Academic literature on the topic 'Bromination of Steroidal'

The synthetic routes to 25-hydroxy derivatives of 4-methylcholest-4-ene and 4,4-dimethylcholest-5-ene from methyl lithocholate and methyl 3β-acetoxy-24-homochol-5-en-25-oate (6) have been investigated. The cholest-5-ene-3β,25-diol (7), readily available from 6, was transformed in a few steps into the title compounds. It was also found that bromination of 24-acetoxy-5β-cholan-3-one (1) and of its enol acetate followed by dehydrobromination is not a regioselective reaction. Formation of mixtures of 2β-bromo-3-oxo and 4β-bromo-3-oxo compounds, which gave mixtures of 24-acetoxychol-4-en-3-one (4) and 24-acetoxy-5β-chol-1-en-3-one (5) of similar polarity was observed. 4-Methyl-25-hydroxycholest-4-en-3-one (14) and 4-methyl-25-hydroxycholesta-1,4-dien-3-one (16) are potential substrates for the preparation of 4-methyl analogs of vitamin D3.

Glucose 6-phosphate dehydrogenase (G6PDH) fulfills an essential role in cell physiology by catalyzing the production of NADPH+ and of a precursor for the de novo synthesis of ribose 5-phosphate. In trypanosomatids, G6PDH is essential for in vitro proliferation, antioxidant defense and, thereby, drug resistance mechanisms. So far, 16α-brominated epiandrosterone represents the most potent hit targeting trypanosomal G6PDH. Here, we extended the investigations on this important drug target and its inhibition by using a small subset of androstane derivatives. In Trypanosoma cruzi, immunofluorescence revealed a cytoplasmic distribution of G6PDH and the absence of signal in major organelles. Cytochemical assays confirmed parasitic G6PDH as the molecular target of epiandrosterone. Structure-activity analysis for a set of new (dehydro)epiandrosterone derivatives revealed that bromination at position 16α of the cyclopentane moiety yielded more potent T. cruzi G6PDH inhibitors than the corresponding β-substituted analogues. For the 16α brominated compounds, the inclusion of an acetoxy group at position 3 either proved detrimental or enhanced the activity of the epiandrosterone or the dehydroepiandrosterone derivatives, respectively. Most derivatives presented single digit μM EC50 against infective T. brucei and the killing mechanism involved an early thiol-redox unbalance. This data suggests that infective African trypanosomes lack efficient NADPH+-synthesizing pathways, beyond the Pentose Phosphate, to maintain thiol-redox homeostasis.