Mechanisms of Orthogonal Photodecarbonylation Reactions of 3-Hydroxyflavone-Based Acid–Base Forms

Abstract

Carbon monoxide is a naturally occurring gasotransmitter combining inherent toxicity with a remarkable therapeutic potential and arduous administration. Photoactivatable carbon monoxide-releasing molecules (photoCORMs) are chemical agents that allow for precise spatial and temporal control over the CO release. In this work, we present a comprehensive mechanistic study of the photochemical CO release from 3-hydroxy-2-phenyl-4H-chromen-4-one, a π-extended 3-hydroxyflavone photoCORM, in methanol using steady-state and transient absorption spectroscopies and quantum chemical calculations. The multiplicity of the productive excited states and the role of oxygen (O2) in the CO production are emphasized, revealing a photoreaction dichotomy of the 3-hydroxyflavone acid and base forms. The utilization of three major orthogonal mechanistic pathways, all of which lead to the CO release, can fuel future endeavors to improve the CO release efficacy of 3-hydroxyflavone-based derivatives and refine their potential medical applications as photoCORMs.

Cyanine‐Flavonol Hybrids for Near‐Infrared Light‐Activated Delivery of Carbon Monoxide

“…[41] In our previous study,aneutral form of the parentf lavonol 1 was shown to be relativelyu nreactive towards singlet oxygen in methanolw ith ab imolecular rate constant k r of 4.3 10 5 m À1 s À1 . [29] The k r valuesf or 1 as well as for 14 B (see below) are in good agreement with those reported for analogous 3. [47] On the contrary,t he parent Cy7 scaffold 4 was found to be more reactive by nearly two orders of magnitude with k r of 1.7 10 7 m À1 s À1 ,t he same order of magnitude as those for heptamethine cyanines.…”

“…These resultss how that 5a-b can release in principlet wo molecules of CO from both flavonol moieties, correspondingt oa pproximately 65 %a nd 55 %y ields of CO per flavonol unit in methanol and PBS, respectively.T he chemicaly ield values obtainedi nb oth methanola nd aqueous solutions are slightly lower than those observed for the parent flavonol 1. [29] The majority of CO wasr eleased within 1-2 ho f irradiation (Figure 2d)a nd is related to the first photochemical process detectedb yU V/Vis spectroscopy ( Figure S57 in the Supporting Information). Under the given conditions, the therapeutic levels of CO (1 mm, [44] corresponding to % 25 %c hemical yield) were reached after about1 5min of irradiationa nd the total dose of light ( % 6.3 Wcm À2 )i sc omparable to doses routinelyused in PDT.…”

“…In our recent mechanistic study of parent flavonol 1,t wo orthogonal pathways of CO release were identified under aerobic conditions (Scheme 2). [29] Both the triplet excited state of acid 1A and ground state of base 1B can undergo decarbonylation. The former species reacts with ground-stateo xygen ( 3 O 2 ,p athway A), whereas the latter reacts with singlet oxygen ( 1 O 2 , pathway B).…”

“…The same thermalr eactivity of the ester was observed for the photoproducts of parent flavonol 1. [29] Ac omplex mixture of products is obtainedu pon exhaustive irradiation owing to the photodegradation of the cyanine scaffold ( Figure S63 in the Supporting Information). However,w ew ere able to detect some of the species formed by photooxidativec leavage of the cyanines caffold at the C2-C1' and C2-C3' positions ( Figure S65 in the Supporting Information), which is in excellent agreement with the extensive work of Schnermann and co-workers.…”

“…[28] Our recent mechanistic investigationo ft his system revealed the existence of three orthogonal pathways for the CO photorelease. [29] meso-CarboxyB ODIPY derivative 2 is currently the only organic photoCORM operating at the edge of ap hototherapeutic window (l max = 652 nm), but it suffers from al ow uncaging cross-section Fe max (Figure 1a,r ight). [30]…”