Intramolecular Charge Transfer in the Azathioprine Prodrug Quenches Intersystem Crossing to the Reactive Triplet State in 6‐Mercaptopurine †
Intramolecular Charge Transfer in the Azathioprine Prodrug Quenches Intersystem Crossing to the Reactive Triplet State in 6‐Mercaptopurine †
复制标题
DOI：
10.1111/php.13513
复制
发表时间：
2021-08
影响因子：
3.3
通讯作者：
Luis A. Ortiz-Rodríguez;Glesmarie Ortiz-Zayas;M. Pollum;Sean J. Hoehn;S. Jockusch;C. Crespo-Hernández-
中科院分区：
文献类型：
--
作者：
Luis A. Ortiz-Rodríguez;Glesmarie Ortiz-Zayas;M. Pollum;Sean J. Hoehn;S. Jockusch;C. Crespo-Hernández-
硫嘌呤前药6 -巯基嘌呤和硫嘌呤是世界上治疗急性淋巴细胞白血病、免疫抑制和一些自身免疫性疾病的基本药物。硫嘌呤前药是有效的UVA吸收剂和单线态氧发生器，这些前药的长期治疗与患者阳光诱导皮肤癌的高发病率相关。在这篇论文中，我们发现在UVA辐射的吸收下，硫代嘌呤的电子弛豫机制和光化学性质与6 -巯基嘌呤有显著的不同。UVA激发的6 -巯基嘌呤产生近100%的三重态产率和高达30%的单线态产氧，而UVA激发的氮杂嘌呤产生的三重态产率为15-3%，取决于水溶液的pH和<1%的单线态产氧。虽然6 -巯基嘌呤和其他硫嘌呤前药的光激发可以促进氧化产生的细胞损伤，但硫嘌呤较差的光敏能力揭示了在光稳定前药的分子设计中使用色素间电荷转移相互作用，在药物代谢前显着减少了光细胞毒性副作用。
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.