Digitalis-like compounds: Synthesis and biological evaluation of seco-D and D-homo derivatives

The synthesis of seco-D and D-homo digitalis derivatives, from the carda-14,20(22)-dienolide I, is described Selective ozonolysis gave the seco-D 14-ketoaldehyde 2a, Modification of the two carbonyl groups and of the alpha, beta-unsaturated lactone ring of the seco-D 14-ketoaldehyde 2a allowed preparation of derivatives with a broad range of binding affinity to the Na+, K+-ATPase receptor. Some of the seco-D derivatives (10, 11b, and 13b) showed a binding affinity similar to that of digitoxigenin, demonstrating that the D-ring is not essential Sor recognition by the digitalis receptor. In the class of D-homo derivatives the highest binding value, about 15 rimes lower than that of digitoxigenin, was that of the the C/D cis compound 29b; the C/D trans analog 28b showed a 7-fold decrease in binding affinity, indicating that the C/D configuration plays all important role in D-homo derivatives as in the classical digitalis compounds. (C) 1996 by Elsevier Science Inc.