4-(3‘α15‘β-Dihydroxy-5‘β-estran-17‘β-yl)furan-2-methyl Alcohol:  An Anti-Digoxin Agent with a Novel Mechanism of Action

Abstract

The synthesis and some pharmacological properties of 4-(3'alpha-15'beta-dihydroxy-5beta-estran-17'beta-yl)furan-2-methyl alcohol (16) have been described. The compound was synthesized by reacting a synthetic 3alpha- benzyloxy-5beta-estr-15-en-17-one with the ethylene acetal of 4-bromo-2-furancarboxyaldehyde, followed by hydrolysis of the ethylene acetal and reduction of the aldehyde. Despite its resemblance to the structure of cardiac steroids (CS), 16 does not bind to the CS receptor on Na(+),K(+)-ATPase and does not increase the force of contraction of heart muscle. However, 16 inhibited the digoxin-induced increase in the force of contraction and arrhythmias in guinea pig papillary muscle and human atrial appendages. The steroid also inhibited digoxin-induced alteration in endocytosed membrane traffic, indicating a novel mechanism of action.

Endogenous cardiac steroids in animal models of mania

“…The structure of this steroid, 4‐(3′α‐15′β‐dihydroxy‐5′β‐estran‐17′β‐yl)furan‐2‐methyl alcohol, termed ‘compound 16’, resembles that of CSs, but does not inhibit Na + , K + ‐ATPase ion transport activity at low (< 100 nM) concentrations. Furthermore, this steroid does not increase cardiac contractility and even inhibits digoxin‐induced increases in heart muscle contraction, in guinea pig papillary muscle and human atrial appendages . Furthermore, ‘compound 16’ inhibited digoxin‐induced transferrin accumulation in NT2 cells .…”

“…Furthermore, this steroid does not increase cardiac contractility and even inhibits digoxin‐induced increases in heart muscle contraction, in guinea pig papillary muscle and human atrial appendages . Furthermore, ‘compound 16’ inhibited digoxin‐induced transferrin accumulation in NT2 cells . These features suggest that the steroid is capable of attenuating some of the CS action.…”

Synthesis and Biological Evaluation of Novel Bufalin Derivatives

“…MS: m / z /(MH+) 369. 1H NMR: δ 7.83 (d, 1H, H-C [ 23 ]), 7.22 (s, 1H, H-C [ 21 ]), 6.25 (d, 1H, H-C [ 22 ]), 5.68 (m, 1H, H-C [ 3 ]) 5.34 (d, 1H, H-C [ 4 ]) 0.94 (s, 3H, CH3 [ 19 ]) 0.71 (s, 3H, CH3 [ 18 ]). 13C NMR: δ 16.71 (C18), 21.83 (C19), 83.93 (C14), 51.47 (C17), 127.46 (C20), 148.62 (C21), 146.94 (C22), 115.46 (C23), and 162.54 (C24).…”

“…Furthermore, our previous study showed that the/orientation of the 3-OH group CS may have a substantial effect on biological activity. Whereas the 3-OH isomer displayed the standard capability of increasing heart contractility, a 3-OH isomer did not boost the force of contraction, but actually inhibited the contractility induced by digoxin [ 19 ].…”