Design, synthesis and biochemical evaluation of inhibitors of aromatase

Amanuel, Y. (2000) Design, synthesis and biochemical evaluation of inhibitors of aromatase. (MPhil thesis), Kingston University, .


The importance of inhibiting the cytochrome P-450 enzyme, aromatase, in the treatment of hormone-dependent breast cancer is discussed, and the current inhibitors reviewed. A number of novel inhibitors of aromatase have been synthesised based on Evans' chiral auxiliary, namely 4-benzyl-2-oxazolidinone. The derivatisation of the 4-benzyl group is described involving nitration and reduction reactions to give the 4-(4'-aminobenzyl)-2-oxazolidinone - the 4-amino group being required to ligate the cytochrome P-450 haem group of aromatase. Alkylation of the oxazolidinone ring is also considered in an attempt to investigate the affect of hydrophobicity on the inhibitory activity of these compounds. The reactions were, in general, found to proceed without major problems and in good yield to give a range of N-alkylated 4-(4'-aminobenzyl)-2-oxazolidinone compounds, the alkylation involved the methyl to the decyl derivatives of both the R and S enantiomers. These potential inhibitors were then subjected to biochemical evaluation using the standard literature procedure (as previously described by Thompson and Siiteri) involving the radiometric analysis of the aromatase catalysed reaction. A number of problems were encountered, however, during the course of the initial screening and only limited results were obtained, for example compounds 61 and 63 gave 39% inhibition at 100¡..tM. After these initial results, the assay failed to provide any more useful data. Extensive analysis of the assay procedure showed that the enzyme had denatured over time - it was discovered that other non-cytochrome P-450 enzymes within the sample (such as oestrone sulphatase) were found to retain their activity. Due to a lack of time, however, new placental preparations could not be prepared and thorough evaluation of the inhibitory activity of the compounds was not achieved.

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