Vincenzo Grande

Water-Soluble Naphthalene Diimides as Singlet Oxygen Sensitizers

Bromo- and/or alkylamino-substituted and hydrosoluble naphthalene diimides (NDIs) were synthesized to study their multimodal photophysical and photochemical properties. Bromine-containing NDIs (i.e., 11) behaved as both singlet oxygen ((1)O2) photosensitizers and fluorescent molecules upon irradiation at 532 nm. Among the NDIs not containing Br, only 12 exhibited photophysical properties similar to those of Br-NDIs, by irradiation above 610 nm, suggesting that for these NDIs both singlet and triplet excited-state properties are strongly affected by length, structure of the solubilizing moieties, and pH of the solution. Laser flash photolysis confirmed that the NDI lowest triplet excited state was efficiently populated, upon excitation at both 355 and 532 nm, and that free amine moieties quenched both the singlet and triplet excited states by intramolecular electron transfer, with generation of detectable radical anions. Time-resolved experiments, monitoring the 1270 nm (1)O2 phosphorescence decay generated upon laser irradiation at 532 nm, allowed a ranking of the NDIs as sensitizers, based on their (1)O2 quantum yields (ΦΔ). The tetrafunctionalized 12, exhibiting a long-lived triplet state (τ ~ 32 μs) and the most promising absorptivity for photodynamic therapy application, was tested as efficient photosensitizers in the photo-oxidations of 1,5-dihydroxynaphthalene and 9,10-anthracenedipropionic acid in acetonitrile and water.

Synthesis, Binding and Antiviral Properties of Potent Core-Extended Naphthalene Diimides Targeting the HIV-1 Long Terminal Repeat Promoter G-Quadruplexes

We have previously reported that stabilization of the G-quadruplex structures in the HIV-1 long terminal repeat (LTR) promoter suppresses viral transcription. Here we sought to develop new G-quadruplex ligands to be exploited as antiviral compounds by enhancing binding toward the viral G-quadruplex structures. We synthesized naphthalene diimide derivatives with a lateral expansion of the aromatic core. The new compounds were able to bind/stabilize the G-quadruplex to a high extent, and some of them displayed clear-cut selectivity toward the viral G-quadruplexes with respect to the human telomeric G-quadruplexes. This feature translated into low nanomolar anti-HIV-1 activity toward two viral strains and encouraging selectivity indexes. The selectivity depended on specific recognition of LTR loop residues; the mechanism of action was ascribed to inhibition of LTR promoter activity in cells. This is the first example of G-quadruplex ligands that show increased selectivity toward the viral G-quadruplexes and display remarkable antiviral activity.

An Aggregating Amphiphilic Squaraine: A Light-up Probe That Discriminates Parallel G-Quadruplexes

G-quadruplexes (G4s) are peculiar DNA or RNA tertiary structures that are involved in the regulation of many biological events within mammalian cells, bacteria, and viruses. Although their role as versatile therapeutic targets has been emphasized for 35 years, G4 selectivity over ubiquitous double-stranded DNA/RNA, as well as G4 differentiation by small molecules, still remains challenging. Here, a new amphiphilic dicyanovinyl-substituted squaraine, SQgl, is reported to act as an NIR fluorescent light-up probe discriminating an extensive panel of parallel G4s while it is non-fluorescent in the aggregated state. The squaraine can form an unconventional sandwich π-complex binding two quadruplexes, which leads to a strongly fluorescent (ΦF =0.61) supramolecular architecture. SQgl is highly selective against non-quadruplex and non-parallel G4 sequences without altering their topology, as desired for applications in selective in vivo high-resolution imaging and theranostics.

Synthesis of a Doubly Boron-Doped Perylene through NHC-Borenium Hydroboration/C−H Borylation/Dehydrogenation

Reaction of an N-heterocyclic carbene (NHC)-borenium ion with 9,10-distyrylanthracene forms four B-C bonds through two selective, tandem hydroboration-electrophilic C-H borylations to yield an isolable, crystallographically characterizable polycyclic diborenium ion as its [NTf2 ]- salt (1). Dehydrogenation of 1 with TEMPO radical followed by acidic workup yields a 3,9-diboraperylene as its corresponding borinic acid (2). This sequence can be performed in one pot to allow the facile, metal-free conversion of an alkene into a small molecule containing a boron-doped graphene substructure. Doubly boron-doped perylene 2 exhibits visible range absorbance and fluorescence in chloroform solution (Φ=0.63) and undergoes two reversible one-electron reductions at moderate potentials of -1.30 and -1.64 eV vs. ferrocenium/ferrocene in DMSO. Despite sterically accessible boron centers and facile electrochemical reductions, compound 2 is air-, moisture-, and silica gel-stable.

Tetrachlorinated Polycyclic Aromatic Dicarboximides: New Electron-Poor π-Scaffolds and NIR Emitters by Palladium-Catalyzed Annulation Reaction

Herein we report a palladium-catalyzed annulation reaction consisting of a Suzuki-Miyaura cross-coupling and a C-H arylation cascade for the synthesis of tetrachlorinated polycyclic aromatic dicarboximides (PADIs). This convergent synthetic route afforded a broad series of hitherto unknown electron-deficient PADIs under optimized reaction conditions by coupling of a dibromo-tetrachloro-perylene dicarboximide with different polycyclic aromatic hydrocarbon (PAH) boronic acid pinacol esters in up to 89 % yields. The new PADI compounds show broad absorption in the visible range and some of them emit in the near-infrared (NIR) region. Cyclic and square wave voltammetric studies revealed that these tetrachlorinated PADIs are more electron-deficient than a non-chlorinated reference compound and they possess lower lying frontier orbitals. Thus, the newly synthesized electron-poor PADIs are potential n-type semiconductors. Moreover, these chlorinated PADIs are interesting building blocks for the construction of large π-extended arrays by metal-mediated coupling reactions.

Water-soluble naphthalene diimides: synthesis, optical properties, and colorimetric detection of biogenic amines

A large number of water-soluble naphthalene diimides (NDIs) bearing an electron-withdrawing chloro and electron-donating amino-substituents with varied electronic character at the core were synthesized by a two-step synthetic approach comprising imidization of 2,6-dichloronaphthalene dianhydride with L-glutamic acid or 2-dimethylaminoethylamine and subsequent nucleophilic substitution of a chlorine atom with primary amines. These new donor–acceptor NDI dyes show absorption and emission maxima beyond 500 nm and fluorescence quantum yields up to 39% in aqueous phosphate buffer solution at acidic and neutral pH values. Our studies revealed a significant effect of core amino-substituents on the optical properties of these NDIs. With increasing electron-withdrawing character of the residues of amino-substituents the absorption and emission maxima are more hypsochromically shifted and the fluorescence quantum yields are markedly increased with the highest value of 39% for NDIs containing a strongly electron withdrawing trifluroethyl group in the amino-substituent. Furthermore, the high reactivity of the core-dichlorinated NDI dye could be utilized for the optical detection of primary amines and biogenic diamines putrescine and cadaverine.

A Catalytic and Selective Scissoring Molecular Tool for Quadruplex Nucleic Acids

A copper complex embedded in the structure of a water-soluble naphthalene diimide has been designed to bind and cleave G-quadruplex DNA. We describe the properties of this ligand, including its catalytic activity in the generation of ROS. FRET melting, CD, NMR, gel sequencing, and mass spectrometry experiments highlight a unique and unexpected selectivity in cleaving G-quadruplex sequences. This selectivity relies both on the binding affinity and structural features of the targeted G-quadruplexes.