Abstract17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed at high levels in the testes and seminal vesicles but has also been shown to be present in prostate tissue, suggesting its potential involvement in both gonadal and non-gonadal testosterone biosynthesis. The role of 17β-HSD3 in testosterone biosynthesis makes this enzyme an attractive molecular target for inhibition by small molecule inhibitors for the treatment of prostate cancer.Here we report the design of selective inhibitors of 17β-HSD3 as potential anti-cancer agents.Due to 17β-HSD3 being a membrane-bound protein a crystal structure is not yet available. A homology model of 17β-HSD3 has been built to aid structure-based drug design. This model has been used with docking studies to identify a series of lead compounds that may give an insight as to how inhibitors interact with the active site. Compound 1 was identified as a potent selective inhibitor of 17β-HSD3 with an IC 50 = 700 nM resulting in the discovery of a novel lead series for further optimization. Using our homology model as a tool for inhibitor design compound 5 was discovered as a novel potent and selective inhibitor of 17β-HSD3 with an IC 50 ~ 200 nM.

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A microwave‐based methodology facilitates reaction of 2‐aminophenylketones with cyclic ketones to form a quinoline scaffold. Syntheses of amido‐ and amino‐linked 17β‐hydroxysteroid dehydrogenase type 3 inhibitors with a benzophenone‐linked motif were pursued using 2‐aminobenzophenone as building block. Two amido‐linked targets were achieved in modest yield, but when using microwave‐assisted reductive amination for the amino‐linked counterparts an unexpected product was observed. X‐ray crystallography revealed it as a quinoline derivative, leading to optimisation of a simple and efficient modification of Friedländer methodology. Using reagents and acetic acid catalyst in organic solvent the unassisted reaction proceeds only over several days and in very poor yield. However, by employing neat acetic acid as both solvent and acid catalyst with microwave irradiation at 160 °C quinoline synthesis is achieved in 5 minutes in excellent yield. This has advantages over the previously reported high temperatures or strong acids required, not least given the green credentials of acetic acid, and examples using diverse ketones illustrate applicability. Additionally, the unassisted reaction proceeds effectively at room temperature, albeit much more slowly.

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Using microwave technology, a new protocol has been developed that improves the reaction rate and overall efficiency of the direct reductive amination of ketones with anilines. When using sodium triacetoxyborohydride as the reducing agent, high product yields and increased reaction rates are achieved for a variety of electronically different anilines. Furthermore, we have found that this protocol can also be applied to aldehydes.