Philip R. Kym

The Pursuit of Differentiated Ligands for the Glucocorticoid Receptor

Glucocorticoids have a pervasive role in human health and physiology. The endogenous members of this family are involved in a breadth of endocrine functions including metabolism of lipids, carbohydrates and proteins, stress response, fluid and electrolyte balance, as well as maintenance of immunological, renal and skeletal homeostasis. The predominant mode of action of glucocorticoids involves regulation of gene expression via the glucocorticoid receptor (GR). Synthetic glucocorticoids have long been the standard for the treatment of inflammatory and immune disorders, yet the benefits of classic steroids such as dexamethasone and prednisolone are accompanied by well-characterized potentiation of homeostatic endocrine functions, leading to the side effects associated with prolonged treatment. In recent campaigns for safer analogs, compounds have been sought which differentiate functional repression of existing transcription factors such as AP-1 and NFkappaB from GR-mediated transcriptional activation arising from binding at glucocorticoid-receptor response elements (GREs). Such differentiated ligands would provide the desired immunoregulatory actions without the endogenous changes in gene expression associated with undifferentiated steroids. We detail the methods for the evaluation of selective GR modulators and describe the evolution of new compounds where varying degrees of selectivity have been reported.

Benz[a]anthracene diols: Predicted carcinogenicity and structure-estrogen receptor binding affinity relationships

Benz[a]anthracenes are ubiquitous environmental carcinogens that exert estrogenic and antiestrogenic effects directly or via hydroxylated metabolites. In this paper, the structure-estrogen receptor binding relationships of four 3,9-benz[a]anthracene diols are described: unsubstituted, 7-methyl, 12-methyl, and 7,12-dimethyl. Compounds unsubstituted at the 12-position have flat molecular topology, whereas methyl substitution at the 12-position in the bay region induces twisting of the molecular framework. The oxygen-oxygen distances (11.94-11.98 A) are similar to diethylstilbestrol (12.1 A). The binding affinities range from 0.43% to 26% that of estradiol. Methyl substitution at the 7-position enhances affinity; 12-methyl substitution decreases it. These results are contrary to many estrogen receptor (ER) ligand systems, in which the compounds with the flatter molecular geometries typically have lower binding affinity. Molecular graphics were used to analyze the fit of the four compounds with a receptor excluded volume model for the ER. These studies suggest that these compounds bind to the ER in a manner in which the anthracene fragment acts as the steroid AB-ring mimic (i.e, the benz[a]anthracene 9-position corresponds to the estradiol 3-position). Molecular orbital (AM1) calculations were used to calculate the charges of selected atoms. The 7-methyl compound was found to have greater charge similarity to estradiol than the other three compounds. The high affinity of the 7-methyl compound is ascribed to its charge similarity to estradiol, hydrophobic interactions in the receptor region that would accommodate a substituent in the planar 6-position of a delta 6,7-steroid, and favorable dispersive interactions with the receptor secondary to its extended planar system. Molecular orbital calculations also suggest that some of the benz[a]anthracene monophenols and diphenols have sufficiently low ionization potentials to act as carcinogens by a radical cation process.

THE EFFECT OF ACCEPTOR GROUP VARIATION ON THE SOLVATOCHROMISM OF DONOR-ACCEPTOR FLUOROPHORES

Abstract The absorption and emission characteristics of five hydroxytetrahydrochrysenes substituted with acceptor groups (nitro, cyano, methylketone, 1° amide and methyl ester) (THC‐NO2, THC‐CN, THC‐COCH3, THC‐CONH2 and THC‐CO2CH3, respectively) were investigated in an extensive set of solvents. The order of absorption and fluorescence bathochromicity are: THC‐NO2 > THC‐COCH3 > THC‐CN ≥ THC‐CO2CH3 > THC‐CONH2 and THC‐NO2 >> THC‐COCH3 > THC‐CO2CH3 > THC‐CN > THC‐CONH2, respectively. The emission spectra of these compounds are sensitive to the solvent polarity (ET[30] scale) in the order: THC‐NO2 > THC‐COCH3 > THC‐CO2CH3 > THC‐CONH2 > THC‐CN. The response of the emission maxima of these compounds to the solvent polarity and hydrogen‐bond donor/acceptor properties (π*/α/β and acity/basity scales) was also determined. The emission energies of THC‐NO2 were most sensitive to π*, β, acity, and basity of the solvent; those of the amide were least sensitive to the solvent π*, β, and basity.

Novel stereoids from cetyltrimethylammonium permanganate-initiated oxidative rearrangements of 16-dehydroprogesterone

Abstract Cetyltrimethylammonium permanganate initiates oxidative opening of the D-ring of 16-dehydroprogesterone in CH 2 Cl 2 . The novel steroids 3 and 4 have been isolated and characterized as the major products obtained from oxidative rearrangement of the steroid backbone. The X-ray crystal structure of the D-homosteroid 3 is provided, and a putative mechanism that invokes a benzilic acid rearrangement for formation of 3 is presented.