Sense and Release: A Thiol-Responsive Flavonol-Based Photonically Driven Carbon Monoxide-Releasing Molecule That Operates via a Multiple-Input AND Logic Gate

Abstract

Molecular structures capable of intracellular information processing that couple responses from biomarker signals to the release of drug molecules represent intelligent delivery systems. Herein we report a chemophotonically driven, sense-of-logic carbon monoxide-releasing molecule (SL-photoCORM). This extended flavonol motif operates via an AND logic gate by first sensing the cellular environment via detection of thiols and then releasing CO when triggered with visible light and O. Overall, this approach couples the detection of a cellular redox biomarker with the ability to release a small-molecule gasotransmitter known to trigger pathways involved in pro- and anti-inflammatory effects in a dose-dependent manner. Significantly, the fluorescence properties of the flavonol-based SL-photoCORM produce a series of chemophotonic input responses via two photochromatic switches (blue-to-green and green-to-colorless), leading to trackability and spatiotemporal control of CO release. Examination of the O requirements of the CO release step revealed that the SL-photoCORM is suitable for use under conditions of variable cellular levels of O. These combined properties within a single-molecular framework advance the field of CO-releasing molecules by providing feedback on the diversity and complexity of the cellular environment prior to CO release.

Tracking CO Release in Cells via the Luminescence of Donor Molecules and/or their By‐Products

“…This novel framework exhibits several advantageous features for the delivery of CO in biological environments. These include: (1) a clean, quantitative visible light‐driven CO release reaction that occurs in both protic and hydrophobic environments, and under atmospheric levels of O 2 (18 %) and hypoxic (1 % O 2 ) conditions;, (2) green fluorescence prior to CO release (Figure ) that enables monitoring of cellular uptake and distribution prior to CO release; and (3) a well‐defined, non‐toxic and non‐emissive organic by‐product (19, Figure ). Recently, 18 was also shown to undergo CO release using two‐photon excitation .…”

“…The 3‐hydroxyflavone and 3‐hydroxyquinolone photoCORM motifs are easily modified structures that can be customized for a variety of applications involving trackable CO delivery. These include sense and release applications wherein the CO‐releasing 3‐OH unit in 18 is unmasked for CO release only in the presence of a specific bioanalyte ,,…”

“…These include sense and release applications wherein the CO-releasing 3-OH unit in 18 is unmasked for CO release only in the presence of a specific bioanalyte. [32,33,35]…”

An H2S‐Sensing/CO‐Releasing Flavonol That Operates via Logic Gates

“…[21,22] In this area we recently reported a thiol-sensing flavonol-based CO-releasing molecule (CORM) that operates via a multiple input AND logic gate ( 1 , Scheme 1(top)). [22] This molecule enables the sequential sensing of a cellular redox biomarker followed by visible light- and O 2 -triggered release of the gasotransmitter CO.…”

“…[21,22] In this area we recently reported a thiol-sensing flavonol-based CO-releasing molecule (CORM) that operates via a multiple input AND logic gate ( 1 , Scheme 1(top)). [22] This molecule enables the sequential sensing of a cellular redox biomarker followed by visible light- and O 2 -triggered release of the gasotransmitter CO. Importantly, the fluorescence responses associated with each step of this sequence represent a series of chemophotonic switches (blue-to-green) by which this intracellular reactivity can be tracked, thus enabling spatiotemporal control of CO release.…”