Probing stereoselectivity with carbohydrates

This thesis describes the use of carbohydrates to probe the effects of oxygenated substituents on the stereoselectivity of free radical and osmium tetroxide dihydroxylation reactions. The first, introduction, chapter briefly surveys literature methods employed in the synthesis of 2-deoxy-β-glycosidic linkages in carbohydrate chemistry. The use of O-acyl thiohydroxamate chemistry on ulosonic acid derivatives in the arabino-series is then presented as a method for the preparation of β-C- and β-O-glycosides. The evidence for an accelerating or stabilizing β-oxygen effect in radical reactions is then outlined. Finally, the stereodirecting effect of an allylic alcohol or ether on the osmylation of alkenes is discussed with particular reference to glycal derivatives. In the second chapter, on the basis of chemical correlation with products of known absolute configuration and/or of proton coupled 13C-nmr spectroscopy, the anomeric configuration of a number of 3-deoxyheptulosonic acid derivatives previously prepared in this laboratory is reassigned. The effect of temperature and of axial substituents in the 3- position on the stereoselectivity of alkoxyglycosyl radical reactions is then briefly examined. The third chapter describes a series of probes designed to identify any stereochemical component to the β-oxygen effect in free radical reactions. By comparison with non-oxygenated analogues it is determined that β-oxygen bonds do indeed accelerate radical reactions. However, competition between stereoisomers reveals that the stereoelectronic component, while real is very small. The fourth chapter outlines a brief investigation into the stereochemistry of osmylation reactions of glycals. In arabino-glycals reaction occurs on the β-face and it is postulated that this is a function of the lone pairs on the ring oxygen. This chapter describes the reversal of this stereoselectivity in going to the ribo-series. Some attempts at the reversal of stereoselectivity by use of chiral ligands for osmium are described. The final chapter is the complete experimental part

Evaluation of Potential Drug-Drug Interaction Risk of Pexidartinib With Substrates of Cytochrome P450 and P-Glycoprotein

Pexidartinib is approved for treatment of adults with symptomatic tenosynovial giant cell tumor. In vitro data showed pexidartinib's potential to inhibit and induce cytochrome P450 (CYP) 3A, inhibit CYP2C9, CYP2C19 and P-glycoprotein (P-gp). Herein, 2 open-label, single-sequence, crossover studies evaluated the drug-drug interaction potential of pexidartinib on CYP enzymes (CYP2C9, CYP2C19, and CYP3A) and P-gp. Thirty-two subjects received single oral doses of midazolam (CYP3A substrate) and tolbutamide (CYP2C9 substrate) alone and after single and multiple oral doses of pexidartinib. Twenty subjects received single oral doses of omeprazole (CYP2C19 substrate) and digoxin (P-gp substrate) alone or with pexidartinib. Analysis of variance was conducted to determine the effect of pexidartinib on various substrates' pharmacokinetics. No drug-drug interaction was concluded if the 90% confidence interval of the ratio of test to reference was within the range 80% to 125%. Coadministration of single and multiple doses of pexidartinib resulted in 21% and 52% decreases, respectively, in the area under the plasma concentration-time curve from time zero to the last measurable time point (AUC(last)) of midazolam, whereas AUC(last)values of tolbutamide increased 15% and 36%, respectively. Omeprazole exposure decreased on concurrent administration with pexidartinib, the metabolite-to-parent ratio was similar following omeprazole administration alone vs coadministration with pexidartinib; pexidartinib did not affect CYP2C19-mediated metabolism. Maximum plasma concentrations of digoxin slightly increased (32%) with pexidartinib coadministration; no significant effect on digoxin AUC(last). These results indicate that pexidartinib is a moderate inducer of CYP3A and a weak inhibitor of CYP2C9 and does not significantly affect CYP2C19-mediated metabolism or P-gp transport.Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]