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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.

Dexrazoxane (ICRF-187) is clinically used to reduce doxorubicin-induced cardiotoxicity. Because dexrazoxane, doxorubicin and daunorubicin all act on DNA topoisomerase II, a study was undertaken to see what effect dexrazoxane had on the growth inhibitory effects of doxorubicin and daunorubicin towards Chinese hamster ovary cells. Dexrazoxane exhibited significant antagonism of doxorubicin- and daunorubicin-mediated growth inhibition when the cells were preincubated with dexrazoxane before the anthracycline was added. Continuous exposure of cells to either anthracycline and low concentrations of dexrazoxane resulted in additive growth inhibitory effects at low anthracycline concentrations, and no effect at higher anthracycline concentrations.

Synthesis of 19(R/S)-hydroxy-5β,19-cycloandrostane-3,17-dione by reductive cyclization of the steroid 4-en-3-one 19-aldehyde with zinc in aqueous acetic acid is reported. On either acid or base treatment the R-isomer is converted to the S-isomer through an intermediate 3-hydroxy-3,5-cyclosteroid.

14β-Hydroxy-5β-pregnane and 14β-hydroxy-21-nor-5β-pregnane derivatives of ouabain were synthesised and their structures established by NMR measurements. Binding affinity in an [ 3 H]ouabain radioligand binding assay was determined. Pregnane derivatives of ouabain are more polar than pregnane rhamnoside derivatives of digitoxigenin. Whereas ouabain binds similarly to digitoxigenin rhamnoside, the pregnane derivatives of ouabain have significantly weaker binding affinity than their congeners from digitoxigenin.

Ozonolysis of digitoxin, digitoxin tetraacetate, digitoxin tetrakis-(2,2,2-trichloroethyl carbonate), digitoxigenin, digitoxigenin acetate, digitoxigenin hemisuccinate and digitoxigenin 2,2,2-trichloroethyl carbonate followed by treatment with excess of zinc in acetic acid gave either the corresponding 21-hydroxy ester after 5 min or the 21-methyl ketone after 20 h. This procedure is more efficient than methods previously reported for the conversion of the α,β-unsaturated γ-lactone into an acetyl group and is applicable to the cardiac glycosides directly to give 14β-hydroxypregnan-20-one derivatives. Acidic hydrolysis of 14,21-dihydroxy-and 14-hydroxy-3β-tris(digitoxosyloxy)-5β,14β-pregnan-20-one is reported. Structures are based on 1H and 12C NMR assignments.

Synthesis of 20α- and 20β-acetamido-, amino-, nitro- and hydroxy-3β-glycoside (α-L-rhamnopyranoside and tris-β-D-digitoxoside) and genin derivatives of 14-hydroxy-5β,14β-pregnane together with the C-20 oxime, hydrazone and amidinohydrazone is described from digitoxin. Ortho esters were also isolated. Structures were established by NMR measurements. These compounds have been shown to bind to the digitalis receptor of heart muscle. The 20β derivatives were consistently more potent than are the corresponding 20α compounds. The 20β-nitro α-L-rhamnoside derivative proved to be the most potent. Receptor binding data are given and structure-activity relationships are presented.

Synthesis of 19(R/S)-hydroxy-5β,19-cycloandrostane-3,17-dione by reductive cyclization of the steroid 4-en-3-one 19-aldehyde with zinc in aqueous acetic acid is reported. On either acid or base treatment the R-isomer is converted to the S-isomer through an intermediate 3-hydroxy-3,5-cyclosteroid.

Synthesis of 20α- and 20β-acetamido-, amino-, nitro- and hydroxy-3β-glycoside (α-L-rhamnopyranoside and tris-β-D-digitoxoside) and genin derivatives of 14-hydroxy-5β,14β-pregnane together with the C-20 oxime, hydrazone and amidinohydrazone is described from digitoxin. Ortho esters were also isolated. Structures were established by NMR measurements. These compounds have been shown to bind to the digitalis receptor of heart muscle. The 20β derivatives were consistently more potent than are the corresponding 20α compounds. The 20β-nitro α-L-rhamnoside derivative proved to be the most potent. Receptor binding data are given and structure-activity relationships are presented.

Ozonolysis of digitoxin, digitoxin tetraacetate, digitoxin tetrakis-(2,2,2-trichloroethyl carbonate), digitoxigenin, digitoxigenin acetate, digitoxigenin hemisuccinate and digitoxigenin 2,2,2-trichloroethyl carbonate followed by treatment with excess of zinc in acetic acid gave either the corresponding 21-hydroxy ester after 5 min or the 21-methyl ketone after 20 h. This procedure is more efficient than methods previously reported for the conversion of the α,β-unsaturated γ-lactone into an acetyl group and is applicable to the cardiac glycosides directly to give 14β-hydroxypregnan-20-one derivatives. Acidic hydrolysis of 14,21-dihydroxy-and 14-hydroxy-3β-tris(digitoxosyloxy)-5β,14β-pregnan-20-one is reported. Structures are based on 1H and 12C NMR assignments.

5 alpha-pregnane-3 beta,14 beta,20 beta-triol 3-alpha-L-rhamnopyranoside (8) and 3 beta-(alpha-L-rhamnopyranosyloxy)-5 alpha-pregn-14-en-20-one (14) were prepared from uzarigenin by ozonolysis followed by zinc and acetic acid reduction and glycosidation. During the glycosidation reaction leading to (8) the corresponding ortho ester (9) was also obtained. Uzarigenin alpha-L-rhamnopyranoside (15) also was prepared. Synthesis of 5 alpha-pregnane-3 beta,14 beta,20 beta-triol (20) is described. Structures were established by analysis of their NMR spectra. The binding affinity of 5 alpha and 5 beta cardenolide and pregnane derivatives as measured in a radioligand binding assay was determined and their structure-activity relationships compared. The receptor binding affinity of the 5 alpha derivatives is less than that of the corresponding 5 beta derivatives.

The preparation of derivatives of 14-hydroxy-21-nor-5 beta,14 beta-pregnane and 5 beta,14 beta-pregnane C-3 alpha-L-rhamnosides and tris-beta-D-digitoxosides is described. These derivatives, possessing a C-17 beta COCH2OH, CH2OH, CO2H, CO2Me, CH2NH2, or CH2NO2 group, bind to the digitalis receptor recognition site of heart muscle as measured in a radioligand binding assay. The 21-norpregnane derivatives consistently show greater binding affinity than the corresponding 20 alpha- and 20 beta-pregnane analogs. The C-20 nitro rhamnoside is comparable to digitoxin in binding affinity. The 17 beta-CH2NO2 group is the most effective replacement for the unsaturated lactone in the binding assay found so far, showing binding affinity comparable to that of the cardiac glycosides.