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Starting from readily available enantiopure azidomethyl‐substituted bicyclic 1,2‐oxazine derivatives and mono‐, di‐ or trialkynes, their copper‐catalyzed (3+2) cycloadditions furnished a series of 1,2,3‐triazolyl‐linked compounds in good yields. These click reactions proceeded smoothly at room temperature when copper iodide as catalyst was used in the presence of triethylamine and tris[(1‐gbenzyl‐1H‐1,2,3‐triazol‐4‐yl)methyl]amine as ligand. Generally, the unprotected bicyclic 1,2‐oxazine derivatives seemed to show slightly higher reactivity and provided better yields compared with their silyl‐protected counterparts. Exhaustive hydrogenolysis with cleavage of the 1,2‐oxazine N−O bonds in the presence of palladium on charcoal as promotor is feasible but was found to be capricious. Reasonable results were obtained when acetic acid was employed as cosolvent. By applying these conditions, several of the bicyclic 1,2‐oxazine derivatives were successfully converted into the expected mono‐ or divalent aminooxepine derivatives which can be regarded as aminoseptanose mimetics. [ABSTRACT FROM AUTHOR]

The combination of lithiated alkoxyallenes with carbohydrate-derived nitrones constitutes a flexible entry to highly functionalized enantiopure 1,2-oxazine derivatives. They can be used as precursors for acyclic and cyclic carbohydrate-like products such as amino sugar alcohols, azetidine and pyrrolidine derivatives. The Lewis acid-promoted rearrangement of 1,3-dioxolanyl-substituted 1,2-oxazines to bicyclic compounds allows an efficient route to novel amino pyran and oxepane derivatives. After subsequent transformations, new carbohydrate mimetics or real carbohydrates were obtained in good yield and often in a stereodivergent fashion. These compounds have already been employed for the preparation of unusual di- and trisaccharide derivatives. Several of the products prepared showed interesting biological activities, e.g., as L- and P-selectin inhibitors with IC50 values in the sub nanomolar range. [ABSTRACT FROM AUTHOR]

N-Methylation of syn- or anti-configured 3,6-dihydro-2H-1,2-oxazines and subsequent treatment with triethylamine smoothly provided enantiopure α,β-unsaturated β-alkoxy-γ-amino aldehydes bearing different protected diol, triol, or tetrol side chains in good to excellent yields. The N-O bond cleavage occurs under mild conditions and involves an internal redox process. The method is also applicable to tetrahydro-2H-1,2-oxazines, which either lead to 4-amino ketose or aldose derivatives (D-sorbose or D-idose configuration). The equivalency of the generated β-alkoxyenal moiety with 1,3-dicarbonyl compounds could be demonstrated by condensation reactions with hydrazine or 2-aminoimidazole derivatives providing a series of new pyrazole or imidazo[1,2-a]pyrimidine derivatives with stereodefined and protected aminopolyol side chains. [ABSTRACT FROM AUTHOR]

The unbound partition coefficient (Kp uu ) allows the estimation of intracellular target exposure from free extracellular drug concentrations. Although the active mechanisms controlling Kp uu are saturable, Kp uu is commonly determined at a single concentration, which may not be appropriate in cases in which drug concentrations can largely vary, e.g., in plasma in vivo or in vitro IC 50 assays. We examined the concentration dependence of Kp uu in vitro using KAT6A inhibitors with varying potency drop-off in ZR75-1 breast cancer cells to account for exposure-related discrepancies between cellular and biochemical IC 50 Considering saturability resulted in a better quantitative bridge between both IC 50 values and gave way to a simplified method to determine Kp uu that is suitable for the prediction of unbound cytosolic drug concentrations without the need to generate f u,cell estimates from binding studies in cell homogenates. As opposed to the binding method, which destroys cellular integrity, this approach provides an alternative f u,cell estimate and directly reflects the fraction of unbound drug in the cell cytosol based on Kp saturation (f u,cyto ) of intact cells. In contrast to the binding method, prediction of intracellular KAT6A exposure with this more physiologic approach was able to bridge the average exposure gap between biochemical and cellular IC 50 values from 73-fold down to only 5.4-fold. The concept of concentration-dependent Kp uu provides a solid rationale for early drug discovery to discriminate between pharmacology and target exposure-related IC 50 discrepancies. The attractiveness of the approach also lies in the use of the same assay format for cellular IC 50 , f u,cyto , and the unbound partition coefficient based on f u,cyto (Kp uu,cyto ) determination. SIGNIFICANCE STATEMENT: Examination of the yet-unexplored concentration dependence of the unbound partition coefficient led to a new experimental approach that resulted in more reliable predictions of intracellular target exposure and is well suited for routine drug discovery projects., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)