Access Type

Open Access Thesis

Date of Award

January 2017

Degree Type

Thesis

Degree Name

M.S.

Department

Chemistry

First Advisor

Jeremy J. Kodanko

Abstract

Abstract

DESIGN, SYNTHESIS AND ANALYSIS OF POTENTIAL PHOTO-ACTIVATABLE CATHEPSIN K INHIBITORS

by

KHALIN NISBETT

May 2017

Advisor: Dr. Jeremy Kodanko

Major: Chemistry

Degree: Master of Science

Tightly regulated cysteine CA proteases play a major role in maintaining the homeostasis within cells. Subsequently, when these proteases are dysregulated and mislocalized they disrupt healthy cell dynamics and contribute to many life-threatening pathologies such arteriosclerosis, osteoporosis and cancer. As such many pharmaceutical companies and research teams are highly interested in these proteases as targets. One emergent strategy is the spatiotemporal control of biological processes. In relation to this, a series of spatiotemporally controlled inhibitors of CA proteases are being developed by the Kodanko Lab. This thesis describes the investigation of two new cathepsin K (CST-K) inhibitor derivatives and a new RuII-inhibitor binding protocol.

With regards to the free inhibitor derivatives, increased basicity at P2 and P3 decreased the efficacy of the inhibitors. Also, described herein is the successful caging and photo-release of one of the dipeptide nitrile inhibitors. The new RuII chaperone ([RuII])–inhibitor binding protocol is aimed at increasing the stability of RuII-inhibitor complexes in cell growth media. The investigation has revealed the drawbacks of the new binding protocol. Spatiotemporal control over protein inhibition was ineffective as a result of the promiscuity of the CST-K active site and the terminal and unshielded position of the warhead. It became clear that the warhead of the inhibitor must be sufficiently hindered when caged to produce a substantial dark/light IC50 ratio (DLIR). This work is expected to improve the conceptualization of future investigations.

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