digoxin and digitoxose

Inspired by Roush's pioneering work on rare sugars, we have developed a scalable, stereoselective, de novo synthesis of orthogonally protected C2-fluoro digitoxose and cymarose, utilizing Sharpless kinetic resolution and organocatalytic fluorination as key steps. The utility of this strategy is demonstrated by the synthesis of a fluorinated analogue of digoxin, which indicates the fluorine on the sugar ring may have a significant impact on biological activity.

Topics: Digoxin; Fluorine; Halogenation; Hexoses; Stereoisomerism

The purpose of this investigation was to define, under controlled in vitro conditions, the processes contributing to the uptake and accumulation of [3H]digoxin by incubated slices of chicken renal cortex. Progressive uptake was evident in time-course experiments with the slice-to-medium concentration ratio (S/M) reaching 5.25 after 120 min. No metabolism was evident. Increasing the ratio of unlabeled to labeled digoxin resulted in a concentration-dependent decrease in relative uptake of the label, suggesting saturability. Incubation under conditions of metabolic inhibition reduced digoxin S/M by about 50%, indicating that both energy-requiring and passive mechanisms contribute to the overall accumulation process. The structural nature of the uptake process was explored by incubating digoxin in the presence of potential inhibitors of transport. The organic cation quinine and the non-glycosidic steroids digoxigenin and spironolactone were without effect even at greater than 1000-fold excess compared to digoxin. Similarly, the sugar digitoxose had no inhibitory activity on digoxin accumulation by the slices. On the other hand, the glycosides digitoxin, digoxigenin-bis-digitoxoside and digoxigenin-mono-digitoxoside inhibited dogoxin uptake in a concentration-dependent manner. These results indicate a structural preference for an intact glycoside rather than for either the steroidal or sugar portion of the molecule alone. An inhibitory effect of ouabain and a stimulatory effect of reduced medium potassium concentration suggest a possible role for Na+,K(+)-ATPase in the uptake of digoxin by the renal cortex.

Topics: Animals; Chickens; Digitoxin; Digoxigenin; Digoxin; Female; Hexoses; Kidney Cortex; Kinetics; Ouabain; Potassium; Probenecid; Quinine; Sodium Cyanide; Spironolactone