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Title: Intramolecular Charge Transfer in the Azathioprine Prodrug Quenches Intersystem Crossing to the Reactive Triplet State in 6‐Mercaptopurine †
Abstract

The thiopurine prodrugs 6‐mercaptopurine and azathioprine are among the world’s essential medications for acute lymphoblastic leukemia, immunosuppression and several autoimmune conditions. Thiopurine prodrugs are efficient UVA absorbers and singlet oxygen generators and the long‐term treatment with these prodrugs correlates with a high incidence of sunlight‐induced skin cancer in patients. In this contribution, we show that the electronic relaxation mechanisms and photochemical properties of azathioprine are remarkably different from those of 6‐mercaptopurine upon absorption of UVA radiation. UVA excitation of 6‐mercaptopurine results in nearly 100% triplet yield and up to 30% singlet oxygen generation, whereas excitation of azathioprine with UVA leads to triplet yields of 15–3% depending on pH of the aqueous solution and <1% singlet oxygen generation. While photoexcitation of 6‐mercaptopurine and other thiopurine prodrugs can facilitate oxidatively generated cell damage, azathioprine's poor photosensitization ability reveals the use of interchromophoric charge‐transfer interactions for the molecular design of photostable prodrugs exhibiting a remarkable reduction in photocytotoxic side effects before drug metabolization.

 
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Award ID(s):
1800052
NSF-PAR ID:
10367668
Author(s) / Creator(s):
 ;  ;  ;  ;  ;  
Publisher / Repository:
Wiley-Blackwell
Date Published:
Journal Name:
Photochemistry and Photobiology
Volume:
98
Issue:
3
ISSN:
0031-8655
Page Range / eLocation ID:
p. 617-632
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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