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 1, 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 for recognition by the digitalis receptor. In the class of D-homo derivatives the highest binding value, about 15 times lower than that of digitoxigenin, was that of 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 an important role in D-homo derivatives as in the classical digitalis compounds.
Prassis Istituto di Ricerche Sigma-Tau, Settimo Milanese, Italy.
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Gobbini
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Benicchio
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Marazzi
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Padoani
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Torri
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Melloni
D004071:Digitalis Glycosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D004073:Digitoxigenin / Q000031:analogs & derivatives / Q000737:chemistry; D010042:Ouabain / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013329:Structure-Activity Relationship
D004071:Digitalis Glycosides; D004073:Digitoxigenin; C011184:canarigenin; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase