Access Type

Open Access Dissertation

Date of Award

January 2018

Degree Type


Degree Name



Pharmaceutical Sciences

First Advisor

Zhihui Qin


Piperlongumine (PL) is an electrophilic anti-cancer natural product. Through non-covalent or covalent interactions with cellular targets, PL inactivates multiple oncogenic pathways and suppresses key components of cellular anti-oxidant/anti-electrophile defense systems. These actions result in pleiotropic anticancer effects and are expected to be effective to heterogeneous acute myeloid leukemia (AML) and prostate cancer (PCa). We applied two approaches to enhance the anticancer potency of PL: 1) To design PL-histone deacetylase inhibitor hybrid drugs (PL-HDACis; e.g., 1-58), and 2) To dimerize PL pharmacophore to generate a dimeric PL (DiPL) warhead that is suitable for further conjugation (e.g., 5-17). Both 1-58 and 5-17 were significantly more potent than PL in inhibiting AML or PCa cell proliferation and displayed broad anti-AML/anti-PCa activities in high-risk and treatment-resistant cell lines. In the PL-HDACi hybrid drugs, both PL and HDACi structural components are essential for cooperatively inducing significant DNA damage and apoptosis in AML cells: PL moiety interferes cellular GSH defense, and the HDACi functionality suppresses DNA repair and antiapoptotic pathways. The chemical reactivity of PL pharmacophore strongly affected potency and selectivity profiles. In PCa VCaP cells, compared to PL, dimeric PL derivatives (DiPLs) more potently inhibited VCaP cell growth without sacrificing selectivity, and more effectively downregulated expression of androgen receptor (AR) and AR splice variant 7 (AR-V7). Both growth inhibition and AR/AR-V7 downregulation were significantly enhanced by GSH synthesis inhibitor BSO, demonstrating the critical role of electrophilicity of DiPL in drug-caused cellular effects. In order to improve disease selectivity and drug bioavailability of the newly obtained HDACi hybrid drugs, H2O2/peroxynitrite (PNT)-activated hydroxamic acid HDACi prodrugs were designed. Model compounds Q-523 and Q-582 were activated in AML cells to release cytotoxic HDACis, evidenced by inducing acetylation markers and reducing viability of AML cells. Intracellular activation and anti-leukemic activities of prodrug were increased or decreased by ROS/PNT inducers and scavengers, respectively. Q-582 and Q-523 also enhanced the potency of chemotherapy drug cytarabine in AML cells, supporting the potentials of this prodrug class in combinatorial treatment. These prototype hybrid molecules, DiPLs and H2O2/PNT-activated HDACi prodrugs may serve as new leads for anticancer drug discovery.