New steroidal diazo ketones as potential photoaffinity labeling reagents for the mineralocorticoid receptor: synthesis and biological activities.

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Davioud E, Fagart J, Souque A, Rafestin-Oblin ME, Marquet A

New steroidal diazo ketones as potential photoaffinity labeling reagents for the mineralocorticoid receptor: synthesis and biological activities.

J Med Chem. 1996 Jul 5;39(14):2860-4.

PubMed ID

8709117 [ View in PubMed

]

Abstract

Three diazo ketones in the progesterone series were synthesized as potential photoaffinity reagents. The diazo ketone group was introduced at the C17 (21-diazopregn-4-ene-3,20-dione, 1) or C13 (18-(diazomethyl)-20-hydroxypregn-4-ene-3,18-dione, 2, 18-(diazomethyl)pregn-4-ene-3, 18,20-trione, 3) position of the pregnene skeleton. Whereas compound 1 could be easily obtained from the corresponding acid chloride, preparation of 2 and 3 required a less straightforward route involving reaction of tosyl azide on the formyl derivative of methyl ketone 5. The affinity of the diazo ketones for the human mineralocorticoid receptor (hMR), expressed in Sf9 insect cells using the Baculovirus system, was estimated by competition experiments using [3H]aldosterone as specific ligand. The affinity of 1 for hMR was almost identical with that of aldosterone. The affinities of 2 and 3 were 1, order of magnitude lower than that of aldosterone. The mineralocorticoid activity of the diazo ketones was measured in cis-trans cotransfection assays in CV-1 cells with the mouse mammary tumor virus as DNA target sequence. Compound 1 exhibits an agonist activity (ED50 = 6 x 10(-9) M) with no antagonist activity. In contrast 2 and 3 behave as antagonists, displaying an IC50 of approximately 10(-6) M whether the substituent at the C20 position is a hydroxy (2) or an oxo (3) group.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Progesterone	Mineralocorticoid receptor	IC 50 (nM)	30	N/A	N/A	Details
Progesterone	Mineralocorticoid receptor	Kd (nM)	0.39	N/A	N/A	Details