Digitoxin, synthesis

Application of this tandem conjugate addition-aldol cyclization methodology may lead to the concise synthesis of digitoxin (Scheme 67) and related cardiac steroids. 

Chemistry of the glycoside linkage. Exceptionally fast and efficient formation of glycosides by remote activation, Carbohydr. Res. 80 07 (1980). (e) K. Wiesner, T. Y. R. Tsai, and H. Jiu, On cardioactive steroids. XVI. Stereoselective P-glycosylation of digitoxose the synthesis of digitoxin, Helv. Chim. Acta 60 300 (1985). (f) R. B. Woodward (and 48 collaborators), Asymmetric total synthesis of erythromycin. 3. Total synthesis of erythromycin, J. Am Chem. Soc. 103 3215 (1981). (g) P. G. M. Wuts and S. S. Bigelow, Total synthesis of oleandrose and the avermecin disaccharide, benzyl ot-L-oleandrosyl-ot-L-4-acetOxyoleandroside, J. Org. Chem. 43 3489 (1983). 

McDonald, F E, Reddy, K S, Convergent synthesis of digitoxin stereoselective synthesis and glycosylation of the digoxin trisaccharide glycal, Angew. Chem. Int. Ed., 40, 3653-3655, 2001. 

Pharmacodynamic-based toxic effects are those where there is altered responsiveness of the target site perhaps due to variations in the receptor. For example, individual variation in the response to digitoxin means that some patients suffer toxic effects after a therapeutic dose (see below Chapter 7). The inhibition of enzymes, blockade of receptors or changes in membrane permeability which underlie these types of effects often rely on reversible interactions. These are dependent on the concentration of the toxic compound at the site of action, and possibly the concentration of an endogenous substrate if competitive inhibition is involved. Therefore, with the loss of the toxic compound from the body, by the processes of metabolism and excretion, the concentration at the site of action falls and the normal function of the receptor or enzyme returns. This is in direct contrast to the type of toxic effect in which a cellular structure or macromolecule is permanently damaged, altered or destroyed by a toxic compound. In some cases, however, irreversible inhibition of an enzyme may occur, which if not fatal for the organism will require the synthesis of new enzyme, as is the case with organophosphorus compounds which inhibit cholinesterases. 

Beale TM, Taylor MS (2013) Synthesis of cardiac glycoside analogs by catalyst-controlled, regioselective glycosylation of digitoxin. Org Lett 15 1358-1361... 

Yu and co-workers achieved the multi-step synthesis of digitoxin 115 by use of 3,4-di-O-tert-butyldiphenylsilyl-D-digitoxosyl o-cyclopropylethynyl-benzoate 110 and digitoxigenin 111 via alternate glycosylation and... 

Studies proposed that inhibition of the Na /K ATPase pump was responsible for the inhibitory effects of CGs on protein synthesis. They expressed the naturally cardiac glycoside-resistant alphal chain of the murine Na /K ATPase pump, which is about 1,000 times less sensitive for CGs than the human alphal subunit, in human cells [27]. Expression of the murine but not the human alpha chain largely rescued the inhibitory effects of digitoxin on intracellular protein expression. The other study also further indicates that inhibition of the Na /K ATPase pump is responsible for the inhibitiOTi of CGs on protein synthesis. For instance, Na /K ATPase pump activity is inhibited by digitoxin in incubating cells for 4—8 h in a sodium-free buffer. The Na -free buffer inhibited both murine and human Na /K ATPase pump activity as determined by intracellular levels and did not affect cell viability in the timeframe of the experiment, resulting in a decreased expressirai of relatively short-lived proteins such as p53 and Janus kinase 2 (JAK2). 

In the meantime, we expect plant cell culture experimentation to be continued even though the initial promise has not yet been fulfilled. More important than the production of compounds may be the use of cultures in biotransformation reactions. The cells may elaborate enzymes that can cause an organic reaction to take place that could be next to impossible to carry out synthetically. An example of this is the 2-p hydroxylation of digitoxin to digoxin by cell lines of Digitalis lanata. Thus, cells from certain woody species might be put to work as part of an overall synthesis of valuable pharmaceuticals. For this to happen, much more work is needed on biotransformations taking place within woody plants. 

SCHEME 38.44. Total synthesis of digitoxin from aglycon by McDonald et al.. 

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