Date of Completion

1-9-2018

Embargo Period

1-9-2018

Major Advisor

M. Kyle Hadden

Associate Advisor

Diane J. Burgess

Associate Advisor

Marcy J. Balunas

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Recently, two separate high-throughput screens (HTS) identified itraconazole (ITZ), a well-known antifungal agent, as both an inhibitor of the hedgehog (Hh) pathway and angiogenesis (IC50 = 690 nM and 160 nM, respectively). Dysregulation of both the Hh pathway and angiogenesis are implemented in the growth and metastasis of various types of cancer. Aberrant Hh signaling may lead to cell proliferation and tumor growth most notably associated with basal cell carcinoma (BCC) and medulloblastoma (MB). Currently, there are a few Hh pathway inhibitors that are FDA approved for the treatment of BCC. However, there has been an emergence of resistance towards these compounds highlighting the need for novel Hh pathway inhibitors. The ITZ scaffold has not been thoroughly explored in terms of Hh pathway inhibition. As a result, four generations of ITZ analogues were designed, synthesized, and evaluated for Hh pathway inhibitory activity. Structure-activity relationship (SAR) studies indicated that the triazole moiety is not necessary for potent Hh pathway inhibition and removal of this functionality also abolishes coordination with CYP3A4. While the stereochemistry of the sec-butyl side chain region was not important, stereochemistry at the 4-position of the dioxolane ring proved to be crucial. In terms of the triazolone/side-chain region of the scaffold, truncation of the side-chain region to the free triazolone and truncation of the triazolone to smaller moieties (–NO2 and –NH2) maintain potency. Amide functionality in replacement of the triazolone/side-chain region is tolerated with preference to polar substituents at the meta- position of the phenyl ring. Early evidence suggests that cyclic functionality is not necessary within the triazolone region indicating that acyclic functionalities could be explored for Hh pathway inhibitory activity. A subset of ITZ analogues was evaluated in two additional assays to explore angiogenesis inhibitory activity. Results indicated that the triazole region of ITZ seems to be important for angiogenesis inhibition. Overall, a total of 60 analogues were designed, synthesized, and evaluated to thoroughly explore the ITZ scaffold in terms of these novel biological activities. In addition to these medicinal chemistry efforts, a preliminary ITZ liposome formulation was designed and evaluated in vitro for Hh pathway inhibition.

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