Structure–Photoreactivity Relationship of 3-Hydroxyflavone-Based CO-Releasing Molecules

Abstract

Carbon monoxide (CO) is an endogenous signaling molecule that regulates diverse physiological processes. The therapeutic potential of CO is hampered by its intrinsic toxicity, and its administration poses a significant challenge. Photoactivatable CO-releasing molecules (photoCORMs) are an excellent tool to overcome the side effects of untargeted CO administration and provide precise spatial and temporal control over its release. Here, we studied the CO release mechanism of a small library of derivatives based on 3-hydroxy-2-phenyl-4H-benzo[g]chromen-4-one (flavonol), previously developed as an efficient photo-CORM, by steady-state and femto/nanosecond transient absorption spectroscopies. The main objectives of the work were to explore in detail how to enhance the efficiency of CO photorelease from flavonols, bathochromically shift their absorption bands, control their acid−base properties and solubilities in aqueous solutions, and minimize primary or secondary photochemical side-reactions, such as self-photooxygenation. The best photoCORM performance was achieved by combining substituents, which simultaneously bathochromically shift the chromophore absorption spectrum, enhance the formation of the productive triplet state, and suppress the singlet oxygen production by shortening flavonol triplet-state lifetimes. In addition, the cell toxicity of selected flavonol compounds was analyzed using in vitro hepatic HepG2 cells.

Cyanine–flavonol hybrids as NIR-light activatable carbon monoxide donors in methanol and aqueous solutions

“…All studied compounds exist predominantly as conjugate acids (the flavonol hydroxyl group) in methanol, as evaluated by the changes in their absorption spectra. 7 Therefore, the major decarbonylation mechanism must be the reaction of tripletexcited compounds with 3 O 2 (path A, 14 Scheme 1), as also observed for hybrids 1. 11 The photochemistry of all studied derivatives was largely suppressed in degassed methanol solutions (Fig.…”

“…3,4 Enzymatically or solvent-mediated CO liberation from these systems can advantageously be replaced by a spatially and temporally more precise process using photoactivatable CORMs (photoCORMs). 5 Several transition-metal-free photoCORMs absorbing biologically benign visible and near-infrared (NIR) light have been developed, [6][7][8][9] although photochemical initiation of chemical processes, especially by substantially less energetic photons within the tissue-transparent (phototherapeutic) window (650-900 nm), 10 is still challenging. So far, only two examples of organic photoCORMs initiated in this wavelength range have been reported.…”

“…The reactions involve the triplet-excited state of flavonol and ground-state oxygen (path A, red) or ground-state flavonol and singlet oxygen ( 1 O 2 ; path B, blue), formed by flavonol photosensitization (Scheme 1). 7,14 In this work, we designed and synthesized six cyanineflavonol hybrid photoCORMs 3-8 bearing different substituents (Scheme 2) to enhance their optical and photochemical properties and solubilities in aqueous solutions. A host-guest interaction of hybrids with cucurbit [7]uril to suppress their aggregation and increase water solubilities was also examined.…”

“…7,14 In this work, we designed and synthesized six cyanineflavonol hybrid photoCORMs 3-8 bearing different substituents (Scheme 2) to enhance their optical and photochemical properties and solubilities in aqueous solutions. A host-guest interaction of hybrids with cucurbit [7]uril to suppress their aggregation and increase water solubilities was also examined. In addition, biocompatibility and cell penetrability of selected compounds were investigated.…”

“…While an electron-withdrawing 2-phenyl ammonium substituent (R 2 ) in 3, 5, 6, and 7 does not affect the absorption band positions compared to that of unsubstituted 4, an electron-donating dimethylamino group in 8 is responsible for a bathochromic shift of B60 nm thanks to excited-state internal charge transfer (ESICT). 7,17 Despite the highly polar substituents, some derivatives (5, 7, and 8) still exhibited a rather poor solubility in polar protic solvents; therefore, the initial evaluation of their physicochemical properties was carried out in methanol containing specific amounts of DMSO (Table 1). None of the compounds showed aggregation in methanol at spectroscopic concentrations (Fig.…”