The Discovery, Development and Demonstration of Three Caged Compounds^†

Abstract

An overview of the history, mechanistic aspects and applications is provided for p-hydroxyphenacyl (pHP) and benzoin photoremovable protecting groups, which release biologically important leaving groups upon photolysis with UV light. Also discussed is (7-diethylaminocoumarin-4-yl)methyl (DEACM), a photoremovable protecting group that absorbs visible light. These are followed by the a-keto amides and naphtho-and benzothiophene-2-carboxanilides as caging groups, which eliminate leaving groups via photochemically produced zwitterionic intermediates. Also covered are amino-1,4benzoquinones, which upon exposure to green and red wavelengths of light photorearrange to an unstable photoproduct that subsequently eliminates leaving groups in aqueous media. Selected examples are given that use these photoremovable protecting (caging) groups for the light-activated release of biologically important substrates under physiological conditions in cells and tissue as practical applications in biology, biochemistry and physiology. These caging groups have found significant applications because their photochemistry is efficient and a single coproduct is formed in addition to the photoreleased substrate.

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

“…46,48 In addition to linear hydrocarbons, we explored the photolysis of several cyclic hydrocarbon-containing Cbl conjugates, including the cyclopropyl (8) and cyclobutyl (10) derivatives, in which the ring is directly appended to the Co. Furthermore, we synthesized the corresponding cyclopropylmethyl (8), cyclobutylmethyl (11), and methylcyclohexyl (12) analogs to assess whether the methylene bridge has any influence on photolysis rate of these cyclic species. The photolytic quantum yield for cyclopropyl-Cbl is modest (0.09) relative to other alkyl-Cbl derivatives [e.g., cyclobutyl-Cbl (0.22)].…”

“…5 Consequently, we examined the photolysis of several of the alkyl-Cbl conjugates in DMF to assess the impact of a nonaqueous solvent on photolysis rates (Table 2). The conjugates analyzed include aliphatic acyclic (4, 7) and cyclic derivatives (8,12), as well as amino acid (15) analogs. The ethyl-Cbl conjugate behaves similarly in aqueous and organic media, likely due to the relatively simple ethyl ligand having few interactions with the surrounding solvent in either system.…”

“…5−7 For example, light-triggered drug delivery offers the promise of diseased site targeting and consequent reduced side effects. 6,8,9 Nitrobenzyl, 10,11 hydroxyphenacyl, 11,12 coumarin-4-yl, 11,12 and a wide assortment of other derivatives 13 have long served in the capacity of light-absorbing/photorelease scaffolds. However, within the last decade, attention has shifted to the design of molecular scaffolds that absorb long-wavelength visible and near-infrared (IR) light, which has the advantage of deeper tissue penetration than that of shorter wavelengths.…”

“…Light-responsive agents have found application in a variety of areas, including polymer synthesis, sensor design, manipulation of intracellular biochemistry, , and drug delivery. − For example, light-triggered drug delivery offers the promise of diseased site targeting and consequent reduced side effects. ,, Nitrobenzyl, , hydroxyphenacyl, , coumarin-4-yl, , and a wide assortment of other derivatives have long served in the capacity of light-absorbing/photorelease scaffolds. However, within the last decade, attention has shifted to the design of molecular scaffolds that absorb long-wavelength visible and near-infrared (IR) light, which has the advantage of deeper tissue penetration than that of shorter wavelengths. , These scaffolds include Bodipy analogs, − cyanine derivatives, − [Ru­(bpy) 3 ] 3+ complexes, − and others. , In this regard, we have found that cobalamin (Cbl; vitamin B12) serves as an unusually flexible molecular launch pad for therapeutic agents that can be tuned to wavelengths in the red, far red, and near IR .…”

Optochemical Control of Immune Checkpoint Blockade via Light‐Triggered PD‐L1 Dimerization

“…Without light irradiation, cBMS‐1 did not block PD‐1/PD‐L1 interaction, resulting in suppressed immune activity of Jurkat T cells. With light irradiation at 420 nm, DEACM was removed to release BMS‐1, [ 20 ] which successfully blocked PD‐1/PD‐L1 interaction and triggered the release of cytokines from Jurkat T cells. [ 21–23 ] The study demonstrated the first example of precisely controlling PD‐1/PD‐L1 interaction with light, paving the way to targeted and controlled immune checkpoint blockade for cancer therapy.…”