Visible-Light-Activated Quinolone Carbon-Monoxide-Releasing Molecule: Prodrug and Albumin-Assisted Delivery Enables Anticancer and Potent Anti-Inflammatory Effects

Document Type

Article

Journal/Book Title

Journal of the American Chemical Society

Publication Date

8-1-2018

Publisher

American Chemical Society

Award Number

NIH 1R15GM124596-01; NSF, Division of Chemistry (CHE) 1301092; NSF, Division of Chemistry (CHE) 1429195; Utah Agricultural Experiment Station UTA-1178; Utah State University Office of Research and Graduate Studies PDRF Fellowship

Funder

NIH; NSF, Division of Chemistry (CHE); Utah Agricultural Experiment Station; Utah State University Office of Research and Graduate Studies

Volume

140

Issue

30

First Page

9721

Last Page

9729

Abstract

The delivery of controlled amounts of carbon monoxide (CO) to biological targets is of significant current interest. Very few CO-releasing compounds are currently known that can be rigorously controlled in terms of the location and amount of CO released. To address this deficiency, we report herein a new metal-free, visible-light-induced CO-releasing molecule (photoCORM) and its prodrug oxidized form, which offer new approaches to controlled, localized CO delivery. The new photoCORM, based on a 3-hydroxybenzo[ g]quinolone framework, releases 1 equiv of CO upon visible-light illumination under a variety of biologically relevant conditions. This nontoxic compound can be tracked prior to CO release using fluorescence microscopy and produces a nontoxic byproduct following CO release. An oxidized prodrug form of the photoCORM is reduced by cellular thiols, providing an approach toward activation in the reducing environment of cancer cells. Strong noncovalent affinity of the nonmetal photoCORM to albumin enables use of an albumin:photoCORM complex for targeted CO delivery to cancer cells. This approach produced cytotoxicity IC50 values among the lowest reported to date for CO delivery to cancer cells by a photoCORM. This albumin:photoCORM complex is also the first CO delivery system to produce significant anti-inflammatory effects when introduced at nanomolar photoCORM concentration.

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