Degree Name

Doctor of Philosophy


Department of Chemistry


Phenoxodiol is an isoflavonoid based drug presently in clinical trials in Australia and America for use in prostate cancer. It has been shown to work through various mechanisms of action, including 5-α-reductase inhibition. The aims of this study were to develop new analogues related to phenoxodiol in order to increase 5-α-reductase inhibition and to introduce α1A adrenoceptor antagonism in the next generation of isoflavonoid derivatives. The α1A adrenoceptor antagonistic activity was expected to ameliorate the symptoms associated with prostate enlargement. Work towards the design of synthetic target molecules was the focus of the initial stages of the study. Pharmacophores for each of the human 5-α-reductase type I and type II and the rat type II isozymes were generated using CATALYST®. Standard parameters were used and variable weight options were trialled during the generation process. The mapping of phenoxodiol on the human-based 5-α-reductase phamacophores predicted that an additional aromatic ring should increase 5-α-reductase inhibition. Pharmacophores for α1A adrenoceptor antagonism, which were previously generated by Bremner et al, were utilized for the mapping of phenoxodiol. It was concluded that a basic nitrogen moiety was required for the introduction of α1A adrenoceptor antagonism. In the light of these findings, isoflavonoids derivatised at the 2- and 4- positions were designed and assessed on the pharmacophores. Isoflavene derivatives 70 and 67, which incorporated a basic nitrogen at the 2- and 4- positions respectively, were predicted to have α1A adrenoceptor antagonism. The synthetic targets which incorporated an additional aromatic group entailed the 5-methyl thienylisoflavene 71, the phenyl hydrazone 76 and the 2-thiazolyl isoflavene 77. In an attempt to integrate an increase of 5AR inhibition and α1A adrenoceptor antagonism, the target compound 78 was designed which encompasses both an extra aromatic moiety and a basic nitrogen. A new approach to 2-substituted isoflavene derivatives was developed based on nucleophilic attack on an isoflavylium salt. The isoflavylium salt intermediate was generated from a preformed isoflavene by hydride abstraction using a trityl salt. Eight derivatives were synthesized using this method. Eight 4-aryl hydrazone derivatives were synthesized by reacting an isoflavone with the appropriate aryl hydrazine. A number of other 4 substituted isoflavene derivatives were synthesised either by nucleophilic attack on the carbonyl of an isoflavone or by electrophilic addition to the enol tautomer of an isoflavone. A new rearrangement of a C-4 thienyl substituted isoflavanol to a benzo[b]furan system was discovered. Another new rearrangement involving the transformation of the imidazolylhydrazone 162 to the benzo[b]furan derivative 163 was also found. While nitrile precursors of targets incorporating basic amine groups were obtained, reduction to the amines was not successfully achieved. A human 5AR type I assay was developed sourcing LnCap cells for the enzyme. Unfortunately, LnCap cell line contamination occurred resulting in corruption of the assay. Compounds synthesised in this study were also tested for biological activity against a variety of cancer cell lines and a number of compounds with potent anti-cancer properties were identified. In particular the p-nitrophenylhydrazone 159d showed excellent growth inhibitory activity against the androgen dependent prostate cancer cell line and is a potential lead compound for further development. This result indicates that the 5AR pharmacophores generated are predictive.



Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.