Synthesis of novel compounds with potential antiandrogen activity

Prostate cancer (PCa) is a major public health problem worldwide. It is estimated that it is the second common malignant neoplasm among men representing 13.5% of all the cancers diagnosed in men worldwide. Several therapies of metastatic PCa are based on the inhibition of the androgen receptor (AR) which is the key regulator of the prostate cancer cell growth.

The AR is activated by androgens like testosterone and 5α–dihydrotestosterone (DHT) and it is the key transcription factor both in healthy prostate function and neoplastic transformation. Antiandrogens or AR antagonists are compounds that interfere in the biological effects of androgens by binding to the AR and inhibiting its functioning. The antagonists that are currently used in the clinic have relatively low affinities for the AR and also evoke resistance. Therefore, it is of paramount importance to develop more potent AR antagonists and also antagonists useful in resistant PCa.

In the research group of Prof. Claessens, as a result of screening a collection of commercially available compounds, the MEL-6 compound was identified as having potential antiandrogen activity and was earmarked for further investigation. Unfortunately, the commercial suppliers did not include information on the stereochemistry of MEL-6. Indeed, preliminary research in our group showed that the activity of the (resynthesized) MEL-6.2 analogue was due to only one of the 4 possible (dia)stereoisomers, the other ones being inactive. The synthesis of this compound was only possible at small scale and the absolute configuration still remains to be determined. Moreover, an in vitro assay using mouse liver microsomes, determined the half-life to be only 4 minutes Thus, the development of metabolically more stable derivatives is the major priority, before embarking in more laborious and expensive preclinical and clinical trials.

For that reason, we planned and prepared three libraries of novel compounds which have been tested for their antiandrogen activity.

A first class of compounds similar to MEL-6 was obtained via two distinct synthetic pathways. In a first approach, the nitroalkene derivative underwent Michael addition from the N-substituted piperazine followed by reduction of the nitro group and acylation to yield the MEL-6 analogue. In a second approach, we proposed the oxidative amination of substituted phenylacetone with N-substituted piperazine and then conversion of the carbonyl group to the oxime moiety followed by reduction and acylation. The two different strategies led to the formation of the active and inactive against prostate cancer MEL-6 analogues which were subjected to in vitro and metabolic studies.

As an alternative class of compounds, we wanted to introduce the 1,2,3-triazole ring which is considered a bioisoster of the amide group. We used our newly developed multicomponent strategy to access fused bicyclic 1,2,3-triazole derivatives from enolizable ketone, primary amines and 4-nitrophenyl azide. The compounds have been tested for their antiandrogen activity. However, in vitro evaluation on ClARE cells showed that none but one compound exhibits moderate AR inhibitory activity. Nevertheless, the triazolo fused derivatives were submitted for general antiviral and anticancer screening. Indeed, some compounds show promising antiviral properties against Coronavirus 229E.

As a variant, we wanted to prepare N-connected triazoles from a homochiral propane-1,3-diamine building block based on the organocatalytic reactions developed in our group. We succeeded in obtaining a small library of bis-1,2,3-tiazoles which were submitted for biological evaluation.