Szteránvázas vegyületek kutatása = Research of steroids

A szteránváz D-gyűrűjéhez kondenzált heterociklusok farmakológiailag jelentős vegyületek. A beszámolási időszakban az androszt-5-én vázhoz 17?-helyzetben kondenzált, két heteroatomot tartalmazó ciklusokat építettünk ki. Az N-fenil-, és az N-szubsztituált-fenil-2-oxazolidonokat a szteránvázhoz fűződő ?,?-haloalkil-N-ariluretánok alkalikus közegű szolvolízisével végeztük. A folyamat egy (N-5) szimbólummal jellemezhető szomszédcsoport részvétel. A 21-hidroximetilidén-pregn-5-én-20-on fenilhidrazinnal és annak szubsztituált származékaival végzett átalakítása két regioizomer N-fenil-pirazolhoz vezet. Arilpirazolin és izoxazolidin származékok előállítását 1,3-dipoláris cikloaddicióval sikerült megvalósítani az androszt-5-én sorban. A folyamat mechanizmusát és sztereoszelektivitását számításokkal sikerült alátámasztani. A 13?-ösztron sorban endo-, és exo-ciklusos ketonok kialakítását sikerült megvalósítani, melyek nitriliminnel végzett 1,3-dipoláris cikloaddícója regioizomer pirazolinokhoz vezetett. Az elállított vegyületek jelentős része jelentős antiproliferativ hatásúnak bizonyult. | Steroids bearing heterocycles attached to the D-ring of the steroid nucleus have been of pharmaceutical interest. During the supported period we carried out synthesis of steroidal two heteroatom-containing heterocycles at position 17? of androst-5-en-3?-ol. For the synthesis of the N-phenyl-, and N-(substituted-phenyl)-2-oxazolidone ring we chose cyclization of the steroidal ?,?-haloalkyl-N-arylurethanes in alkaline media. The cyclization takes place with (N-5) neighboring group participation. The reaction of 21-hydroxymethylidenepregn-5-en-20-one with phenylhydrazine, or p-substituted phenylhydrazines affords two regioisomer steroidal N-phenylpyrazolyl derivatives. Arylpyrazolynes and isoxazolidines in the androst-5-ene series were prepared by 1,3-dipolar cycloaddition. The mechanism and stereoselectivity of the reactions were elucidated. Effective syntheses of endo- and exocyclic ?,?-unsaturated ketones were carried out in the 13?-estrone series. The 1,3-dipolar cycloadditions of 15,16-unsaturated ketones with nitrilimines stereoselectively furnished two regioisomers of new condensed pyrazolynes. Several compounds exerted marked in vitro antiproliferative activity on different malignant human cell lines

A molecular understanding of d-homoestrone-induced G2/M cell cycle arrest in HeLa human cervical carcinoma cells

2-Methoxyestradiol (ME), one of the most widely investigated A-ring-modified metabolites of estrone, exerts significant anticancer activity on numerous cancer cell lines. Its pharmacological actions, including cell cycle arrest, microtubule disruption and pro-apoptotic activity, have already been described in detail. The currently tested d-ring-modified analogue of estrone, d-homoestrone, selectively inhibits cervical cancer cell proliferation and induces a G2/M phase cell cycle blockade, resulting in the development of apoptosis. The question arose of whether the difference in the chemical structures of these analogues can influence the mechanism of anticancer action. The aim of the present study was therefore to elucidate the molecular contributors of intracellular processes induced by d-homoestrone in HeLa cells. Apoptosis triggered by d-homoestrone develops through activation of the intrinsic pathway, as demonstrated by determination of the activities of caspase-8 and -9. It was revealed that d-homoestrone-treated HeLa cells are not able to enter mitosis because the cyclin-dependent kinase 1-cyclin B complex loses its activity, resulting in the decreased inactivation of stathmin and a concomitant disturbance of microtubule formation. However, unlike 2-ME, d-homoestrone does not exert a direct effect on tubulin polymerization. These results led to the conclusion that the d-homoestrone-triggered intracellular processes resulting in a cell cycle arrest and apoptosis in HeLa cells differ from those in the case of 2-ME. This may be regarded as an alternative mechanism of action among steroidal anticancer compounds

Dehydroepiandrosterone sulfate (DHEAS) is neuroprotective when administered either before or after injury in a focal cortical cold lesion model

Dehydroepiandrosterone and its sulfate (DHEAS) are sex hormone precursors that exert marked neurotrophic and/or neuroprotective activity in the central nervous system. The present study evaluated the effects of DHEAS and 17�-estradiol (E2) in a focal cortical cold lesion model, in which DHEAS (50 mg/kg, sc) and E2 (35 mg/kg, sc) were administered either as pretreatment (two subsequent injections 1 d and 1 h before lesion induction) or posttreatment (immediately after lesion induction). The focal cortical cold lesion was induced in the primary motor cortex by means of a cooled copper cylinder placed directly onto the cortical surface. One hour later, the animals were killed, the brains cut into 0.4-mm-thick slices, and the sections stained with 1% triphenyltetrazolium chloride. The volume of the hemispheric lesion was calculated for each animal. The results demonstrated that the lesion area was significantly attenuated in both the DHEAS- and E2- preand posttreated groups and that in the presence of letrozole, a nonsteroidal aromatase inhibitor, no neuroprotection was observed, suggesting that the beneficial effect of DHEAS on the cold injury might depend on the conversion of DHEAS to E2 within the brain. It is concluded that even a single posttraumatic administration of DHEAS may be of substantial therapeutic benefit in the treatment of focal brain injury with vasogenic edema