A General Strategy to Access Fluorogenic Heptamethine Cyanines through Polymethine Reactivity

Fluorogenic heptamethine cyanines are highly desirable for biomedical imaging due to high signal-to-background ratio from region of interest, however, there are limited strategies to develop them. Here we report a general strategy to synthesize fluorogenic heptamethine cyanines using intrinsic reactivity of the polymethine scaffold. In our strategy, a meso-carboxylate group undergoes intramolecular nucleophilic attack at the γ-position of the polymethine chain to form a five-membered cyclized structure that disrupts π-conjugation and suppresses nearinfrared fluorescence; referred to as cyclizing-heptamethine cyanines (c-Cy7). This c-Cy7s have solvent dependent equilibrium between the open, conjugated form (polar solvent) and the closed, cyclized form (nonpolar solvent). A library of symmetrical and unsymmetrical c-Cy7s containing electron-withdrawing groups were synthesized to demonstrate that electronic substitution modulates the cyclization equilibrium. Collectively, this work demonstrates that polymethine reactivity can be harnessed for developing fluorogenic heptamethine cyanines.