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81.
Parvateesam Yenda Naresh Kumar Katari Balasubramanian Satheesh Rambabu Gundla Siva Krishna Muchakayala Vijay Kumar Rekulapally 《Journal of separation science》2023,46(11):2200770
The design of an appropriate analytical method for assessing the quality of pharmaceuticals requires a deep understanding of science, and risk evaluation approaches are appreciated. The current study discusses how a related substance method was developed for Nintedanib esylate. The best possible separation between the critical peak pairs was achieved using an X-Select charged surface hybrid Phenyl Hexyl (150 × 4.6) mm, 3.5 μm column. A mixture of water, acetonitrile, and methanol in mobile phase-A (70:20:10) and mobile phase-B (20:70:10), with 0.1% trifluoroacetic acid and 0.05% formic acid in both eluents. The set flow rate, wavelength, and injection volumes were 1.0 ml/min, 285 nm, and 5 μl, respectively, with gradient elution. The method conditions were validated as per regulatory requirements and United States Pharmacopeia general chapter < 1225 >. The correlation coefficient for all impurities from the linearity experiment was found to be > 0.999. The % relative standard deviation from the precision experiments ranged from 0.4 to 3.6. The mean %recovery from the accuracy study ranged from 92.5 to 106.5. Demonstrated the power of the stability-indicating method through degradation studies; the active drug component is more vulnerable to oxidation than other conditions. Final method conditions were further evaluated using a full-factorial design. The robust method conditions were identified using the graphical optimization from the design space. 相似文献
82.
《Arabian Journal of Chemistry》2023,16(2):104499
In medicinal chemistry for the purpose of lead optimization, hit selection of new isofunctional chemotypes are crucial for the success of identifying novel chemical entities of increased potency. Using fragment-based design approach with the N-selective inhibitor RXP407, a novel phosphinic peptide scaffold that consisted of modified RXP407 fragments was generated. The presented synthetic route is straightforward and produces the desired product Z-RXP407 in moderate yield. The (S,R,S,S)-Z-RXP407 analog has been evaluated for the C- and N-domain constructs of angiotensin-converting enzyme. The potency of this analog has been much lower compared to the parent compound RXP407, providing thus valuable insights regarding further design based on structure–activity relationships. 相似文献
83.
84.
Postfunctionalization of BN‐Embedded Polycyclic Aromatic Compounds for Fine‐Tuning of Their Molecular Properties 下载免费PDF全文
Dr. Xiao‐Ye Wang Dong‐Chu Yang Fang‐Dong Zhuang Jia‐Jie Liu Dr. Jie‐Yu Wang Prof. Jian Pei 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(24):8867-8873
New BN‐embedded, thiophene‐fused, polycyclic aromatic compounds with planar geometry were designed and synthesized. The molecules showed excellent stability and chemical robustness. Postfunctionalization on this skeleton was demonstrated with a series of electrophilic bromination, palladium‐catalyzed cross‐coupling, and Knoevenagel condensation reactions. The π skeleton remained intact during these late‐stage transformations. The optical and electronic properties have been well tuned through incorporation of electron‐rich and ‐deficient groups on the backbone. This work shows the great advantage of the postfunctionalization strategy on BN‐containing polycyclic aromatic compounds for fast diversification and materials screening. 相似文献
85.
Optimization of Experimental Parameters to Explore Small‐Ligand/Aptamer Interactions through Use of 1H NMR Spectroscopy and Molecular Modeling 下载免费PDF全文
Dr. Florence Souard Dr. Sandrine Perrier Dr. Vincent Noël Dr. Claire Fave Emmanuelle Fiore Prof. Eric Peyrin Prof. Julian Garcia Dr. Cécile Vanhaverbeke 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(44):15740-15748
Aptamers constitute an emerging class of molecules designed and selected to recognize any given target that ranges from small compounds to large biomolecules, and even cells. However, the underlying physicochemical principles that govern the ligand‐binding process still have to be clarified. A major issue when dealing with short oligonucleotides is their intrinsic flexibility that renders their active conformation highly sensitive to experimental conditions. To overcome this problem and determine the best experimental parameters, an approach based on the design‐of‐experiments methodology has been developed. Here, the focus is on DNA aptamers that possess high specificity and affinity for small molecules, L ‐tyrosinamide, and adenosine monophosphate. Factors such as buffer, pH value, ionic strength, Mg2+‐ion concentration, and ligand/aptamer ratio have been considered to find the optimal experimental conditions. It was then possible to gain new insight into the conformational features of the two ligands by using ligand‐observed NMR spectroscopic techniques and molecular mechanics. 相似文献
86.
Karolina Graczyk Tobias Haven Prof. Dr. Lutz Ackermann 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(24):8812-8815
The so‐called magic methyl effect significantly boosts the bioactivities and physical properties of pharmacologically active drugs. Direct introduction of the methyl group by C?H activation was accomplished with a versatile iron catalyst, which enabled the C?H methylation of (hetero)benzamides, anilides, alkenes, and even alkanes by triazole assistance in a chemo‐, site‐ and diastereo‐selective fashion. 相似文献
87.
Aromatic Interactions in Organocatalyst Design: Augmenting Selectivity Reversal in Iminium Ion Activation 下载免费PDF全文
Dr. Constantin Daniliuc Dr. W. Bernd Schweizer Prof. Dr. Ryan Gilmour 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(28):10031-10038
Substituting N‐methylpyrrole for N‐methyindole in secondary‐amine‐catalysed Friedel–Crafts reactions leads to a curious erosion of enantioselectivity. In extreme cases, this substrate dependence can lead to an inversion in the sense of enantioinduction. Indeed, these closely similar transformations require two structurally distinct catalysts to obtain comparable selectivities. Herein a focussed molecular editing study is disclosed to illuminate the structural features responsible for this disparity, and thus identify lead catalyst structures to further exploit this selectivity reversal. Key to effective catalyst re‐engineering was delineating the non‐covalent interactions that manifest themselves in conformation. Herein we disclose preliminary validation that intermolecular aromatic (CH–π and cation–π) interactions between the incipient iminium cation and the indole ring system is key to rationalising selectivity reversal. This is absent in the N‐methylpyrrole alkylation, thus forming the basis of two competing enantio‐induction pathways. A simple L ‐valine catalyst has been developed that significantly augments this interaction. 相似文献
88.
89.
Frontispiece: Hydrogenated Graphenes by Birch Reduction: Influence of Electron and Proton Sources on Hydrogenation Efficiency,Magnetism, and Electrochemistry 下载免费PDF全文
90.
Design and Synthesis of High‐Affinity Dimeric Inhibitors Targeting the Interactions between Gephyrin and Inhibitory Neurotransmitter Receptors 下载免费PDF全文
Dr. Hans Michael Maric Vikram Babu Kasaragod Dr. Linda Haugaard‐Kedström Dr. Torben Johann Hausrat Prof. Dr. Matthias Kneussel Prof. Dr. Hermann Schindelin Prof. Dr. Kristian Strømgaard 《Angewandte Chemie (International ed. in English)》2015,54(2):490-494
Gephyrin is the central scaffolding protein for inhibitory neurotransmitter receptors in the brain. Here we describe the development of dimeric peptides that inhibit the interaction between gephyrin and these receptors, a process which is fundamental to numerous synaptic functions and diseases of the brain. We first identified receptor‐derived minimal gephyrin‐binding peptides that displayed exclusive binding towards native gephyrin from brain lysates. We then designed and synthesized a series of dimeric ligands, which led to a remarkable 1220‐fold enhancement of the gephyrin affinity (KD=6.8 nM ). In X‐ray crystal structures we visualized the simultaneous dimer‐to‐dimer binding in atomic detail, revealing compound‐specific binding modes. Thus, we defined the molecular basis of the affinity‐enhancing effect of multivalent gephyrin inhibitors and provide conceptually novel compounds with therapeutic potential, which will allow further elucidation of the gephyrin–receptor interplay. 相似文献