Organic Chemistry

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

Authors

Abstract

Photolabile Protecting Groups (PPGs) are chemical tools used in photopharmacology for the oxygen-independent release of bioactive payloads, enabling spatiotemporal activation of their bioactivity. However, red-shifting of PPG activation wavelengths into the NIR range, light which penetrates the deepest in tissue, has been laborious, and often results in inefficient or insoluble PPGs. This challenge prohibits the use of current photocages in complex biological targets, hindering the progression of photopharmacology into the clinic. To directly address 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 clinically-employed NIR dyes possessing ideal properties, such as NIR-absorption, very high molecular absorptivity, and excellent solubility in aqueous media, can be successfully converted into Cy7-PPG. We report a facile organic synthesis towards Cy7-PPG from easily accessible precursors and confirm its function as an oxygen-independent NIR-PPG. Cy7-PPG is the most redshifted PPG to date (max wavelength = 746 nm), with unmatched molecular absorptivity and solubility, and excellent uncaging efficiency, paving the way for the use of PPGs in the clinic.

Content

Thumbnail image of Cy7 PPG Manuscript ChemRxiv.pdf

Supplementary material

Thumbnail image of Cy7 PPG SI Final.pdf
Supporting Information: Computational Design, Synthesis and Photochemistry of Cy7-PPG, an Efficient NIR-activated Photolabile Protecting Group for Therapeutic Applications
Full synthetic methods, analytical and photochemical data, and computational data are provided as Supporting Information for our manuscript: Computational Design, Synthesis and Photochemistry of Cy7-PPG, an Efficient NIR-activated Photolabile Protecting Group for Therapeutic Applications