New 3‐(Heteroaryl)‐2‐iminocoumarin‐based Borate Complexes: Synthesis, Photophysical Properties, and Rational Functionalization for Biosensing/Biolabeling Applications

Abstract

Members of a series of boron difluoride complexes with 3-(heteroaryl)-2-iminocoumarin ligands bearing both a phenolic hydroxyl group (acting as a fluorogenic center) and an N-aryl substituent (acting as a stabilizing moiety) have been synthesized in good yields by applying a straightforward two-step method. These novel fluorogenic dyes belong to the family of "Boricos" (D. Frath et al., Chem. Commun.- 2013, 49, 4908-4910) and are the first examples of phenol-based fluorophores of which the photophysical properties in the green-yellow spectral range are dramatically improved by N,N-chelation of a boron atom. Modulation of their fluorescence properties through reversible chemical modification of their phenol moieties has been demonstrated by the preparation of the corresponding 2,4-dinitrophenyl (DNP) ethers, which led to a dramatic "OFF-ON" fluorescence response upon reaction with thiols. Additionally, to expand the scope of these "7-hydroxy-Borico" derivatives, particularly in biolabeling, amine or carboxylic acid functionalities amenable to (bio)conjugation have been introduced within their scaffold. Their utility has been demonstrated in the preparation of fluorescent bovine serum albumin (BSA) conjugates and "Borico"-DOTA-like scaffolds in an effort to design novel monomolecular multimodal fluorescence- radioisotope imaging agents.

Redesigning the Coumarin Scaffold into Small Bright Fluorophores with Far-Red to Near-Infrared Emission and Large Stokes Shifts Useful for Cell Imaging

“…The presence of diagnostic NOE cross-peaks such as the one between H3 proton of the coumarin in the minor rotamer and the meta protons of the pyridine (Figure 1) allowed to conclude that the E rotamer was the one preferred (as usually drawn in the manuscript). A similar behavior was found for the 4-trifluoromethylcoumarin analogue (8), in which an  93:7 mixture of the two rotamers was identified in solution by NMR ( Figures S5-S6). Again, 1 H-1 H NOESY experiments allowed to conclude that the E rotamer was the major species in solution.…”

“…N,N-dialkylamino or hydroxy/alkoxy) that partner with the electronwithdrawing lactone moiety to create a push-pull effect. Based on this premise, great efforts have been devoted to red-shift the emission of coumarins by introducing additional electron-withdrawing groups (EWG) at positions 3 and/or 4 (CN, CF 3 , carboxyl), by extending the conjugation system through position 3 with methine, carbonyl o heteroaryl linkages, 7 or by fusion of aromatic cycles, 8 including other fluorescent scaffolds such as rhodamine 9 or BODIPY. 7b,10 Despite huge synthetic efforts dedicated to the coumarin scaffold, little work has been devoted to modifying the lactone function.…”

Red-Emitting Tetracoordinate Organoboron Chelates: Synthesis, Photophysical Properties, and Fluorescence Microscopy

“…[8][9][10] Especially tetra-coordinate boron(III) compounds with bidentate chelating ligands have been in the focus of these efforts. [11][12][13][14][15] The coordinative saturation of the boron center confers increased chemical stability and rigidity, often accompanied by significantly high fluorescence quantum yields. Par excellence examples for boron(III) dyes with widespread application in chemical biology and sensing are Bodipy dyes.…”

High Photostability in Nonconventional Coumarins with Far-Red/NIR Emission through Azetidinyl Substitution

“…Comparison of the normalized absorption (solid lines) and fluorescence (dotted lines) spectra of 7-azetidinyl-COUPY dyes (compounds 4Az-7Az) in toluene (black lines) and in PBS buffer (red lines).7-Azetidinyl derivatives (4Az-7Az) reproduced the behavior of 7-N,N-dialkylamino-COUPYdyes(4)(5)(6)(7) and showed emission in the far-red to NIR region(Figures 1 and S9), with the emission maximum ranging from 605 nm (4Az, ACN) to 681 nm (7Az, ACN). As shown in…”