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Synthesis of Nitro‐Aryl Functionalised 4‐Amino‐1,8‐Naphthalimides and Their Evaluation as Fluorescent Hypoxia Sensors
Author(s) -
Adair Liam D.,
Trinh Natalie,
Vérité Pauline M.,
Jacquemin Denis,
Jolliffe Katrina A.,
New Elizabeth J.
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202002088
Subject(s) - fluorescence , combinatorial chemistry , nitro , chemistry , aryl , nanotechnology , biophysics , materials science , organic chemistry , biology , alkyl , physics , quantum mechanics
Fluorescent sensors are a vital research tool, enabling the study of intricate cellular processes in a sensitive manner. The design and synthesis of responsive and targeted probes is necessary to allow such processes to be interrogated in the cellular environment. This remains a challenge, and requires methods for functionalisation of fluorophores with multiple appendages for sensing and targeting groups. Methods to synthesise more structurally complex derivatives of fluorophores will expand their potential scope. Most known 4‐amino‐1,8‐naphthalimides are only functionalised at imide and 4‐positions, and structural modifications at additional positions will increase the breadth of their utility as responsive sensors. In this work, methods for the incorporation of a hypoxia sensing group to 4‐amino‐1,8‐naphthalimide were evaluated. An intermediate was developed that allowed us to incorporate a sensing group, targeting group, and ICT donor to the naphthalimide core in a modular fashion. Synthetic strategies for attaching the hypoxia sensing group and how they affected the fluorescence of the naphthalimide were evaluated by photophysical characterisation and time‐dependent density functional theory. An extracellular hypoxia probe was then rationally designed that could selectively image the hypoxic and necrotic region of tumour spheroids. Our results demonstrate the versatility of the naphthalimide scaffold and expand its utility. This approach to probe design will enable the flexible, efficient generation of selective, targeted fluorescent sensors for various biological purposes.