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Targeting Prostate Cancer Cells by Combined Oxidative Stress Induction and Androgen Receptor Antagonism

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Technical Report,01 Aug 2014,21 Jul 2015

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Wayne State University Detroit United States

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Efficient synthetic routes were developed for the synthesis of Enzalutamide Enz, MDV-3100 and EPI-001 derived hybrid drugs that target AR C-terminal ligand binding domain or N-terminal domain meanwhile inducing oxidative stress. Five classes of hybrid drugs have been designed and synthesized, i.e. Enz-PL e.g. compd 28, Enz-catechol e.g., compds 29, 30, Enz-HDACi e.g., compds 24, 31, 33, chirally pure EPI scaffold carrying alternative electrophiles i.e. compds 53, 55, 58 and 60. Biological assays, e.g., anti-proliferation assay, AR luciferase reporter assay and visualization of AR distribution in human prostate stromal cells were successfully established in collaborators lab and will be used to study novel multifunctional hybrid drugs. Effects of Enz and piperlongumine PL on LAPC4 cell proliferation were also investigated, both compounds inhibited R1881-induced cell proliferation at 10 M but not at 1 M in single drug treatment. After 72h treatment, Enz 10 M and PL 10 M combination significantly inhibited LAPC4 cell growth compared to Enz treatment alone, the inhibitory effect was also stronger than PL single treatment, but was not statistically significant. Further experiments using combinations with different doses will be conducted. It would be straightforward to expand hybrid drugdrug combination libraries and to conduct structure-activity relationship studies based on current accomplishments.

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