Digitoxigenin derivative

Glycosides of the gitoxigenin series are less active than the corresponding members of the digitoxigenin-derived series. Digitoxin is the only compound routinely used as a drug, and it is employed in congestive heart failure and treatment of cardiac arrhythmias, particularly atrial fibrillation. 

An analogous dehydration in the synthesis of lactone substituted derivatives of digitoxigenin is reported in reference [21a]. 

Perhaps the strongest support for the argument, that enhancement of cardiotonic activity by the carbohydrate component is a function of hydroxylation, may be gained by inspection of the potencies of the completely deoxygenated 3-tetrahydropyranyl derivatives of digitoxigenin (1) and of strophanthidin (2) (see Table I). In each case, the value ob-... 

Human liver alcohol dehydrogenase (Table 4-1) catalyzes the oxidation of digitoxigenin and derivatives. This is a potentially important detoxification pathway. Liver alcohol dehydrogenase may also toxify chemicals, metabolizing several xylyl alcohols to aldehydes that are toxic to lung and allyl alcohol to the extremely neurotoxic acrolein. 

Although the limitations in the cases that provide good yields may appear to be very restrictive, this last example is suggestive of the potential applications of this procedure. Rather obvious possibilities that follow from this case include derivatives of the equilinin steroidal hormone system,11 and of the steroidal cardiotonic agents, e.g., the cardenolides, digitoxigenin, bufadienolides, etc.12... 

Certain steroids derived from plants are potent inhibitors (K 10 nM) of the Na+-K+ pump. Digitoxigenin and ouabain are members of this class of inhibitors, which are known as cardiotonic steroids because of their strong effects on the heart (Figure 13.7). These compounds inhibit the dephosphorylation of the E2-P form of the ATPase when applied on the... 

In Digitalis lanata, four tritium atoms were incorporated from [2i - H,2- 0,37 ]-mevalonate into tigogenin (91), whereas digitoxigenin (92) in the same experiment retained three tritium atoms. Furthermore, both [4- " C,15j - H]progest-erorte and [15,21- H5]pregn-5-en-3/i-ol-20-one were incorporated with no loss from C-15. Hence A " -derivatives are not involved. An alternative intermediate is a A h(ierivative N.B. direct hydroxylation at C-15 would require inversion of configuration, and is thus unlikely). Further work on the bufatenolides confirms that cholesterol is a precursor. ... 

Smith, P., Brown, L., Boutagy, J., and Thomas. R., Cardenolide analogues. Part 14. Synthesis and biological activity of glucosides of C17P-modified derivatives of digitoxigenin, J. Med. Chem., 25, 1222, 1982. 

The reaction of various digitoxigenin (497) derivatives with osmium tetroxide has been investigated. Treatment of 3-0-acetyl- 14-anhydrodigitoxigenin (501)... 

Finally, the stereochemistry of cyclic 14,20-oxido-cardenolides derived from digitoxigenin (497), digoxigenin (506), 3, 14,15 -trihydroxy-5/ ,14jS-card-20(22)-enolide (507), and gitoxigenin (508), has been discussed. 

Figure 4.7. Shape of the molecular electrostatic potential in the outer space of digitoxigenin when occupying the probable receptor-bound conformation. Using the co-ordinates derived from X-ray crystal structure analysis, the equipotential energy contours (expressed in kJtmol) are calculated with the use of an optimized monopol expansion. The energy contours refer to the plane laid across carbon atoms 6, 8, and 9 involved in forming rings B and C. Reproduced from [128],...

This interpretation appears to be complemented by the findings that the hydroxy carbonic acid of digitoxigenin, formed by saponification of the lactone moiety, and the similar derivative with -CH=CH-COO at C-17y5 are virtually inactive [19]. This may be assumed to result from the presence of a repellant negative charge in the lactone binding site, which could represent the counter ion in the two-point attachment suggested by Thomas et al. [19]. 

Dehydrogenation at the 16-position by Trichothecium roseum on digitoxigenin has been reported (T-1013). Since this organism is normally a 17a-hydroxylator, the question remains whether the 17a-hydroxy derivative of digitoxigenin is the precursor of the observed product. 

---