Ryzhkov Ruslan F. Nasybullin Anatoly N. Vereshchagin Mikhail P. Egorov 《Helvetica chimica acta》2016,99(9):724-731
The general ‘on‐solvent’ PASE approach was found to be medicinally relevant for 4H,5H‐pyrano[4,3‐b]pyran‐5‐one and 4,6‐dihydro‐5H‐pyrano[3,2‐c]pyridine‐5‐one scaffolds. Ammonium acetate‐catalyzed multicomponent reaction of aldehydes and two different C–H acids in the presence of small amounts of EtOH results in fast (3 – 15 min) and efficient formation of scaffolds, promising for many diverse oriented medical applications. 相似文献
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The optically active β‐hydroxyl‐γ‐butyrolactones were synthesized from nonchiral starting material by employing reductive cleavage reaction, sharpless asymmetric epoxidation and dihydroxylation, and Lewis acid‐catalysed cyclization as key steps. This strategy can be used to prepare many chiral β‐hydroxyl‐γ‐butyrolactone analogues. 相似文献
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H. K. Lee C. S. Ho M. Hu B. Tomlinson C. K. Wong 《Biomedical chromatography : BMC》2013,27(11):1369-1374
A sensitive and specific liquid chromatography tandem mass spectrometric method was developed and validated for the simultaneous determination of rosuvastatin (ROS) and N‐desmethyl rosuvastatin (NOR‐ROS) in human plasma using deuterium‐labeled internal standards. The plasma samples were prepared using liquid–liquid extraction with diethyl ether. Chromatographic separation was accomplished on an Xterra MS C18 column. The mobile phase consisted of a gradient mixture of 15 µmol/L ammonium acetate in water and in methanol, maintained at a flow rate of 0.4 mL/min. Mass spectrometric detection was carried out in negative electrospray ionization mode and monitored by quantification and qualification transitions for each analyte. Using 300 μL plasma samples, the lower limits of quantification of ROS and NOR‐ROS were 0.05 and 0.02 µg/L respectively. The linearity of ROS and NOR‐ROS ranged from 0.05 to 42 and 0.02 to 14 µg/L respectively. The relative standard deviations of ROS and NOR‐ROS were <13 and 9%, respectively, while the deviations from expected values were within ?4.7–9.8 and ?5.2–4.6%, respectively. The present method offered high sensitivity and was successfully applied to a 24 h pharmacokinetic study of ROS and NOR‐ROS in healthy subjects receiving a single dose of 10 mg ROS. Copyright © 2013 John Wiley & Sons, Ltd. 相似文献
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Qing‐Chao Liu Tian‐Tian Guo Shou‐Dong Guo Wen‐Hong Li Dong Li 《Helvetica chimica acta》2013,96(1):142-149
The four hederagenin glycosides 1 – 4 were efficiently synthesized through one‐pot sequential glycosylations with glycose 1‐(trichloroacetimidate)s as donors, resulting in a significantly simplified synthetic procedure without isolation of glycosylation intermediates. The activity of the synthetic hederagenin glycosides 1 – 4 against α‐glucosidase type IV was evaluated; hederagenin glycoside 4 containing an α‐L ‐rhamnopyranosyl unit showed the best activity with an IC50 value of 47.9 μM . 相似文献
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Three new chiral heterocalix [4] crowns containing aza thio atoms bearing two chiral sites provided by (R)‐cysteine ester were synthesized. All new compounds were characterized by 1H NMR, MS and elemental analysis. 相似文献
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Yasemin Tümer Hümeyra Bati Prof. Dr. Nezihe Çalişkan Çi˘dem Yüksektepe Orhan Büyükgüngör 《无机化学与普通化学杂志》2008,634(3):597-599
The new cyclotriphosphazene derivative N3P3(OC6H3OCH3COH)6 ( 1 ) was synthesized from hexachlorocyclotriphosphazene, N3P3Cl6, and 4‐hydroxy‐3‐methoxybenzaldehyde in acetonitrile in the presence of K2CO3. The structure of 1 was verified by means of elemental analysis, IR, 1H NMR, 13C NMR, 31P NMR spectra, thermal analysis and X‐ray diffraction. 相似文献
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A simple and practical approach for the preparation of unsymmetric bis(indolyl)methanes (BIMs) was realized by Lewis acid InBr3‐catalyzed Friedel‐Crafts reaction of indoles with 3‐indolyl‐substituted phthalides in water. 相似文献
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A practical synthesis of (R)‐4‐(benzyloxy)‐3‐methylbutanenitrile, a potential chiral building block, from the corresponding α‐keto ester in high yield and large scale was presented. 相似文献
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In the presence of NH4I as catalyst and m‐chloroperbenzoic acid as oxidant, the Se–Se bond cleavage of diselenides undergoes smoothly. The in situ generated reactive electrophilic Se species reacts with alkenes quickly, and a series of β‐hydroxy selenides are prepared in good yields. This new catalytic method for synthesis of β‐hydroxy selenides is a stereospecific anti addition, which occurs with a Markovnikov orientation. 相似文献
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The title compounds, the P(3)‐axially and P(3)‐equatorially substituted cis‐ and trans‐configured 8‐benzyl‐3‐fluoro‐2,4‐dioxa‐8‐aza‐3‐phosphadecalin 3‐oxides (=8‐benzyl‐3‐fluoro‐2,4‐dioxa‐8‐aza‐3‐phosphabicyclo[4.4.0]decane 3‐oxides=2‐fluorohexahydro‐6‐(phenylmethyl)‐4H‐1,3,2‐dioxaphosphorino[5,4‐c]pyridine 2‐oxides) were prepared (ee>98%) and fully characterized (Schemes 2 and 3). The absolute configurations were established from that of their precursors, the enantiomerically pure cis‐ and trans‐1‐benzyl‐4‐hydroxypiperidine‐3‐methanols which were unambiguously assigned. Being configuratively fixed and conformationally constrained phosphorus analogues of acetyl γ‐homocholine (=3‐(acetyloxy)‐N,N,N‐trimethylpropan‐1‐aminium), they are suitable probes for the investigation of molecular interactions with acetylcholinesterase. As determined by kinetic methods, all of the compounds are weak inhibitors of the enzyme. 相似文献
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Melamine trisulfunic acid is employed as a recyclable catalyst for the condensation reaction of aromatic aldehydes with 3‐methyl‐l‐phenyl‐2‐pyrazolin‐5‐one. This condensation reaction was performed in ethanol under refluxing conditions giving 4,4′‐(arylmethylene)‐bis‐(3‐methyl‐1‐phenyl‐1H‐pyrazol‐5‐ols) in 80‐96% yields. 相似文献
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Dieter Seebach Estelle Dubost Raveendra I. Mathad Bernhard Jaun Michael Limbach Markus Löweneck Oliver Flögel James Gardiner Stefania Capone Albert K. Beck Hans Widmer Daniel Langenegger Dominique Monna Daniel Hoyer 《Helvetica chimica acta》2008,91(9):1736-1786
Cyclo‐β‐tetrapeptides are known to adopt a conformation with an intramolecular transannular hydrogen bond in solution. Analysis of this structure reveals that incorporation of a β2‐amino‐acid residue should lead to mimics of ‘α‐peptidic β‐turns’ (cf. A, B, C ). It is also known that short‐chain mixed β/α‐peptides with appropriate side chains can be used to mimic interactions between α‐peptidic hairpin turns and G protein‐coupled receptors. Based on these facts, we have now prepared a number of cyclic and open‐chain tetrapeptides, 7 – 20 , consisting of α‐, β2‐, and β3‐amino‐acid residues, which bear the side chains of Trp and Lys, and possess backbone configurations such that they should be capable of mimicking somatostatin in its affinity for the human SRIF receptors (hsst1–5). All peptides were prepared by solid‐phase coupling by the Fmoc strategy. For the cyclic peptides, the three‐dimensional orthogonal methodology (Scheme 3) was employed with best success. The new compounds were characterized by high‐resolution mass spectrometry, NMR and CD spectroscopy, and, in five cases, by a full NMR‐solution‐structure determination (in MeOH or H2O; Fig. 4). The affinities of the new compounds for the receptors hsst1–5 were determined by competition with [125I]LTT‐SRIF28 or [125I] [Tyr10]‐CST14. In Table 1, the data are listed, together with corresponding values of all β‐ and γ‐peptidic somatostatin/Sandostatin® mimics measured previously by our groups. Submicromolar affinities have been achieved for most of the human SRIF receptors hsst1–5. Especially high, specific binding affinities for receptor hsst4 (which is highly expressed in lung and brain tissue, although still of unknown function!) was observed with some of the β‐peptidic mimics. In view of the fact that numerous peptide‐activated G protein‐coupled receptors (GPCRs) recognize ligands with turn structure (Table 2), the results reported herein are relevant far beyond the realm of somatostatin: many other peptide GPCRs should be ‘reached’ with β‐ and γ‐peptidic mimics as well, and these compounds are proteolytically and metabolically stable, and do not need to be cell‐penetrating for this purpose (Fig. 5). 相似文献
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Annabelle Gillig Somi Reddy Majjigapu Bernard Sordat Pierre Vogel 《Helvetica chimica acta》2012,95(1):34-42
FK866 (also named APO866 or WK175) is a potent NAMPT inhibitor being evaluated (Phase II) as a potential anticancer drug. The preparation of the C‐iminoribofuranoside analog (2E)‐N‐[4‐(1‐benzoylpiperidin‐4‐yl)butyl]‐3‐{3‐[(2S,3S,4R,5R)‐3,4‐dihydroxy‐5‐(hydroxymethyl)pyrrolidin‐2‐yl]phenyl}prop‐2‐enamide ((?)‐ 1 ) is reported. 相似文献
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[1,3‐Dihydro‐4‐phenyl(1,5)benzodiazepin‐2‐ylidene]malononitrile 1a was treated with formaline and some different primary amines to give the corresponding pyrimido(1,5)benzodiazepines 2a–d . Treatment of compound 1a with halo reagents yielded the corresponding pyrrolobenzodiazepines 3a,b . The reaction of compound 1a with active methylenes, bidentates, S,S‐ and N,S‐acetals afforded the corresponding spiro(1,5)‐benzodiazepines 4a‐c–8a,b , respectively. 相似文献
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A new one‐step synthesis of highly substituted thiophen‐2(3H)‐one derivatives was developed. 2‐Aryl‐1‐(morpholin‐4‐yl)ethanethiones were reacted with 2‐chloro‐2‐phenylacetyl chloride in DMF in the presence of a base to give the title compounds in moderate‐to‐good yields. 相似文献