Synthesis and activity evaluation of a series of cholanamides as modulators of the liver X receptors.

The Liver X receptors (LXRs) are members of the nuclear receptor family, that play fundamental roles in cholesterol transport, lipid metabolism and modulation of inflammatory responses. In recent years, the synthetic steroid N,N-dimethyl-3β-hydroxycholenamide (DMHCA) arised as a promising LXR ligand. This compound was able to dissociate certain beneficial LXRs effects from those undesirable ones involved in triglyceride metabolism.

Neuroprotective action of synthetic steroids with oxygen bridge. Activity on GABAA receptor.

Allopregnanolone (A) and pregnanolone (P) are able to modify neural activities acting through the GABAA receptor complex. This capacity makes them useful as anticonvulsant, anxiolytic, or anti-stress compounds. In this study, the performance of seven synthetic steroids (SS) analogous of A or P containing an intramolecular oxygen bridge was evaluated using different assays.

Synthesis and GABA(A) receptor activity of 2,19-sulfamoyl analogues of allopregnanolone.

The synthesis of new analogues of allopregnanolone with a bridged sulfamidate ring over the beta-face of ring A has been achieved from easily available precursors, using an intramolecular aziridination strategy. The methodology also allows the synthesis of 3alpha-substituted analogues such as the 3alpha-fluoro derivative. GABA(A) receptor activity of the synthetic analogues was evaluated by assaying their effect on the binding of [(3)H]flunitrazepam and [(3)H]muscimol.

Differential recruitment of tetratricorpeptide repeat domain immunophilins to the mineralocorticoid receptor influences both heat-shock protein 90-dependent retrotransport and hormone-dependent transcriptional activity.

The mineralocorticoid receptor (MR) forms oligomers with the heat-shock protein 90 (Hsp90) -based heterocomplex, which contains tetratricopeptide repeat (TPR) domain immunophilins (IMMs). Here we investigated the unknown biological role of IMMs in the MR.Hsp90 complex.

Novel synthetic approach to 1alpha,25-dihydroxyvitamin D3 and analogues.

A mild and stereoconvergent synthesis of 1alpha,25-dihydroxyvitamin D(3) (calcitriol, 1a) is described. The key step is a cascade process consisting of two consecutive transformations: An initial palladium-catalyzed 6-exo-cyclocarbopalladation of vinyl triflate 4 followed by a Negishi cross-coupling reaction with alkenyl zinc 3. This approach is of interest for the rapid synthesis of a variety of new vitamin D(3) analogues of therapeutic potential, especially those modified at the triene and ring-A.

Synthesis of 6,19-sulfamidate bridged pregnanes.

Conformationally restrained substituted pregnane-20-one derivatives were obtained by an intramolecular nitrene addition onto a C-5/C-6 double bond involving a tethered C-19 sulfamoyl moiety. The resulting aziridine underwent regioselective nucleophilic ring opening at C-5 at room temperature with cyanide, fluoride, and acetate. In the isolated case of acetate, a reversal of regioselectivity was observed at higher temperatures, a result attributed to a rearrangement process involving aziridine ring opening at the C-5 position and subsequent migration of the acetyl moiety to C-6.

Antiherpes virus activities of new 6-19 carbon-bridged steroids and some synthetic precursors.

Three synthetic 6,19-carbon bridged steroids: 3beta,20beta-diacetyloxy-5alpha-chloro-19a(R)-hydroxy-6,19-methanopregnane, 3beta,20beta-diacetyloxy-5alpha-chloro-6,19-methanopregnane, 6,19-methanopregn-4-ene-3,20-dione and four synthetic precursors: 3beta,20beta-diacetyloxy-19-hydroxypregn-5-ene, 3beta,20beta-diacetyloxy-pregn-5-en-19-al, 3beta,20beta-diacetyloxy-19(E)-(methoxymethylidene)-pregn-5-ene and 20beta-acetyloxy-3beta-hydroxy-19(E)-(methoxymethylidene)-pregn-5-ene were tested against herpes virus replication in cell cultures. Several compounds were cytotoxic for stationary cells. Antiviral studies performed with all compounds against HSV-1 indicated a dose-dependent virus susceptibility with selectivity indexes (SI) values in the range 1.

6,19-carbon-bridged steroids. Synthesis of 6,19-methanoprogesterone.

6,19-Methanoprogesterone (4) was synthesized in nine steps from the readily available 3 beta,20 beta-diacetyloxy-5 alpha-bromo-6,19-oxidopregnane (5) in 14% overall yield. The additional carbon atom was introduced by reaction of a C-19 aldehyde with Ph3PCHOCH3 under salt free conditions and subsequent hydrolysis to give the homologous aldehyde. Intramolecular addition of the newly incorporated carbonyl (C-19a) to the olefinic C-6 in ring B was achieved by means of a Prins reaction with TiCl4 as Lewis acid.

Intramolecular PhI=O mediated copper-catalyzed aziridination of unsaturated sulfamates: a new direct access to polysubstituted amines from simple homoallylic alcohols.

[reaction: see text] Olefinic sulfamates derived from primary and secondary alcohols undergo intramolecular copper-catalyzed aziridination in the presence of iodosylbenzene to afford novel bicyclic fused aziridines. The latter were opened by various nucleophiles to give the corresponding substituted cyclic sulfamates, which in turn reacted, after nitrogen activation, with a second nucleophile at the carbon atom bearing the oxygen atom. Concomitant removal of the sulfonyloxy moiety thus gave access to polysubstituted amines.

Differences in nuclear retention characteristics of agonist-activated glucocorticoid receptor may determine specific responses.

We studied the glucocorticoid response to the synthetic steroid pregna-1,4-diene-11beta-ol-3,20-dione (DeltaHOP) in several cell types and correlated its biological effect with the ability of the glucocorticoid receptor (GR) to be retained in the nuclear compartment. We observed that the DeltaHOP-transformed GR was diffusely distributed in the nucleus compared to the discrete structures observed for the dexamethasone (DEX)-transformed GR. Despite the fact that the receptor was entirely nuclear upon binding of each steroid and exhibited identical nuclear export rates, a greater amount of DeltaHOP-transformed GR was recovered in the cytoplasmic fraction after hypotonic cell lysis.

Modification of an essential amino group in the mineralocorticoid receptor evidences a differential conformational change of the receptor protein upon binding of antagonists, natural agonists and the synthetic agonist 11,19-oxidoprogesterone.

The alkylation of amino groups of the mineralocorticoid receptor (MR) with pyridoxal 5'-phosphate or 2,4,6-trinitrobenzenesulphonate (TNBS) under controlled conditions modifies only one lysyl residue, which accounts for a 70% inhibition of steroid binding capacity. The Kd of aldosterone for MR is not affected by the treatment, but the total number of binding sites is greatly decreased. The modified receptor is capable of dynamically conserving its association with the hsp90-based heterocomplex.

Oxidative Cyclization of Iodo Ketones. Synthesis of 6-Oxa-5alpha-pregnane-3,20-dione.

The steroidal delta- and gamma-iodo ketones 1 and 9 were converted to the cyclic hemiketals 3 and 10, by oxidation to the iodoso derivatives with m-CPBA. Spontaneous cyclization of the latter intermediates to the corresponding oxocarbenium ions, followed by stereoselective addition of water, rendered the hemiketals. Depending on the reaction conditions, the five-membered oxocarbenium ion derived from the gamma-iodo ketone 9 may add H(2)O or m-CPBA to give either the hemiketal or a Baeyer-Villiger type product 12, while the oxocarbenium derived from 1 gives exclusively the hemiketal.