Structure–Activity Relationships for the Marine Natural Product Sintokamides: Androgen Receptor N-Terminus Antagonists of Interest for Treatment of Metastatic Castration-Resistant Prostate Cancer

Abstract

Synthetic analogues of the marine natural product sintokamides have been prepared in order to investigate the structure–activity relationships for the androgen receptor N-terminal domain (AR NTD) antagonist activity of the sintokamide scaffold. An in vitro LNCaP cell-based transcriptional activity assay with an androgen-driven luciferase (Luc) reporter was used to monitor the potency of analogues. The data have shown that the chlorine atoms on the leucine side chains are essential for potent activity. Analogues missing the nonchlorinated methyl groups of the leucine side chains (C-1 and C-17) are just as active and in some cases more active than the natural products. Analogues with the natural R configuration at C-10 and the unnatural R configuration at C-4 are most potent. Replacing the natural propionamide N-terminus cap with the more sterically hindered pivaloylamide N-terminus cap leads to enhanced potency. The tetramic acid fragment and the methyl ether on the tetramic acid fragment are essential for activity. The SAR optimized analogue 76 is more selective, easier to synthesize, more potent, and presumed to be more resistant to proteolysis than the natural sintokamides.

A chemical probe for BAG1 targets androgen receptor-positive prostate cancer through oxidative stress signaling pathway

“…A number of advances have already been made in recent years in the development of such inhibitors. For example, there are inhibitors that bind directly to the AR NTD to inhibit AR action ( DeMol et al., 2016 ; Yan et al., 2021 ), others cause proteasomal degradation of both the full-length AR and AR-Vs ( Ponnusamy et al., 2017 , 2019 ), or bind AR coregulators to inhibit AR action and AR-positive PCa growth ( Jin et al., 2017 ; Welti et al., 2021 ). However, none of these new compounds has been clinically approved, although a few are in clinical trials.…”

Bifunctional Doscadenamides Activate Quorum Sensing in Gram-Negative Bacteria and Synergize with TRAIL to Induce Apoptosis in Cancer Cells

“…To further diversify the doscadenamide family, structurally and functionally, we have developed a robust scheme to synthesize different structural and configurational doscadenamide analogues, including different degrees of unsaturation ( 1k – n , 2a – b , 3a – c ). Notably, a related pyrrolinone core with two different pendant side chains is also the scaffold of the sponge-derived sintokamides, and natural and synthetic diversification has been reported , for this class of natural products.…”

Current and emerging approaches to noncompetitive AR inhibition

“…Recently, Sadar and Anderson explored the SAR surrounding the sintokamide pharmacophore, using a PSA‐luciferase assay to tune the potency 106 . It was established that transcriptional inhibition was proportional to the number of chlorine atoms present within the scaffold.…”

“…105 Recently, Sadar and Anderson explored the SAR surrounding the sintokamide pharmacophore, using a PSAluciferase assay to tune the potency. 106 It was established that transcriptional inhibition was proportional to the number of chlorine atoms present within the scaffold. Another modification was the replacement of the propionamide moiety at the N-terminus with a bulkier, more lipophilic N-pivaloyl group to afford the more potent synthetic analog LPY36 (Figure 15A).…”