Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jul 4;61(27):e202201308.
doi: 10.1002/anie.202201308. Epub 2022 Mar 10.

Computational Design, Synthesis, and Photochemistry of Cy7-PPG, an Efficient NIR-Activated Photolabile Protecting Group for Therapeutic Applications

Affiliations

Computational Design, Synthesis, and Photochemistry of Cy7-PPG, an Efficient NIR-Activated Photolabile Protecting Group for Therapeutic Applications

Georgios Alachouzos et al. Angew Chem Int Ed Engl. .

Abstract

Photolabile Protecting Groups (PPGs) are molecular tools used, for example, in photopharmacology for the activation of drugs with light, enabling spatiotemporal control over their potency. Yet, red-shifting of PPG activation wavelengths into the NIR range, which penetrates the deepest in tissue, has often yielded inefficient or insoluble molecules, hindering the use of PPGs in the clinic. To solve this problem, we report herein a novel concept in PPG design, by transforming clinically-applied NIR-dyes with suitable molecular orbital configurations into new NIR-PPGs using computational approaches. Using this method, we demonstrate how Cy7, a class of NIR dyes possessing ideal properties (NIR-absorption, high molecular absorptivity, excellent aqueous solubility) can be successfully converted into Cy7-PPG. We report a facile synthesis towards Cy7-PPG from accessible precursors and confirm its excellent properties as the most redshifted oxygen-independent NIR-PPG to date (λmax =746 nm).

Keywords: Density Functional Theory; NIR Light; Photochemistry; Photolabile Protecting Groups; Photopharmacology.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
PPGs in photocaging, current PPG designs and the undiscovered ideal PPG for use in tissue.
Figure 2
Figure 2
An overview of the function of PPGs and our novel DFT‐based workflow for designing ideal NIR‐PPGs.
Scheme 1
Scheme 1
Attempted synthetic approaches to Cy7‐PPG.
Scheme 2
Scheme 2
An efficient synthesis toward Cy7‐PPG, with two methods for loading ZS‐OH with a payload.
Figure 3
Figure 3
Cy7‐PPG‐OAc ideal photocage properties and payload uncaging with 760 nm light. a) Ideal wavelength λmax, molecular absorptivity ϵ, low fluorescence and singlet oxygen photosensitization quantum yields Φfluor and ΦP.S., and high stability of Cy7‐PPG‐OAc. b) UV/Vis monitored uncaging of Cy7‐PPG‐OAc upon irradiation with 760 nm light (*1 μM in degassed 99 : 1 milli‐Q H2O/DMSO). c) NMR monitored uncaging of Cy7‐PPG‐OAc and comparison of its uncaging cross‐section ϵ×Φhet to BODIPY‐PPG‐OAc (see Supporting Information).
Figure 4
Figure 4
Cy7‐PPG‐OAc uncaging with 760 nm light inside of tissue phantoms. a) Preparation of 1 cm cuboid tissue phantoms of Hollandse Nieuwe (raw herring) and Speklap (raw pork belly). b) Mounted tissue phantoms containing a sample of Cy7‐PPG‐OAc (0.5 ml, 2 mM in 1 : 1 D2O/d6DMSO). c) Rate of PL uncaging upon 760 nm irradiation through the tissue phantoms (*given in nmol/min).

References

    1. Lerch M. M., Hansen M. J., van Dam G. M., Szymanski W., Feringa B. L., Angew. Chem. Int. Ed. 2016, 55, 10978–10999; - PubMed
    2. Angew. Chem. 2016, 128, 11140–11163.
    1. Hüll K., Morstein J., Trauner D., Chem. Rev. 2018, 118, 10710–10747. - PubMed
    1. Jia S., Sletten E. M., ACS Chem. Biol. 2021, 10.1021/acschembio.1c00518. - DOI - PMC - PubMed
    1. Velema W. A., Szymanski W., Feringa B. L., J. Am. Chem. Soc. 2014, 136, 2178–2191. - PubMed
    1. Fuchter M. J., J. Med. Chem. 2020, 63, 11436–11447. - PubMed

Publication types

LinkOut - more resources