Explorations into the Effect of meso‐Substituents in Tricarbocyanine Dyes: A Path to Diverse Biomolecular Probes and Materials

Abstract

Polymethine cyanine dyes have been widely recognized as promising chemical tools for a range of life science and biomedical applications, such as fluorescent staining of DNA and proteins in gel electrophoresis, fluorescence guided surgery, or as ratiometric probes for probing biochemical pathways. The photophysical properties of such dyes can be tuned through the synthetic modification of the conjugated backbone, for example, by altering aromatic cores or by varying the length of the conjugated polymethine chain. Alternative routes to shaping the absorption, emission, and photostability of dyes of this family are centered around the chemical modifications on the polymethine chain. This Minireview aims to discuss strategies for the introduction of substituents in the meso‐position, their effect on the photophysical properties of these dyes and some structure–activity correlations which could help overcome common limitations in the state of the art in the synthesis.

Structure‐Activity Studies of Nitroreductase‐Responsive Near‐Infrared Heptamethine Cyanine Fluorescent Probes

“…The research field has progressed from fluorescent probes with visible wavelength emission to probes that absorb and emit NIR light which is known to penetrate further through opaque biological media including skin and tissue [16,17] . Heptamethine cyanine dyes are commonly employed as the molecular scaffold because they have favorable NIR fluorescence properties [18–24] . But as the field matures and moves toward clinical translation, there is a need to optimize the molecular design and create NTR responsive probes that have a precise combination of favorable photophysical and pharmaceutical properties [25]…”

“…A recent example is work by the Štacko group who devised a versatile method for making heptamethine cyanine dyes by ring opening of Zincke salts [18,27] . This new methodology enables access to new heptamethine structures with different substituents along the polymethine chain, what is especially helpful is the opportunity to explore substituents beyond the traditional option of an electron‐rich heteroatom, such as Cl, O, or N, at the heptamethine 4’‐position which is known to produce compounds that are chemically or photochemically unstable in physiological environments [23,28–30] . In this regard, the ability to prepare heptamethine dyes with C−C bonds at the 4‘‐position has great potential to produce next‐generation dyes.…”

“…[16,17] Heptamethine cyanine dyes are commonly employed as the molecular scaffold because they have favorable NIR fluorescence properties. [18][19][20][21][22][23][24] But as the field matures and moves toward clinical translation, there is a need to optimize the molecular design and create NTR responsive probes that have a precise combination of favorable photophysical and pharmaceutical properties. [25] Heptamethine cyanine dyes are inherently hydrophobic molecules, and it is a synthetic challenge to design and prepare them as selective NTR probes with high water solubility, along with rapid enzyme-catalyzed kinetics and a high level of "turn on" NIR fluorescence.…”

“…To meet this challenge, new synthetic methods are being devised to prepare novel classes of cyanine dye structures with multiple functional groups. [21][22][23] A recent example is work by the Štacko group who devised a versatile method for making heptamethine cyanine dyes by ring opening of Zincke salts. [18,27] This new methodology enables access to new heptamethine structures with different substituents along the polymethine chain, what is especially helpful is the opportunity to explore substituents beyond the traditional option of an electron-rich heteroatom, such as Cl, O, or N, at the heptamethine 4'-position which is known to produce compounds that are chemically or photochemically unstable in physiological environments.…”

Systematic Exploration of Furoindolizine‐Based Molecular Frameworks towards a Versatile Fluorescent Platform

“…[3] Moreover, donor-acceptor-type (DA-type) dyes built on naphthalene or benzoxazine building blocks have been efficient for monitoring pH change, [4] hydrophobicity, [5] or membrane fluidity [6] in biological systems (Figure 1B). Although classical fluorescent scaffolds provided well-defined physicochemical properties, their intrinsic photophysical properties, such as molar absorptivity, emission wavelength, and Stokes shift, were often challenging to be harnessed due to synthetic feasibility [7] and limited tunability. [8] Notably, a privileged boron dipyrromethene (BOD-IPY) has emerged as a versatile platform with synthetic amenability and tunable photophysical properties.…”