Access Type

Open Access Thesis

Date of Award

January 2016

Degree Type


Degree Name



Pharmaceutical Sciences

First Advisor

Zhihui Qin


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.