Synthesis of Toward a HDACi-Synthesis of Toward a HDACi-ARi Hybrid Prodrug and The Potential of Histone-Deacetylase Inhibitor Prodrugs for Therapeutic Treatment
Vallan, Madison E.
Prostate cancer is the second most lethal cancer in American men and is most commonly found in men over the age of 50 years old1. Androgen deprivation therapy and chemotherapy are the primary therapeutic treatment options for prostate cancer. Though, when the cancer reaches the aggressive castration-resistant form, the cells become capable of growing and dividing via the ignition of the Androgen Receptor (AR) signaling pathways despite the lack of extracellular ligands triggering intracellular enzymatic cascades. In a previous study, a hybrid compound containing the AR inhibitor, Enzalutamide, and the HDAC inhibitor, Suberoylanilide Hydroxamic Acid (SAHA), was synthesized and tested in prostate cancer tumors, showing excellent antitumor characteristics2. Therefore, a histone deacetylase inhibitor-androgen receptor inhibitor (HDACi-ARi) hybrid prodrug is proposed with the aim of effectively preventing the AR-induced cell proliferation, while simultaneously minimizing unwanted side effects of the anti-cancer agent. A boronic acid was added to the compound as a prodrug with the aim to reduce unwanted side effects, increase metabolic stability, and target the drug directly to the diseased cells. Steps towards the synthesis of the drug were achieved and efforts are being made to improve the the synthetic route of the secondary intermediate. It was found that shorter reaction with high equivalence of methyl hydrazine proved most successful, but due to the high amount of impurities, other methods of synthesis are being investigated. Further, a brief review of HDAC inhibitor prodrug compounds in relation to other diseases such as Alzheimer’s Disease, Huntington’s Disease, Parkinson’s Disease, and Cerebral Ischemia is explored looking at cellular triggers and possible prodrug moieties for the neurological diseases.
vii, 30 p.
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