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Small-molecule inhibitors of DNA methyltransferases such as RG108 represent promising candidates for cancer drug development. We report the synthesis and in vitro analysis of a biotinylated RG108 conjugate, 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(5-[3-[5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)pentanoylamino]propoxy]-1H-indol-3-yl)propionic acid (bio-RG108), for the evaluation of interactions with DNA methyltransferase enzymes. The structural design of the chemically modified inhibitor was aided by molecular modeling, which suggested the possibility for extensive chemical modifications at the 5-position of the tryptophan moiety in RG108. The inhibitory activity of the corresponding derivative was confirmed in a cell-free biochemical assay, where bio-RG108 showed an undiminished inhibition of DNA methyltransferase activity (IC50 = 40 nM). Bio-RG108 therefore represents a suitable bioconjugate for the elucidation of inhibitory mechanisms and for the affinity purification of RG108-associated proteins.

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Inhibition of rat intestinal retinyl ester hydrolase by alpha-tocopherol (vitamin E) and phylloquinone (vitamin K1) was non-competitive. Maximum inhibition occurred within 10 min, and, particularly with alpha-tocopherol, was substantially reversible. Consequently, increasing tissue concentrations of retinyl esters, which might occur with advancing age or changes in diet, would not diminish the effects of the inhibitors. These data further support the notion that alpha-tocopherol may, at physiological concentrations, influence the concentration of vitamin A and its ester in tissues.

Synthesis and in vitro Evaluation of (S)-2-([ 11 C]Methoxy)-4-[3-methyl-1-(2-piperidine-1-yl-phenyl)-butyl-carbamoyl]-benzoic Acid ([ 11 C]Methoxy-repaglinide):A Potential β-Cell Imaging Agent. -A method is given for the synthesis of enantiomerically pure 11 C-labeled methoxy-repaglinide (I). In vitro evaluation studies of the non-radioactive analogue of (I) show that this compound binds with high affinity to the human SUR1 receptor of the pancreas. -(WAENGLER, B.; BECK, C.; SHIUE, C. Y.; SCHNEIDER, S.; SCHWANSTECHER, C.; SCHWANSTECHER, M.; FEILEN, P. J.; ALAVI, A.; ROESCH, F.; SCHIRRMACHER*, R.; Bioorg. Med.