An aqueous capillary electrophoretic method was developed for chiral analysis of the novel anti-diabetic drug, sitagliptin. The acid-base profiling of the analyte was carried out using both capillary electrophoresis and nuclear magnetic resonance pH titrations. The apparent complex stability and chiral separation properties were investigated with 30 different cyclodextrins under acidic conditions. The effect of concentration and pH of the BGE, temperature of the capillary, and the type and concentration of the chiral selector on the enantiomer resolution were thoroughly investigated. The effects of dual cyclodextrin systems on separation were also extensively studied. Complete separation of racemic sitagliptin with good resolution (R(S)=2.24) was achieved within a short time (15 min) with optimized parameters (10°C, pH=4.4, 40 mM phosphate buffer) of a sulfobutylether-β-cyclodextrin (averaged degree of substitution ~4) and native β-cyclodextrin dual system. The averaged stoichiometry of the inclusion complex was determined using the Job plot method with both (1)H and (19)F NMR experiments and resulted in a 1:1 complex. The structure of the inclusion complex was elucidated using 2-D ROESY NMR experiments.
An efficient and facile gold(I)-catalyzed one-pot cascade protocol has been developed for the synthesis of tryptamine-fused polycyclic privileged structures through the treatment of substituted tryptamines and 2-ethynylbenzoic acids or 2-ethynylphenylacetic acids. This strategy features the formation of one C-C bond and two C-N bonds with high yields and broad substrate tolerance. The selected reduced target molecules are validated to perform as α1-adrenergic receptors antagonists. The most potent one, 4bh, exhibits an IC50 value of 277 nM on α1A subtype with a selectivity ratio of 15.8 over α1B subtype.
An additive-free and highly diastereoselective Michael addition reaction of an N-tert-butanesulfinyl imidate to α,β-unsaturated diesters has been developed using LDA as a base with good to excellent yields. The utility of this chemistry is further demonstrated by the asymmetric synthesis of 3-substituted indanone derivatives 8a, 8d, 8e, and 8i with high enantiomeric excess, which are potential building blocks for preparing biologically active lead compounds.
The major advantage of information-centric networking (ICN) lies in in-network caching. Ubiquitous cache nodes reduce the user’s download latency of content and the drain of network bandwidth, which enables efficient content distribution. Due to the huge cost of updating an entire network infrastructure, it is realistic for ICN to be integrated into an IP network, which poses new challenges to design a cache system and corresponding content router. In this paper, we firstly observed that the behavior pattern of data requests based on a name resolution system (NRS) makes an ICN cache system implicitly form a hierarchical and nested structure. We propose a complete design and an analytical model to characterize an uncooperative hierarchical ICN caching system compatible with IP. Secondly, to facilitate the incremental deployment of an ICN cache system in an IP network, we designed and implemented a cache-supported router with multi-terabyte cache capabilities. Finally, the simulation and measurement results show the accuracy of proposed analytical model, the significant gains on hit ratio, and the access latency of the hierarchical ICN cache system compared with a flat cache system based on naming routing, as well as the high performance of the implemented ICN router.
Oncogenic mutations in critical nodes of cellular signaling pathways have been associated with tumorigenesis and progression. The B-Raf protein kinase, a key hub in the canonical MAPK signaling cascade, is mutated in a broad range of human cancers and especially in malignant melanoma. The most prevalent B-RafV600E mutant exhibits elevated kinase activity and results in constitutive activation of the MAPK pathway, thus making it a promising drug target for cancer therapy. Herein, we described the development of novel B-RafV600E selective inhibitors via multi-step virtual screening and hierarchical hit optimization. Nine hit compounds with low micromolar IC50 values were identified as B-RafV600E inhibitors through virtual screening. Subsequent scaffold-based analogue searching and medicinal chemistry efforts significantly improved both the inhibitor potency and oncogene selectivity. In particular, compounds 22f and 22q possess nanomolar IC50 values with selectivity for B-RafV600E
in vitro and exclusive cytotoxicity against B-RafV600E harboring cancer cells.
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