Cardenolide analogs. 7. Synthesis and biological activity of some new steroidal guanylhydrazones

Gelbart, Alex; Thomas, Richard

doi:10.1021/jm00201a010

Cited by 24 publications

(8 citation statements)

References 3 publications

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“…was observed. Other chemical shifts agree with those reported by Gelbart & Thomas (1978). Synthesis of 3/I-hydroxy-a-vinyl-5a-androstane-17/Imethanol (II) and…”

Section: Vol 240supporting

confidence: 89%

“…Preparation of the intermediate aldehyde 3,/-hydroxy-17,f-formyl-androstane (I) (Scheme 1) was achieved by using a modification of the method described by Gelbart & Thomas (1978). In order to increase the yield of the crucial acetoxylation product (3,6,21-diacetoxy-5apregnane-20-one) to 80%, the ratio of Pb(OAc)4 to Rat ovarian cytosol (4 ml obtained from 10 ovaries) was applied to a 2 ml column of poly(L-lysine)-agarose equilibrated in 10 mM-potassium phosphate containing 12 mM-monothioglycerol and 1 mM-EDTA, pH 6.0.…”

Section: Steroid Synthesismentioning

confidence: 99%

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Active-site directed inactivation of rat ovarian 20 α-hydroxysteroid dehydrogenase

Ricigliano¹,

Penning²

1986

Biochemical Journal

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Rat ovarian 20 alpha-hydroxysteroid dehydrogenase plays a pivotal role in leuteolysis and parturition by catalysing the reduction of progesterone to give the progestationally inactive steroid 20 alpha-hydroxyprogesterone. Putative mechanism based inhibitors of this enzyme were synthesized as potential progestational maintaining agents, including the epimeric allylic alcohol pair 3 beta-hydroxy-alpha-vinyl-5 alpha-androstane-17 beta-methanol and the related vinyl ketone 1-(3 beta-hydroxy-5 alpha-androstan-17 beta-yl)-2-propen-1-one. The vinyl ketone inactivates rat ovarian 20 alpha-hydroxysteroid dehydrogenase, semi-purified by poly(L-lysine)-agarose column chromatography, in a rapid time-dependent manner. Analysis of the pseudo-first-order inactivation plots gave a Ki of 2.0 microM for the inhibitor and a t1/2 for the enzyme of 20 s at saturation. These data indicate that the vinyl ketone is a potent and efficient inactivator of the ovarian dehydrogenase. Neither dialysis in the presence or absence of a competing nucleophile nor gel filtration reserves the inactivation, suggesting that a stable covalent bond is formed between the enzyme and steroid ligand. Both substrates (20 alpha-hydroxyprogesterone and NADP+) protect the enzyme from inactivation; moreover, initial velocity measurements in the presence of saturating concentrations of both substrates indicate that the vinyl ketone can behave as a competitive inhibitor, yielding a Ki value identical with that obtained in the inactivation experiments. Our results imply that the vinyl ketone is an active-site directed alkylating agent. By contrast the allylic alcohol pair 3 beta-hydroxy-alpha-vinyl-5 alpha-androstane-17 beta-methanol are neither substrates nor inhibitors of the ovarian enzyme and appear to be excluded from the catalytic site. The rapid inactivation observed with the vinyl ketone suggests that this compound may be useful as a progestational maintaining agent.

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“…was observed. Other chemical shifts agree with those reported by Gelbart & Thomas (1978). Synthesis of 3/I-hydroxy-a-vinyl-5a-androstane-17/Imethanol (II) and…”

Section: Vol 240supporting

confidence: 89%

Section: Steroid Synthesismentioning

confidence: 99%

Active-site directed inactivation of rat ovarian 20 α-hydroxysteroid dehydrogenase

Ricigliano¹,

Penning²

1986

Biochemical Journal

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“…It has to be pointed out that the corresponding semicarbazone, similar but non-ionic, does not elicit any activity. The activity of some monoguanylhydrazones at C17 of the pregnane system [110] (bearing C/D trans junction and variability in A/B junction -cis, trans, quasiplanar-) have also been studied. These compounds inhibit Na + ,K + -ATPase, but they produce a transient increase of myocardial contractility followed by a strong negative inotropic effect.…”

Section: Aminoguanidines In Digitalis Compoundsmentioning

confidence: 99%

A Short Review on Cardiotonic Steroids and Their Aminoguanidine Analogues

2000

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“…Introduction of a 14p-OH moiety into progesterone converts the C/D junction to the cis configuration and confers a positive inotropic action to that steroid. In this regard the work of Gelbart & Thomas (1978) is particularly relevant. They found that 17p-formyl-guanylhydrazone derivatives of a series of non-digitalis-like steroids (C/D trans) inhibited myocardial Na,K-ATPase but had only a depressant effect on myocardial contractility.…”

Section: Solubility Ofsteroids In Aqueous Buffersmentioning

confidence: 99%

14β‐Hydroxyprogesterone binds to the digitalis receptor, inhibits the sodium pump and enhances cardiac contractility

Böse

Elliott

Kobayashi

et al. 1988

British J Pharmacology

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Certain derivatives of progesterone are potent inhibitors of high affinity, specific binding of 3H‐cardiac glycosides. The steroids interact at the cardiac glycoside site on Na,K‐ATPase and inhibit the enzyme (the sodium pump) in cardiac and other tissues. However, the active congeners identified previously have been, unlike the cardiac glycosides, predominantly cardiodepressant. Because a 14β‐hydroxy substituent is an important determinant of activity of the cardiotonic cardiac glycosides, we synthesized 14β‐hydroxyprogesterone. This derivative has about one‐tenth the potency of the aglycone, ouabagenin, in a [3H]‐ouabain binding assay. Like ouabagenin, but in contrast to the cardiodepressant congeners of progesterone, 14β‐hydroxyprogesterone consistently elicited positive inotropy in isolated cardiac muscle and enhanced both the magnitude and frequency of fluctuations in scattered light (an index of oscillatory intracellular release of calcium). Thus, at least one hydroxylated derivative (and putative endogenous metabolite) of progesterone, mimics the cardiac effects of cardiac glycosides including enhanced contractility.

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Cardenolide analogs. 7. Synthesis and biological activity of some new steroidal guanylhydrazones

Cited by 24 publications

References 3 publications

Active-site directed inactivation of rat ovarian 20 α-hydroxysteroid dehydrogenase

Active-site directed inactivation of rat ovarian 20 α-hydroxysteroid dehydrogenase

A Short Review on Cardiotonic Steroids and Their Aminoguanidine Analogues

14β‐Hydroxyprogesterone binds to the digitalis receptor, inhibits the sodium pump and enhances cardiac contractility

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