Synthesis of potential cytochrome P45011β-generated intermediates

Coustal, Suzy; Fagart, Jérôme; Davioud, Elisabeth; Marquet, Andrée

doi:10.1016/0040-4020(95)00099-t

Cited by 11 publications

(5 citation statements)

References 28 publications

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“…The synthesis of acetylenic compounds started from 3‐ O ‐acetyl‐ ( 1 ) or 3‐ O ‐methyl betulinic aldehyde ( 2 ) 12, 13 (Scheme ). Their reaction with ethynyl magnesium bromide 14 afforded the corresponding 28‐ethynyl‐betulinols as an inseparable mixture of diastereomers; hence, a direct transformation to compounds 3 and 4 was carried out by Jones oxidation 15. During the reaction of 1 with lithium acetylide 16 cleavage of the acetyl group occurred and led to the formation of 5 in 80% yield.…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Encapsulation and Antitumor Activity of New Betulin Derivatives

Csuk

Barthel

Sczepek

et al. 2010

Archiv der Pharmazie

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Novel betulin derivatives were prepared and tested for their antitumor activity. Starting from 3-O-acetyl- or 3-O-methyl-betulinic aldehyde, the synthesis of C-28 ethynyl derivatives was performed; their subsequent transformation with several 1,3-dipolarophiles afforded pyrazoles and 1,2,3-triazoles. Their screening for antitumor activity was performed in a panel of 15 human cancer cell lines by a colorimetric SRB-assay. Thereby, several compounds revealed a higher cytotoxicity than betulinic acid. In addition, the encapsulation of the lead structure 7 into liposomes was investigated. The results from a dye exclusion test and from DNA laddering experiments provided evidence for an apoptotic cell death.

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Section: Resultsmentioning

confidence: 99%

Synthesis, Encapsulation and Antitumor Activity of New Betulin Derivatives

Csuk

Barthel

Sczepek

et al. 2010

Archiv der Pharmazie

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“…Aldosterone and spironolactone were purchased from Sigma-Aldrich. 18-Oxo-18-vinylprogesterone was a gift from A. Marquet (19).…”

Section: Methodsmentioning

confidence: 99%

Finerenone Impedes Aldosterone-dependent Nuclear Import of the Mineralocorticoid Receptor and Prevents Genomic Recruitment of Steroid Receptor Coactivator-1

Amazit

Billan

Kolkhof

et al. 2015

Journal of Biological Chemistry

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132

123

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Background: Finerenone is a novel nonsteroidal mineralocorticoid antagonist, currently in clinical phase IIb trials. Results: Finerenone delays mineralocorticoid receptor nuclear import and inhibits its binding and transcriptional coactivator recruitment onto target gene promoters. Conclusion: Finerenone impedes three critical steps of the mineralocorticoid receptor signaling pathway. Significance: Finerenone, which behaves differently from currently available mineralocorticoid antagonists, is potentially a promising molecule to treat cardiorenal diseases.

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“…18-VP and 18-EP were synthesized as described previously (Viger et al, 1988). 18-Hydroxy-18-vinylprogesterone (18-OHVP) and were synthesized in our laboratory (Coustal et al, 1995). NADPH, dithiothreitol and EDTA were obtained from Boehringer.…”

Section: Methodsmentioning

confidence: 99%

“…To provide insight about this latter hypothesis, postulated reactive intermediates, 18-OHVP and 1 8-OVP, were synthesized in our laboratory (Coustal et al, 1995). We examined whether these compounds were released in the incubation mixture as metabolites of ['HIIS-VP.…”

Section: Protection By Deoxycorticosterone From Inactivation By 18-vpmentioning

confidence: 99%

Mechanism‐Based Inactivation of Bovine Cytochrome P‐450U_11β by 18‐Unsaturated Progesterone Derivatives

Delorme

Piffeteau

Sobrio³

et al. 1997

European Journal of Biochemistry

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Two 18-unsaturated progesterone derivatives, 18-vinylprogesterone (18-VP) and 1 8-ethynylprogesterone (1 8-EP) have proved to be potent inhibitors of the bovine cytochrome P-450, ,/!, the enzyme involved in the last steps of aldosterone biosynthesis [Delorme, C., Piffeteau, A., Viger, A. & Marquet, A. (1995) E m J. Biochem. 232, 247-2561. In the present study, we demonstrate that these two compounds exhibit the characteristics of mechanism-based inactivators of this enzyme. Inactivation followed pseudo-firstorder and saturation kinetics. The kinetic parameters of inactivation were k, = 0.11 min-' and K, = 4 pM for 18-VP, and k, =0.12 min-' and 22 pM for 18-EP. Inactivation of P-450,,, activity was strictly dependent on the presence of NADPH. Protection by the substrate deoxycorticosterone was observed, demonstrating a selective modification at the substrate-binding site. With radiolabeled 18-VP, inactivation was shown to be irreversible with a stoichiometry of 1.4 mol bound ['H]18-VP/mol inactivated cytochrome P-45OlIp. SDS/PAGE analysis of the [3H] 18-VP-inactivated enzyme showed that, under conditions preventing heme dissociation, the P-450,,, band was labeled, while no labeling of the apoprotein was observed under denaturating conditions. Furthermore, the loss of catalytic activity could be correlated with the destruction of the P-450 chromophore evaluated by the Fe"-CO versus Fe" difference spectra. These arguments led us to propose that 18-vinylprogesterone inactivates cytochrome P-450, , , by heme destruction rather than by protein modification.Keywords: cytochrome P-450,,,; mechanism-based inactivator; aldosterone biosynthesis ; 18-vinylprogesterone; 18-ethynylprogesterone.Aldosterone overproduction leads to oedematous diseases and hypertension (Corvol et al., 1990). These disorders are clinically treated with spirolactones, which act as antagonists at the receptor level. We developed an approach focusing on the inhibition of cytochrome P-450, (P-450,,,), an enzyme implied in the last steps of aldosterone biosynthesis. For this purpose, several progesterone analogs, designed as mechanism-based inhibitors of P-450,,,, were synthesized in our laboratory (Viger et al., 1988(Viger et al., , 1989.These compounds could potentially belong to the three wellknown classes of inactivators of cytochrome P-450, i.e. those binding covalently to the prosthetic, heme group, those binding to the protein, and those coordinating quasi-irreversibly the iron atom (Ortiz de Montellano, 1984). Among them, two 18-unsaturated progesterone derivatives, 18-vinylprogesterone (1 8-VP) and 18-ethynylprogesterone (18-EP; Fig. 1) were the most potent inhibitors tested on a rat adrenal cell-free extract since they completely inhibited aldosterone production at concentrations of 0.8 pM and 8 pM, respectively (Viger et al., 1989 Enzyme. Steroid 1 ID-monooxygenase (EC 1.14.15.4).ined the inhibition of P-450 11P-hydroxylase and 18-hydroxylase activities with a reconstituted enzyme system with a purified bovine P-450,,,) preparation containin...

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Synthesis of potential cytochrome P45011β-generated intermediates

Cited by 11 publications

References 28 publications

Synthesis, Encapsulation and Antitumor Activity of New Betulin Derivatives

Synthesis, Encapsulation and Antitumor Activity of New Betulin Derivatives

Finerenone Impedes Aldosterone-dependent Nuclear Import of the Mineralocorticoid Receptor and Prevents Genomic Recruitment of Steroid Receptor Coactivator-1

Mechanism‐Based Inactivation of Bovine Cytochrome P‐450U_11β by 18‐Unsaturated Progesterone Derivatives

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Synthesis of potential cytochrome P45011β-generated intermediates

Cited by 11 publications

References 28 publications

Synthesis, Encapsulation and Antitumor Activity of New Betulin Derivatives

Synthesis, Encapsulation and Antitumor Activity of New Betulin Derivatives

Finerenone Impedes Aldosterone-dependent Nuclear Import of the Mineralocorticoid Receptor and Prevents Genomic Recruitment of Steroid Receptor Coactivator-1

Mechanism‐Based Inactivation of Bovine Cytochrome P‐450U11β by 18‐Unsaturated Progesterone Derivatives

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Mechanism‐Based Inactivation of Bovine Cytochrome P‐450U_11β by 18‐Unsaturated Progesterone Derivatives