Patients exposed to a surgical safety checklist experience better postoperative outcomes, but this could simply reflect wider quality of care in hospitals where checklist use is routine.
Purines and related
heterocycles substituted at C-2 with 4′-sulfamoylanilino
and at C-6 with a variety of groups have been synthesized with the
aim of achieving selectivity of binding to CDK2 over CDK1. 6-Substituents
that favor competitive inhibition at the ATP binding site of CDK2
were identified and typically exhibited 10–80-fold greater
inhibition of CDK2 compared to CDK1. Most impressive was 4-((6-([1,1′-biphenyl]-3-yl)-9H-purin-2-yl)amino) benzenesulfonamide (73)
that exhibited high potency toward CDK2 (IC50 0.044 μM)
but was ∼2000-fold less active toward CDK1 (IC50 86 μM). This compound is therefore a useful tool for studies
of cell cycle regulation. Crystal structures of inhibitor–kinase
complexes showed that the inhibitor stabilizes a glycine-rich loop
conformation that shapes the ATP ribose binding pocket and that is
preferred in CDK2 but has not been observed in CDK1. This aspect of
the active site may be exploited for the design of inhibitors that
distinguish between CDK1 and CDK2.
The short average service life of traditional dental composite restorative materials and increasing occurrence of secondary caries adjacent to composite restorations and sealants are necessitating the development of new, longer lasting compositions. Novel monomers and their polymers, reinforcing fillers, and adhesive components are needed. The goal of this research is to develop resin systems for use in restorations, sealants, and other dental services that are superior in properties and endurance to currently used bisphenol A glycidyl dimethacrylate/triethylene glycol dimethacrylate (Bis-GMA/TEGDMA) and urethane–dimethacrylate products. Ether-based monomers and their polymers that were not susceptible to enzymatic or hydrolytic degradation were prepared and characterized. They showed no degradation under hydrolytic and enzymatic challenges, whereas the hydrolysis of ester links weakened contemporary resins within 16 days under these challenges. The success of the ether-based materials is promising in making durable systems that are subjected to long-term biochemical and hydrolytic challenges in oral environments.
Small-molecule drug discovery requires reliable synthetic methods for attaching amino compounds to heterocyclic scaffolds. Trifluoroacetic acid-2,2,2-trifluoroethanol (TFA-TFE) is as an effective combination for achieving SN Ar reactions between anilines and heterocycles (e.g., purines and pyrimidines) substituted with a leaving group (fluoro-, chloro-, bromo- or alkylsulfonyl). This method provides a variety of compounds containing a "kinase-privileged fragment" associated with potent inhibition of kinases. TFE is an advantageous solvent because of its low nucleophilicity, ease of removal and ability to solubilise polar substrates. Furthermore, TFE may assist the breakdown of the Meisenheimer-Jackson intermediate by solvating the leaving group. TFA is a necessary and effective acidic catalyst, which activates the heterocycle by N-protonation without deactivating the aniline by conversion into an anilinium species. The TFA-TFE methodology is compatible with a variety of functional groups and complements organometallic alternatives, which are often disadvantageous because of the expense of reagents, the frequent need to explore diverse sets of reaction conditions, and problems with product purification. In contrast, product isolation from TFA-TFE reactions is straightforward: evaporation of the reaction mixture, basification and chromatography affords analytically pure material. A total of 45 examples are described with seven discrete heterocyclic scaffolds and 2-, 3- and 4-substituted anilines giving product yields that are normally in the range 50-90 %. Reactions can be performed with either conventional heating or microwave irradiation, with the latter often giving improved yields.
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