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Golec, Daniel

University of British Columbia

All current hormone therapies for prostate cancer (PC), including metastatic castration-resistant prostate cancer (mCRPC), target the androgen receptor (AR). The most effective treatments for mCRPC target the C-terminal ligand-binding domain (LBD) of the AR, which ultimately fail with resumed transcriptional activity. Another target, the AR N-terminal domain (NTD) contains activation function-1 (AF-1), which is essential for AR transcriptional activity. Blocking the AR AF-1 has the potential to by-pass AR-resistance mechanisms, including constitutively active AR splice variants (AR-V) that lack the LBD. New anti-androgen drug classes, ralaniten and sintokamides, have been shown to directly interact with the AR AF-1. Fluorination of the bisphenol-A (BPA) bridge allows for a flexible drug design imparting hydrophilicity without compromising the active drug. Synthesis and biological evaluation of fluorinated ralaniten analogs, BU-86 (2.24), BU-87 (2.25), was undertaken in order to investigate the activity of the chlorohydrin side-chain and whether or not the secondary hydroxyl group is necessary for active site drug binding. Fluorinated ralaniten ketone, BU-88 (2.26), and its potential degradation product, BU-89 (2.33), were investigated as the ketone functionality has the potential for reversible covalent binding. However, its chemical and metabolic stability is questionable, despite clear signs of potency in vivo. Sterically hindered tertiary alcohol analogs BU-130 (2.45), and BU-170 (2.46), were investigated by introducing a methylated glycidol ether in the hope of achieving greater metabolic stability at no cost to potency. This modification is possible due to the enhanced solubility of bridge fluorinated BPA. Sintokamide analogs LPY37 (3.41) and LPY36 (3.42) have previously been shown to inhibit transcription by splice variant driven PC cell lines in vitro, reducing the expression of prostate specific antigen (PSA). In order to study them further in an animal model, a scaled-up synthesis was required. In order to have a more soluble sintokamide inspired drug, LPY80 (3.51) and LPY39 (3.52) were tested. The evaluation of the most potent ralaniten analog, BU-170 (2.46) and the most potent sintokamide analog LPY36 (3.42) in combination with enzalutamide is ongoing. These AR-NTD antagonists provide new insights into a novel therapy for the treatment of CRPC.

Text

2024-03-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/81091

Chemistry

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/