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

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.