Synthesis and structure-activity relationships of 17beta-substituted 14beta-hydroxysteroid 3-(alpha-L-rhamnopyranoside)s: steroids that bind to the digitalis receptor.
The preparation of 17beta-substituted 14beta-hydroxysteroid C-3 alpha-L-rhamnopyranosides is described. These derivatives have a 14beta,20-ether, 14beta,20-lactone, or 17beta-CH2CH2OH, -CH2CH2NH2, -CH=CHNO2(E), -CH=CHCOOH(E), -CH(OH)CH2NO2(R), -CH(OMe)CH2NO2(R), -CH2-CH2COOH, or -CH(OH)CH2NH2(R) group. Derivatives were assayed in a radioligand binding assay for [3H]ouabain in membranes from canine heart muscle. The digitalis "receptor" comprises isoenzymes of the ion-pumping enzyme, Na+,K+-ATPase. The 17beta-CH=CHNO2(E), 17beta-CH=CHCOOH(E), and 17beta-CH(OMe)CH2NO2(R) derivatives were the most potent and equivalent to ouabain with low-nanomolar IC50 values. The very potent binding affinity of the disubstituted compound 17beta-CH(OMe)CH2NO2(R) further demonstrates that 17beta-unsaturated substitution is not required for potent binding affinity. This observation may be of value in the separation of cardiotonic and cardiotoxic effects. Tosylation of the 17beta-CH2OH, prepared from the 17beta-CHO by lithium aluminum hydride reduction, yielded the 14beta,17beta-ether. Synthesis of the 17beta-CH2COOH gave the epimeric 14alpha,17alpha- and 14beta,17beta-lactones. Structures have been established by NMR analysis.
Templeton
J F
JF
Faculty of Pharmacy and Department of Chemistry, University of Manitoba, Winnipeg, Canada.
Ling
Y
Y
Marat
K
K
LaBella
F S
FS
D000818:Animals; D004285:Dogs; D009682:Magnetic Resonance Spectroscopy; D008861:Microsomes / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D010042:Ouabain / Q000378:metabolism; D011485:Protein Binding; D011869:Radioligand Assay; D012210:Rhamnose / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013329:Structure-Activity Relationship
C027082:digitalis receptor; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase; D012210:Rhamnose