Assessment of Photoreleasable Linkers and Light-Capturing Antennas on a Photoresponsive Cobalamin Scaffold

Abstract

Cobalamin has shown promise as a light-sensitive drug delivery platform owing to its ease of modification and the high quantum yields for drug photorelease. However, studies to date on the general photochemistry of alkyl cobalamins have primarily focused on methyl and adenosyl-substituted derivatives, the natural cofactors present in various enzymatic species. We describe the synthesis and photolytic behavior of cobalamin conjugates comprised of different combinations of fluorophores and β-axial ligands. In general, cobalamin conjugates containing β-axial alkyl substituents undergo efficient photolysis under aqueous conditions, with quantum yields up to >40%. However, substituents that are large and hydrophobic, or unable to readily support the presumed radical intermediate, suffer less efficient photolysis (<15%) than smaller, water-soluble, analogs. By contrast, quantum yields improve by 2-fold in DMF for cobalamins containing large hydrophobic β-axial substituents. This suggests that drug release from carriers comprised of membranous compartments, such as liposomes, may be significantly more efficient than the corresponding photorelease in an aqueous environment. Finally, we explored the impact of fluorophores on the photolysis of alkyl cobalamins under tissue-mimetic conditions. Cobalamins substituted with efficient photon-capturing fluorophores display up to 4-fold enhancements in photolysis relative to unsubstituted derivatives. In summary, we have shown that the photosensitivity of alkyl cobalamin conjugates can be tuned by altering the Co-appended alkyl moiety, modulating the polarity of the environment (solvent), and installing photon-capturing fluorophores onto the cobalamin framework.

meso-Methyl BODIPY Photocages: Mechanisms, Photochemical Properties, and Applications

“…The xanthene photocages ( 10 in Figure ) were among the first organic photocages developed to absorb above 500 nm, but have not seen significant use, perhaps because they have not been obtained yet as pure substances . Photocleavage of metal–ligand bonds have also been exploited, typically using ruthenium , or cobalt , as the metal center (e.g., 8 or 14 in Figure ), providing the ability for photoactivation using visible light.…”

“…PPGs that operate by single photon absorption at such long wavelengths are scarce. , Others include dye-sensitized cobalamine PPGs ( 23 in Figure ), which are believed to operate via a dye-sensitized photoinduced electron transfer from the dye to cobalt (λ irr = 550 to 800 nm, depending on the fluorophore), resulting in homolytic scission of the Co–C bond. H atom abstraction by the released leaving group radical then provides the free ligand.…”

Turning Red without Feeling Embarrassed─Xanthenium-Based Photocages for Red-Light-Activated Phototherapeutics

“…Last but not least, oxygen independency of the photorelease process should also be considered especially when the hypoxic environment of solid tumors is the target area . Some of these challenges were addressed recently with the development of novel photocages such as π-extended coumarin, − BODIPY, − and cyanine frames ,,, as well as metal-complex-based PPGs (see Figure for examples). ,− Unfortunately, advancement into one direction often results in the loss of other important features. In practice, this usually translates to PPGs with absorption bands >600 nm with improved aqueous solubilities but considerably decreased photocaging quantum yields .…”

Watching Excited State Dynamics with Optical and X-ray Probes: The Excited State Dynamics of Aquocobalamin and Hydroxocobalamin

“…11,42 The photostability of H 2 OCbl + and HOCbl is essential to the gene regulation function of the AerR proteins. 43−46 In addition to this natural biological function, cobalamins also provide a promising platform in optogenetics, 34,35,47 as light-activated agents for spatially and temporally controlled delivery of therapeutic agents, 8,9 and as a biocompatible scaffold for CO-releasing metal carbonyls. 48,49 Thus, the factors controlling the photochemistry of cobalamins are also of significant practical interest.…”

“…The reactions of these molecules exploit changes in oxidation state, spin state, axial ligation, and electronic structure. In addition to their ground state reactivity, the strong optical absorption of the conjugated ring has led to a variety of photochemical applications ranging from light harvesting and energy conversion to photodynamic therapy, gene regulation, and drug delivery. − Ultrafast transient absorption spectroscopy in the visible and ultraviolet regions of the spectrum has proven to be an invaluable tool in the study of these photochemical transformations. Unfortunately, UV–visible transient absorption spectra can be ambiguous to interpret and do not typically provide a direct link to molecular structure.…”