Fluorescent 4-amino-1,8-naphthalimide Tröger's bases (TBNaps) possessing (orthogonal) 'α-amino acids', esters and di-peptides and their solvent dependent photophysical properties.

The synthesis of fifteen luminescent bis-naphthalimide based Tröger's bases (TBNaps) derived from 4-amino-1,8-naphthalimide (4-Amino-Nap) precursors is described; these scaffolds possess α-amino acids, esters or di-peptides conjugated at the imide site and show minor fluorescence in aqueous solution while being highly emissive in organic solvents. The investigation shows that these TBNaps possessing ICT excited state properties are capable of generating either positive or negative solvatochromic effects in response to changes in polarity and/or the hydrogen bonding capabilities of the medium.

One-pot facile synthesis of 4-amino-1,8-naphthalimide derived Tröger's bases via a nucleophilic displacement approach.

We report here a novel one-pot synthetic strategy for the synthesis of a family of N-alkyl-1,8-naphthalimide based Tröger's bases via a nucleophilic substitution reaction of a common 'precursor' (or a 'synthon') N-aryl-1,8-naphthalimide Tröger's base heated at 80 °C in neat aliphatic primary amine, in overall yield of 65-96%. This methodology provides an efficient and one-step facile route to design 1,8-naphthalimide derived Tröger's base structures in analytically pure form without the use of column chromatography purification, that can be used in medicinal chemistry and as supramolecular scaffolds. We also report the formation of the corresponding anhydride, and the crystallographic analysis of two of the resulting products, that of the N-phenyl-4-amino-1,8-naphthalimide and the anhydride derived Tröger's bases.

Synthesis, photophysical and cytotoxicity evaluations of DNA targeting agents based on 3-amino-1,8-naphthalimide derived Tröger's bases.

The synthesis and characterisation of five bis-1,8-naphthalimide containing Tröger's bases 1­5 formed from their corresponding 3-amino-1,8-naphthalimide precursors 6­10 is described. The photophysical investigations of 1­5 and 6­10 were carried out in several organic solvents as well as in water and as a function of pH using UV-Vis absorption and fluorescence spectroscopies. The DNA binding affinities of 1­5 in aqueous solution at pH 7.4 were also investigated using several UV-Vis absorption and fluorescence experiments by using calf thymus DNA (ct-DNA). These molecules exhibited significant DNA binding affinities; where large binding values (Kb) in the range of 10(6) M(−1) were determined, even in competitive media (50 mM and 160 mM NaCl at pH 7.4). Thermal denaturation measurements also showed that 1­5 significantly stabilised the DNA helix. Using linear and circular dichroism we further demonstrated that the DNA binding interaction occurs both by intercalation and by groove binding. The Tröger's bases were further shown to be rapidly taken up into cells using confocal fluorescence spectroscopy; and cytotoxic studies in HeLa and MCF-7 cells showed that most of the Tröger's bases were effective cytotoxic agents with EC50 values of between 1.1­12 µM and that all the active compounds induced programmed cell death by apoptosis, where up to 70% cellular death was observed after 24 h of incubation for 4.

Recent advances in the development of 1,8-naphthalimide based DNA targeting binders, anticancer and fluorescent cellular imaging agents.

The development of functional 1,8-naphthalimide derivatives as DNA targeting, anticancer and cellular imaging agents is a fast growing area and has resulted in several such derivatives entering into clinical trials. This review gives an overview of the many discoveries and the progression of the use of 1,8-naphthalimides as such agents and their applications to date; focusing mainly on mono-, bis-naphthalimide based structures, and their various derivatives (e.g. amines, polyamine conjugates, heterocyclic, oligonucleotide and peptide based, and those based on metal complexes). Their cytotoxicity, mode of action and cell-selectivity are discussed and compared. The rich photophysical properties of the naphthalimides (which are highly dependent on the nature and the substitution pattern of the aryl ring) make them prime candidates as probes as the changes in spectroscopic properties such as absorption, dichroism, and fluorescence can all be used to monitor their binding to biomolecules. This also makes them useful species for monitoring their uptake and location within cells without the use of co-staining. The photochemical properties of the compounds have also been exploited, for example, for photocleavage of nucleic acids and for the destruction of tumour cells.

Colorimetric and fluorescent anion sensors: an overview of recent developments in the use of 1,8-naphthalimide-based chemosensors.

This critical review focuses on the development of anion sensors, being either fluorescent and/or colorimetric, based on the use of the 1,8-naphthalimide structure; a highly versatile building unit that absorbs and emits at long wavelengths. The review commences with a short description of the most commonly used design principles employed in chemosensors, followed by a discussion on the photophysical properties of the 4-amino-1,8-naphthalimide structure which has been most commonly employed in both cation and anion sensing to date. This is followed by a review of the current state of the art in naphthalimide-based anion sensing, where systems using ureas, thioureas and amides as hydrogen-bonding receptors, as well as charged receptors have been used for anion sensing in both organic and aqueous solutions, or within various polymeric networks, such as hydrogels. The review concludes with some current and future perspectives including the use of the naphthalimides for sensing small biomolecules, such as amino acids, as well as probes for incorporation and binding to proteins; and for the recognition/sensing of polyanions such as DNA, and their potential use as novel therapeutic and diagnostic agents (95 references).

Synthesis, photophysical, and DNA binding studies of fluorescent Tröger's base derived 4-amino-1,8-naphthalimide supramolecular clefts.

The synthesis and characterization of three bis-1,8-naphthalimide-containing Tröger's bases 1-3, formed from the corresponding 4-amino-1,8-naphthalimide precursors 7-9 in a single step, is described. The photophysical investigation of 1-3 and 7-9 was carried out in various organic solvents as well as in water and as a function of pH using UV/vis and fluorescence spectroscopy. As for their 4-amino-1,8-naphthalimide precursors 7-9, both the ground-state and excited-state characteristics of 1-3 were dependent on the polarity and the hydrogen-bonding ability of the solvent medium. The DNA-binding affinities of 1-3 were also studied in aqueous solution at pH 7.4, in the presence of calf-thymus DNA (ct-DNA), using various UV/vis absorption and fluorescence spectroscopic methods. These molecules exhibited significant DNA-binding ability, where large binding values K(b) in the range of 10(6) M(-1) were determined. Such strong binding to ct-DNA was maintained even in competitive media (50 and 160 mM NaCl) and was also found to be irreversible regardless of the concentration of the ionic strength. Thermal denaturation experiments also demonstrated that the interaction of 1-3 with ct-DNA gave rise to significant stabilization in the double-helical structure of DNA. The binding affinity of 1-3 for ct-DNA was also compared to that of their 4-amino-1,8-naphthalimide precursors 7-9, determined by fitting of data using "intrinsic" methods and ethidium bromide displacement assays. The latter method gives outstanding binding constants for 1-3 in the range of 10(7) M(-1).

Demonstration of bidirectional photoinduced electron transfer (PET) sensing in 4-amino-1,8-naphthalimide based thiourea anion sensors.

The thiourea based 4-amino-1,8-naphthalimide molecules 1-5 were designed as fluorescent anion sensors and their photophysical properties investigated upon recognition of biologically relevant anions such as acetate, dihydrogen phosphate and fluoride in DMSO. Synthesised in a single step from their respective aniline precursors, 6-9, these molecules were designed on the fluorophore-spacer-receptor principle, where in the case of sensors 1-3 the thiourea anion recognition moieties were connected to the fluorophore via the 4-amino moiety, while sensors 4 and 5 had the thiourea moieties connected to the 'imide' via a CH2 spacer. The current study showed that 1-5 operated as photoinduced electron transfer (PET) sensors, as no significant changes were observed in their absorption spectra, while their fluorescence emissions were quenched upon recognition of ions such as AcO(-), H2PO4(-) and F(-), which demonstrates that bidirectional PET sensing occurs in such naphthalimide based anion sensors.

Bidirectional photoinduced electron-transfer quenching is observed in 4-amino-1,8-naphthalimide-based fluorescent anion sensors.

The synthesis and photophysical evaluations of two new fluorescent photoinduced electron-transfer (PET) anion sensors, 1 and 2, is described. These are based on 4-amino-1,8-naphthalimide fluorophores and diarylthiourea anion receptors, connected via a methylene spacer to the imide. The sensing of acetate, phosphate, and fluoride, on all occasions, gave rise to quenching in the fluorescence of 1 and 2, similar to that seen for the structural isomer 3. These results demonstrate that bidirectional PET sensing occurs in such naphthalimide-based anion sensors.

Glycosidase activated release of fluorescent 1,8-naphthalimide probes for tumor cell imaging from glycosylated 'pro-probes'.

Glycosylated 4-amino-1,8-naphthalimide derivatives possess a native glycosidic linkage that can be selectively hydrolysed in situ by glycosidase enzymes to release the naphthalimide as a fluorescent imaging or therapeutic agent. In vitro studies using a variety of cancer cell lines demonstrated that the naphthalimides only get taken up into cells upon enzymatic cleavage from the glycan unit; a mechanism that offers a novel approach for the targeted delivery of probes/drugs.

4-Amino-1,8-naphthalimide-based Tröger's bases as high affinity DNA targeting fluorescent supramolecular scaffolds.

The synthesis and photophysical and biological investigation of fluorescent 1,8-naphthalimide conjugated Troger's bases 1-3 are described. These structures bind strongly to DNA in competitive media at pH 7.4, with concomitant modulation in their fluorescence emission. These structures also undergo rapid cellular uptake, being localized within the nucleus within a few hours, and are cytotoxic against HL60 and (chronic myeloid leukemia) K562 cell lines.