The Synthesis and Evaluation of Non-Targeted Near-Infrared Heptamethine Molecular Probes

Detecting and quantifying biomolecules is an important tool in biological research. Ideal dyes have to have a number of characteristics i.e. low toxicity and limited autofluorescence. The properties of near infrared dyes make these ideal for cell and tissue imaging. The work within this thesis focuses on the development of three families of NIR dyes (linear, rigid and substituted polymethine) and these are actively compared against the clinical standard Indocyanine Green (ICG) and its structural derivative New Indocyanine Green (IR-820). The ultimate aim being to identify dyes which can be used alongside the clinical standards. The compounds developed within this thesis are structurally based on the NIR heptamethine cyanine (Cy7) dyes. To expand, variations fall into three categories, linear, rigid and polymethine substituted, each being synthesised using either existing methodology or through the development of a novel cascade reaction. The photophysical properties of each dye have been evaluated experimentally, focusing on absorption and emission wavelengths, fluorescence quantum yields and Stokes shifts. It is noted that most dyes synthesised within this thesis, show comparable Stokes shift but increased fluorescence quantum yields when compared against ICG and IR-820. All dyes absorb and emit within the NIR region based on excitation at 785 nm. The growth inhibition characteristic is an important criterion which determines the practical use of the dyes in living cells. Most of the dyes which showed no growth inhibition were the dyes bearing the sulfonic acid group, suggesting the sulfonic acid limited cellular uptake as a result of decreased membrane permeability. Dyes possessing growth inhibitory characteristics all contain linear N-alkyl moieties. It is thus postulated that the increased lipophilicity of these molecules result in increased lipid distortion and subsequent toxicity

Synthesis and photophysical properties of meso‐aminophenyl‐substituted heptamethine dyes as potential leads to new contrast agents

The series of rigidmeso-aminophenyl-substituted heptamethine dyes presented herein exhibit surprisingfluorescence properties, demonstrating larger Stokes shifts when compared with both structurally similar rigidmeso-chlorophenyl and linear heptamethine dyes. Based on their photophysical properties, these are ofconsiderable importance to the development of contrast agents, within biology and medicine

N-Alkylated Linear Heptamethine Polyenes as Potent Non-Azole Leads against Candida Albicans Fungal Infections

In this study, eighteen heptamethine dyes were synthesised and their antifungal activities were evaluated against three clinically relevant yeast species.. The eighteen dyes were placed within classes based on their core subunit i.e. 2,3,3-trimethylindolenine (5a-f), 1,1,2-trimethyl-1H-benzo[e]indole (6a-f), or 2-methylbenzothiazole (7a-f). The results presented herein imply that the three families of cyanine dyes, in particular compounds 5a-f, show high potential as selective scaffolds to treat C. albicans infections. This opens up the opportunity for further optimisation and investigation of this class compounds for potential antifungal treatment

Promising near-infrared non-targeted probes: benzothiazole heptamethine cyanine dyes

A series of benzothiazole heptamethine cyanine dyes have been synthesized and their photophysical properties evaluated in relation to their structural features. These have been compared against two classical probes of this type: Indocyanine Green (IGC) and New Indocyanine Green (IR-820). Growth inhibitory studies were also performed using a eukaryotic, unicellular organism, fission yeast Schizosaccharomyces pombe. Herein we highlight some potentially interesting candidates with improved fluorescence quantum yields when compared with ICG and IR-820

N-Alkylated 2,3,3-trimethylindolenines and 2-methylbenzothiazoles. Potential lead compounds in the fight against Saccharomyces cerevisiae infections.

The synthesis of a variety of N-alkylated 2,3,3-trimethylindolenines and 2-methylbenzothiazoles is reported herein. Their potential as antifungal agents is evaluated by preliminary screening against Saccharomyces cerevisiae (S. cerevisiae), Schizosaccharomyces pombe (S. pombe), and Candida albicans (C. albicans). Statistical analyses illustrate a strong relationship between chain length and growth inhibition for S. cerevisiae and S. pombe (p < 0.0001 in every case). Of particular interest is the activity of both sets of compounds against S. cerevisiae, as this is emerging as an opportunistic pathogen, especially in immunosuppressed and immunocompromised patients. Bioassays were set up to compare the efficacy of our range of N-alkylated compounds against classic antifungal agents; Amphotericin B and Thiabendazole