Synthesis and Biological Evaluation of 14 -Methoxy Digitalis Derivatives

Abstract

Abstract:The synthesis and biological evaluation of 14β-methoxy derivatives of digitoxigenin and of other digitalis-like compounds are reported. These compounds have a 14β-oxygen, which can be a hydrogen bonding acceptor, as is the case of 14β,15β-epoxide derivatives, but not a hydrogen bonding donor as is the case of 14β-hydroxy derivatives. All the new 14β-methoxy derivatives show a considerable reduced binding affinity on Na + ,K + -ATPase when compared with the 14 β-hydroxy analogues and also with the 14β,15β-epoxy derivatives. These results could mean that the digitalis receptor does not permit the presence of a bulky substituent in the 14β region, even of relatively small volume like the methyl group.

Novel analogues of Istaroxime, a potent inhibitor of Na+,K+-ATPase: Synthesis, structure–activity relationship and 3D-quantitative structure–activity relationship of derivatives at position 6 on the androstane scaffold

“…The 6a-methoxymethyl derivative 19 (0.50 lM) decreased the activity: this could be due to the increasing space requirement or to the impossibility to act as a hydrogen-bond donor (moreover, also 14b-OMe digitoxigenin showed a binding affinity for the Na + ,K + -ATPase receptor about 90 times lower than digitoxigenin itself). 13 The 6b-epimer of 17 ; there is no difference in the a-or b-face for the two diastereoisomeric oxiranes, probably because the strained ring reduces the a and bcharacteristic of the oxygen; the electronic effect of the oxygen is negligible since the spirocyclopropane analogue 4 showed a comparable potency (0.85 lM). A more favorable effect of a polar group in the a-face was confirmed by the two epimeric nitrosyl compounds, 6a-ONO 2 (26, 0.33) and 6b-ONO 2 (27, 2.9 lM).…”

Digitalis-like Compounds: the Discovery of the O-aminoalkyloxime Group as a Very Powerful Substitute for the Unsaturated γ-Butyrolactone Moiety

“…4); on the contrary, a 14β-OMe substituent on digitoxigenin 6 ( Fig. 1) results in a reduced binding affinity of about two orders of magnitude in comparison with the parent compound [34]. Other hydroxy groups can be present in positions 1, 5, 12, 16, and 19 always on the β side (ouabain 1, digoxin 2, gitoxin 5, and digitoxigenin 6; Fig.…”