دورية أكاديمية
أعرض في EDS

Elucidating and Optimizing the Photochemical Mechanism of Coumarin-Caged Tertiary Amines.

التفاصيل البيبلوغرافية
العنوان: Elucidating and Optimizing the Photochemical Mechanism of Coumarin-Caged Tertiary Amines.
المؤلفون: Banala S; Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia 20147, United States., Jin XT; Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27101, United States., Dilan TL; Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia 20147, United States., Sheu SH; Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia 20147, United States., Clapham DE; Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia 20147, United States., Drenan RM; Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27101, United States., Lavis LD; Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia 20147, United States.
المصدر: Journal of the American Chemical Society [J Am Chem Soc] 2024 Jul 31; Vol. 146 (30), pp. 20627-20635. Date of Electronic Publication: 2024 Jul 18.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 7503056 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5126 (Electronic) Linking ISSN: 00027863 NLM ISO Abbreviation: J Am Chem Soc Subsets: MEDLINE
أسماء مطبوعة: Publication: Washington, DC : American Chemical Society
Original Publication: Easton, Pa. [etc.]
مواضيع طبية MeSH: Coumarins*/chemistry , Amines*/chemistry , Photochemical Processes*, Molecular Structure ; Photolysis
مستخلص: Photoactivatable or "caged" pharmacological agents combine the high spatiotemporal specificity of light application with the molecular specificity of drugs. A key factor in all optopharmacology experiments is the mechanism of uncaging, which dictates the photochemical quantum yield and determines the byproducts produced by the light-driven chemical reaction. In previous work, we demonstrated that coumarin-based photolabile groups could be used to cage tertiary amine drugs as quaternary ammonium salts. Although stable, water-soluble, and useful for experiments in brain tissue, these first-generation compounds exhibit relatively low uncaging quantum yield (Φ u < 1%) and release the toxic byproduct formaldehyde upon photolysis. Here, we elucidate the photochemical mechanisms of coumarin-caged tertiary amines and then optimize the major pathway using chemical modification. We discovered that the combination of 3,3-dicarboxyazetidine and bromine substituents shift the mechanism of release to heterolysis, eliminating the formaldehyde byproduct and giving photolabile tertiary amine drugs with Φ u > 20%─a 35-fold increase in uncaging efficiency. This new "ABC" cage allows synthesis of improved photoactivatable derivatives of escitalopram and nicotine along with a novel caged agonist of the oxytocin receptor.
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معلومات مُعتمدة: R21 DA044460 United States DA NIDA NIH HHS; R33 DA044460 United States DA NIDA NIH HHS
المشرفين على المادة: 0 (Coumarins)
0 (Amines)
A4VZ22K1WT (coumarin)
تواريخ الأحداث: Date Created: 20240718 Date Completed: 20240731 Latest Revision: 20240804
رمز التحديث: 20240804
مُعرف محوري في PubMed: PMC11295134
DOI: 10.1021/jacs.4c03092
PMID: 39023430
قاعدة البيانات: MEDLINE
الوصف
تدمد:1520-5126
DOI:10.1021/jacs.4c03092