Herein, we describe the design and synthesis of novel inhibitors of 17β-hydroxysteroid dehydrogenase type 3 which converts androstenedione into testosterone, which is then converted into dihydrotestosterone (DHT). This isozyme has been implicated in the growth of prostate cancer, which is stimulated by the presence of DHT. Using an in silico pharmacophore model based upon established activity, initial targets were planned, based around a diphenylether hydrophobic head linked to a 4-substituted piperidine ring. Over 45 compounds were synthesised and many show significant biological activity when evaluated in a 17β-HSD Type 3 biological assay. The most potent compound in this series is 1-(4-[2-(4-chloro-phenoxy)-phenylamino]-piperidin1-yl)-ethanone (101) with an IC50 of 700 nM. The amine linked compounds are significantly more active than the amide equivalents. Synthesis of the amine-linked compounds was problematic and led to the development of a novel and general microwave assisted procedure for the reductive amination of anilines, enabling aromatic amine-linked compounds to be synthesised in excellent yields. A series of benzylamine linked inhibitors was also prepared. Over 30 analogues were synthesised and several show very promising biological activity. The most active compound is N-(2-([2-(4-chloro-phenoxy)-phenylamino]-methyl)-phenyl)-acetamide (126), which exhibits an IC50 of 900 nM. Effects of chirality were also explored. The enantiomers of N-(2-(1-[2-(4-chloro-phenoxy)-phenylamino]-but-2-enyl)-phenyl)- acetamide (172) were separated by chiral HPLC and X-ray crystallography was used to determine the absolute configuration. These individual enantiomers and many other novel inhibitors are awaiting biological evaluation. The synthesis of compounds with a benzophenone linked hydrophobic head group led to an unexpected product. X-ray crystallography was used to determine the structure, as a quinoline derivative. This led to optimisation of a novel modification of the Friedländer synthesis of quinolines. The potent inhibitors synthesised are selective over 17β-HSD Types 1 and 2. One inhibitor (165) also shows potentially interesting activity against the leukaemia cell line CCRF-CEM, in the NCI screening, with a GI50 of 10 nM.
|Date of Award||1 Nov 2007|
|Supervisor||Barry Potter (Supervisor) & Nigel Vicker (Supervisor)|
- enzyme inhibitors
- hydroxysteroid dehydrogenase
- medicinal chemistry