Incorporating a Piperidinyl Group in the Fluorophore Extends the Fluorescence Lifetime of Click-Derived Cyclam-Naphthalimide Conjugates

Abstract

Ligands incorporating a tetraazamacrocycle receptor, a ‘click’- derived triazole and a 1,8-naphthalimide fluorophore have proven utility as probes for metal ions. Three new cyclam-based molecular probes are reported, in which a piperidinyl group has been introduced at the 4-position of the naphthalimide fluorophore. These compounds have been synthesized using the copper(I)-catalyzed azide-alkyne Huisgen cycloaddition and their photophysical properties studied in detail. The alkylamino group induces the expected red-shift in absorption and emission spectra relative to the simple naphthalimide derivatives and gives rise to extended fluorescence lifetimes in aqueous buffer. The photophysical properties of these systems are shown to be highly solvent-dependent. Screening the fluorescence responses of the new conjugates to a wide variety of metal ions reveals significant and selective fluorescence quenching in the presence of copper(II), yet no fluorescence enhancement with zinc(II) as observed previously for the simple naphthalimide derivatives. Reasons for this different behaviour are proposed. Cytotoxicity testing shows that these new cyclam-triazole-dye conjugates display little or no toxicity against either DLD-1 colon carcinoma cells or MDA-MB-231 breast carcinoma cells, suggesting a potential role for these and related systems in biological sensing applications.

Selective Displacement of a Scorpionand Triazole Ligand from Metallocyclam Complexes Visualised with NMR Spectroscopy

“…An alternative route from 9 to 10 was also explored, by alkylation of 9 with bromoacetonitrile, reduction of the nitrile, and diazo transfer to the resulting amine (Schemes and S1); this route proved inferior and is discussed in more detail in the Supporting Information. Azide 10 was treated with phenylacetylene under the modified click conditions reported previously to afford the Boc‐protected ligand 13 in good yield (68 %). HCl‐mediated Boc deprotection gave the HCl salt of 7 , which was neutralised with excess Ambersep® 900 hydroxide‐form resin in ethanol to give the cyclam–phenyl ligand 7 in quantitative yield.…”

A direct method for the N-tetraalkylation of azamacrocycles

“…This is due in part to the versatility of these macrocycles towards N -functionalisation, in part to the tendency of functionalised cyclams and cyclens to coordinate selectively a wide range of metal cations, and in part to the diverse and interesting physical and chemical behaviour displayed by the resulting complexes [2]. These systems typically exhibit high thermodynamic and kinetic stability and have found application within biomimetic systems [1,7–10], in biomedicine [3,6,11–16], as catalysts [17–22], and as fluorescent probes [5,23–28]. …”

“…We sought a simple route to cyclam and cyclen derivatives N -tetraalkylated with propargyl (CH 2 C≡CH) and aromatic groups, as part of ongoing efforts to develop multi-functionalised cyclam derivatives for fluorescence sensing [25–28 40–41] and other biomedical applications [14–16 42–43]. However, we found the previously reported methods to be at best capricious when it comes to substitution with propargyl groups, and the other larger, hydrophobic moieties in which we are interested, leading primarily to over-alkylation and the formation of quaternary amine salts.…”

Molecular Switches for any pH: A Systematic Study of the Versatile Coordination Behaviour of Cyclam Scorpionands

“…From intermediate 18,t he divergents ynthesis of protected ligands 19-25 was achieved using ac ombination of S N 2r eac-tions, carbonyl chemistry,a nd metal-catalysed cross couplings (Scheme2,T able 1). Acid-mediated Boc-deprotection to afford ligands 5-11 was accomplished as previouslyr eported for related systems, [53][54][55] with modified workup required in some cases to avoid alkaline hydrolysis of the pendant group (Scheme 2, Ta ble 2). Triazole ligands 12 and 13 were prepared from tri-Boc-cyclam 16 via the N-propargyl and N-azidoethyl derivatives, respectively,asr eportedp reviously.…”