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A Structurally-Tunable 3-Hydroxyflavone Motif for Visible Light-Induced Carbon Monoxide-Releasing Molecules (CORMs).

Anderson SN, Richards JM, Esquer HJ, Benninghoff AD, Arif AM, Berreau LM - ChemistryOpen (2015)

Bottom Line: Molecules that can be used to deliver a controlled amount of carbon monoxide (CO) have the potential to facilitate investigations into the roles of this gaseous molecule in biology and advance therapeutic treatments.This has led to the development of light-induced CO-releasing molecules (photoCORMs).Herein, we report a new biologically-inspired organic photoCORM motif that exhibits several features that are desirable in a next-generation photoCORM.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry & Biochemistry, Utah State University 0300 Old Main Hill, Logan, UT, 84322-0300, USA.

ABSTRACT
Molecules that can be used to deliver a controlled amount of carbon monoxide (CO) have the potential to facilitate investigations into the roles of this gaseous molecule in biology and advance therapeutic treatments. This has led to the development of light-induced CO-releasing molecules (photoCORMs). A goal in this field of research is the development of molecules that exhibit a combination of controlled CO release, favorable biological properties (e.g., low toxicity and trackability in cells), and structural tunability to affect CO release. Herein, we report a new biologically-inspired organic photoCORM motif that exhibits several features that are desirable in a next-generation photoCORM. We show that 3-hydroxyflavone-based compounds are easily synthesized and modified to impart changes in absorption features and quantum yield for CO release, exhibit low toxicity, are trackable in cells, and can exhibit both O2-dependent and -independent CO release reactivity.

No MeSH data available.


Related in: MedlinePlus

Fluorescence microscopy images of human lung cancer (A549) cells treated with 4 for 1 h, then exposed to visible light (X-Cite 120 LED light source (Lumen Dynamics) with a 120 W lamp used at 18 % power (∼4×1016 photons s−1) and a 38HE filter) for a) 30 s, b) 3 min, and c) 10 min.18 Pictures represent overlay images for fluorescence detection of 4 (green) and the nuclear Hoechst stain (blue). Loss of fluorescence with increasing length of exposure to visible light is consistent with photoinduced CO release from 4. See Figure S12 in the Supporting Information for separate images of each detection channel and the complete field of view observed.
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fig03: Fluorescence microscopy images of human lung cancer (A549) cells treated with 4 for 1 h, then exposed to visible light (X-Cite 120 LED light source (Lumen Dynamics) with a 120 W lamp used at 18 % power (∼4×1016 photons s−1) and a 38HE filter) for a) 30 s, b) 3 min, and c) 10 min.18 Pictures represent overlay images for fluorescence detection of 4 (green) and the nuclear Hoechst stain (blue). Loss of fluorescence with increasing length of exposure to visible light is consistent with photoinduced CO release from 4. See Figure S12 in the Supporting Information for separate images of each detection channel and the complete field of view observed.

Mentions: Compound 4 exhibits several features that suggest that it could be a useful CO-release agent in biological systems. First, it exhibits minimal toxicity, as determined by MTT cell viability assays using A549 cells (IC50=41.5 μm; Figure S11 in the Supporting Information), and the organic product remaining following CO-release is nontoxic. Importantly, the fluorescent nature of 4 makes it trackable in cells prior to CO release. The cellular uptake properties of 4 were evaluated in A549 cells, which were exposed to Hoechst stain for 10 min (to enable visualization of nuclei), followed by incubation with 4 for 1 h in the dark. Fluorescence microscopy images of the cells were collected after 30 s, 3 min, and 10 min of visible light exposure (Figure 3; see also Figure S12 in the Supporting Information).18 The observed green emission at the first two time points provides evidence that 4 is taken up by almost all cells. The compound is not associated with the plasma membrane but is distributed throughout the cytoplasm and appears to concentrate around the nucleus. Importantly, continued exposure of the cells to visible light results in a decrease in the observed green fluorescence of the compound after 3 min, with complete loss after 10 min. This observation provides strong evidence for the photoinduced cleavage of the 3-hydroxy-4-pyrone ring and CO-release reactivity within the cell as the photoproduct does not display any emission. It should be noted that use of the intracellular CO Probe 1 (COP-1) is not feasible in this system because the emission of 4, which disappears upon CO release, overlaps with the emission feature of CO-incorporated COP-1.19


A Structurally-Tunable 3-Hydroxyflavone Motif for Visible Light-Induced Carbon Monoxide-Releasing Molecules (CORMs).

Anderson SN, Richards JM, Esquer HJ, Benninghoff AD, Arif AM, Berreau LM - ChemistryOpen (2015)

Fluorescence microscopy images of human lung cancer (A549) cells treated with 4 for 1 h, then exposed to visible light (X-Cite 120 LED light source (Lumen Dynamics) with a 120 W lamp used at 18 % power (∼4×1016 photons s−1) and a 38HE filter) for a) 30 s, b) 3 min, and c) 10 min.18 Pictures represent overlay images for fluorescence detection of 4 (green) and the nuclear Hoechst stain (blue). Loss of fluorescence with increasing length of exposure to visible light is consistent with photoinduced CO release from 4. See Figure S12 in the Supporting Information for separate images of each detection channel and the complete field of view observed.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608525&req=5

fig03: Fluorescence microscopy images of human lung cancer (A549) cells treated with 4 for 1 h, then exposed to visible light (X-Cite 120 LED light source (Lumen Dynamics) with a 120 W lamp used at 18 % power (∼4×1016 photons s−1) and a 38HE filter) for a) 30 s, b) 3 min, and c) 10 min.18 Pictures represent overlay images for fluorescence detection of 4 (green) and the nuclear Hoechst stain (blue). Loss of fluorescence with increasing length of exposure to visible light is consistent with photoinduced CO release from 4. See Figure S12 in the Supporting Information for separate images of each detection channel and the complete field of view observed.
Mentions: Compound 4 exhibits several features that suggest that it could be a useful CO-release agent in biological systems. First, it exhibits minimal toxicity, as determined by MTT cell viability assays using A549 cells (IC50=41.5 μm; Figure S11 in the Supporting Information), and the organic product remaining following CO-release is nontoxic. Importantly, the fluorescent nature of 4 makes it trackable in cells prior to CO release. The cellular uptake properties of 4 were evaluated in A549 cells, which were exposed to Hoechst stain for 10 min (to enable visualization of nuclei), followed by incubation with 4 for 1 h in the dark. Fluorescence microscopy images of the cells were collected after 30 s, 3 min, and 10 min of visible light exposure (Figure 3; see also Figure S12 in the Supporting Information).18 The observed green emission at the first two time points provides evidence that 4 is taken up by almost all cells. The compound is not associated with the plasma membrane but is distributed throughout the cytoplasm and appears to concentrate around the nucleus. Importantly, continued exposure of the cells to visible light results in a decrease in the observed green fluorescence of the compound after 3 min, with complete loss after 10 min. This observation provides strong evidence for the photoinduced cleavage of the 3-hydroxy-4-pyrone ring and CO-release reactivity within the cell as the photoproduct does not display any emission. It should be noted that use of the intracellular CO Probe 1 (COP-1) is not feasible in this system because the emission of 4, which disappears upon CO release, overlaps with the emission feature of CO-incorporated COP-1.19

Bottom Line: Molecules that can be used to deliver a controlled amount of carbon monoxide (CO) have the potential to facilitate investigations into the roles of this gaseous molecule in biology and advance therapeutic treatments.This has led to the development of light-induced CO-releasing molecules (photoCORMs).Herein, we report a new biologically-inspired organic photoCORM motif that exhibits several features that are desirable in a next-generation photoCORM.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry & Biochemistry, Utah State University 0300 Old Main Hill, Logan, UT, 84322-0300, USA.

ABSTRACT
Molecules that can be used to deliver a controlled amount of carbon monoxide (CO) have the potential to facilitate investigations into the roles of this gaseous molecule in biology and advance therapeutic treatments. This has led to the development of light-induced CO-releasing molecules (photoCORMs). A goal in this field of research is the development of molecules that exhibit a combination of controlled CO release, favorable biological properties (e.g., low toxicity and trackability in cells), and structural tunability to affect CO release. Herein, we report a new biologically-inspired organic photoCORM motif that exhibits several features that are desirable in a next-generation photoCORM. We show that 3-hydroxyflavone-based compounds are easily synthesized and modified to impart changes in absorption features and quantum yield for CO release, exhibit low toxicity, are trackable in cells, and can exhibit both O2-dependent and -independent CO release reactivity.

No MeSH data available.


Related in: MedlinePlus