Design, Synthesis, and Photochemical Properties of Clickable Caged Compounds

Abstract

Caged compounds enable the photo-mediated manipulation of the cell physiology with high spatiotemporal resolution. However, the limited structural diversity of currently available caging groups and the difficulties in synthetic modification without sacrificing their photolysis efficiencies are obstacles to expanding the repertoire of caged compounds for live cell applications. As the chemical modification of coumarin-type photocaging groups is a promising approach for the preparation of caged compounds with diverse physical and chemical properties, we report a method for the synthesis of clickable caged compounds that can be modified easily with various functional units via the copper(I)-catalyzed Huisgen cyclization. The modular platform molecule contains a (6-bromo-7-hydroxycoumarin-4-yl)methyl (Bhc) group as a photo-caging group, which exhibits a high photolysis efficiency compared to those of the conventional 2-nitrobenzyls. General procedures for the preparation of clickable caged compounds containing amines, alcohols, and carboxylates are presented. Additional properties such as the water solubility and cell targeting ability can be readily incorporated into clickable caged compounds. Furthermore, the physical and photochemical properties, including the photolysis quantum yield, were measured and were found to be superior to those of the corresponding Bhc caged compounds. The described protocol could therefore be considered a potential solution for the lack of structural diversity in the available caged compounds.

Visible-to-NIR-Light Activated Release: From Small Molecules to Nanomaterials

“…The dialkyl­aminomethyl C8 substituents of 49a – d (Table ) significantly reduced the acidity of the 7-OH group in 49c (p K a = 4.9) and 49d (p K a = 3.8) relative to the parent 40a (p K a = 6.2), presumably because the aminomethyl group forms an intramolecular hydrogen bond with the phenolic hydroxyl group, leading to greater photouncaging efficiency at the lower end of the physiological pH range. The liberation of carboxylic acids, diols, amines (as carbamic acids), and phenols (as carbonic acids) from 49a – d occurred with quantum efficiencies similar to or slightly exceeding that for 40a upon both 1P (Φ r = 0.06–0.014, λ irr = 360 nm) and 2P excitation (δ unc = 0.5–1.4 GM, 755 nm). ,,, The 8-bis­(carboxymethyl)­aminomethyl moiety of 49c increased water solubility , (to >2 mM in acetonitrile/HEPES buffer 5:95, pH 7.2), and the appended alkyne of 49d enabled further conjugation of the PPG via copper-mediated click chemistry. , Singh and co-workers developed the π-extended coumarin derivatives 50 and 51 (Table ), , which exhibited broad-range absorption extending to 400 or 550 nm, respectively. The 2-(2′-hydroxyphenyl)­benzothiazole (HBT) moiety in 50 facilitated pH-dependent excited-state intramolecular proton transfer (ESIPT); at pH < 7.4, the 7-OH group enabled an ESIPT process resulting in emission at 528 nm, but at higher pH values, the hydroxy group was ionized and ESIPT was prevented, resulting in blue-shifted emission with λ max em = 480 nm .…”

“…The liberation of carboxylic acids, diols, amines (as carbamic acids), and phenols (as carbonic acids) from 49a – d occurred with quantum efficiencies similar to or slightly exceeding that for 40a upon both 1P (Φ r = 0.06–0.014, λ irr = 360 nm) and 2P excitation (δ unc = 0.5–1.4 GM, 755 nm). 418 , 460 , 461 , 463 The 8-bis(carboxymethyl)aminomethyl moiety of 49c increased water solubility 418 , 460 (to >2 mM in acetonitrile/HEPES buffer 5:95, pH 7.2), and the appended alkyne of 49d enabled further conjugation of the PPG via copper-mediated click chemistry. 461 , 463 Singh and co-workers developed the π-extended coumarin derivatives 50 and 51 ( Table 9 ), 464 , 465 which exhibited broad-range absorption extending to 400 or 550 nm, respectively.…”

“… 418 , 460 , 461 , 463 The 8-bis(carboxymethyl)aminomethyl moiety of 49c increased water solubility 418 , 460 (to >2 mM in acetonitrile/HEPES buffer 5:95, pH 7.2), and the appended alkyne of 49d enabled further conjugation of the PPG via copper-mediated click chemistry. 461 , 463 Singh and co-workers developed the π-extended coumarin derivatives 50 and 51 ( Table 9 ), 464 , 465 which exhibited broad-range absorption extending to 400 or 550 nm, respectively. The 2-(2′-hydroxyphenyl)benzothiazole 466 (HBT) moiety in 50 facilitated pH-dependent excited-state intramolecular proton transfer 467 (ESIPT); at pH < 7.4, the 7-OH group enabled an ESIPT process resulting in emission at 528 nm, but at higher pH values, the hydroxy group was ionized and ESIPT was prevented, resulting in blue-shifted emission with λ max em = 480 nm.…”