Open Access Thesis
Date of Award
Isothiocyanate (ITC), such as sulforaphane (SFN), is an active metabolite of dietary glucosinolate from cruciferous vegetables. SFN-rich extracts have been recently tested in recurrent prostate cancer (PCa) patients and notably prolonged PSA doubling time without Grade 3 adverse events. One of the anti-PCa mechanisms of SFN is to inhibit HDAC6, which further triggering androgen receptor (AR) degradation. We have incorporated ITC to the chemical scaffold of enzalutamide (Enz) to create Enz-ITC hybrid molecules with an intention to intracellularly deliver ITC to AR-Hsp90-HDAC6 complex and therefore improving anti-PCa efficacy of both parental drugs. Two Enz-ITCs and one Enz-ITC N-acetyl cysteine (NAC) conjugate, i.e. compound 12b (C6-ITC), 12a (C4-ITC) and 13 (C6-NAC) were successfully synthesized. Our results support that Enz-ITCs inhibit AR transcriptional activity, induce AR protein down-regulation (more effective than SFN) and suppress proliferation of both androgen-sensitive and insensitive prostate cancer cells. The AR antagonist activity of Enz-ITC was confirmed by the results of MTT and ARE-luciferase assays. We’ve also synthesized amide analogue of Enz-ITC 19 with reduced AR affinity while keeps the activity of ITC for future mechanistic studies. As a relevant strategy to study AR-directed HDAC inhibition, a representative Enz-HDAC inhibitor (HDACi) hybrid, compound 1005 was synthesized. 1005 and its prodrug 29 suppressed proliferation of both androgen-sensitive and insensitive prostate cancer cells.
Ou, Siyu, "Design And Synthesis Of Enzalutamide-Isothiocyanate Hybrid Drug As Anti-Prostate Cancer Agent" (2016). Wayne State University Theses. 498.