title: Computer-aided structure analysis of an epimerized dehydroepiandrosterone derivative and its biological effect in a model of reactive gliosis.
abstract: The naturally occurring steroid dehydroepiandrosterone (DHEA) is reported to reduce glial fibrillary acidic protein (GFAP) overexpression in a model of reactive gliosis due to its conversion to estradiol by the enzyme aromatase. In the present study we examined the biological effect of a new epimerized derivative of DHEA, 16alpha-iodomethyl-13alpha-dehydroepiandrosterone derivative (16alpha-iodomethyl-13alpha-DHEAd, 16alpha-iodomethyl-13alpha-androst-5-en-3beta,17beta-diol), using the same model system, and compared the 3D structure of this molecule with that of DHEA and two steroidal type aromatase inhibitors, formestane and exemestane. The synthetic compound, in contrast to the reported effect of DHEA, was able to reduce GFAP overexpression only if the enzyme aromatase was inhibited. Data obtained from computational calculations fortified by X-ray crystallography revealed that contrary to the nearly planar sterane framework of DHEA, the synthetic derivative 16alpha-iodomethyl-13alpha-DHEAd has a bent sterane skeleton, resulting in a 3D structure that is similar to that of formestane or exemestane. Moreover, 16alpha-iodomethyl-13alpha-DHEAd resulted to be metabolically more stable than DHEA. The results suggest that epimerization of the sterane skeleton of DHEA inclines the plane of the D ring, leading to a significantly altered biological activity. The synthetic molecule has a DHEA-like effect on GFAP overexpression when the enzyme aromatase is inhibited and the naturally occurring DHEA is ineffective in this respect. On the other hand, based on their structural similarity it can be hypothesized that 16alpha-iodomethyl-13alpha-DHEAd applied alone might have a biological effect similar to that of formestane or exemestane.
authors.affiliation: Institute of Biophysics, Biological Research Center, Szeged, Temesvári krt. 62, H-6726 Szeged, Hungary.
authors.forename: Zsófia
authors.initials: Z
authors.lastname: Hoyk
authors.forename: Eszter
authors.initials: E
authors.lastname: Csákvári
authors.forename: Agota
authors.initials: A
authors.lastname: Szájli
authors.forename: János
authors.initials: J
authors.lastname: Kóti
authors.forename: Gábor
authors.initials: G
authors.lastname: Paragi
authors.forename: Andrea
authors.initials: A
authors.lastname: Gyenes
authors.forename: János
authors.initials: J
authors.lastname: Wölfling
authors.forename: Roland
authors.initials: R
authors.lastname: Pfoh
authors.forename: Stephan
authors.initials: S
authors.lastname: Rühl
authors.forename: Arpád
authors.initials: A
authors.lastname: Párducz
mesh_terms: D000730:Androstadienes / Q000737:chemistry / Q000378:metabolism; D000735:Androstenedione / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001141:Aromatase / Q000737:chemistry / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000730:Androstadienes; D047072:Aromatase Inhibitors; D005904:Glial Fibrillary Acidic Protein; D000735:Androstenedione; D003687:Dehydroepiandrosterone; D001141:Aromatase; C056516:exemestane; C014594:formestane