BODIPY Research Articles

Novel π-extended polycyclic chromenopyridines: Synthesis, DFT, electrochemical, and thermogravimetric evaluation

Polycyclic aromatic hydrocarbons (PAHs) doped with heteroatoms such as thiophene, carbazole, and boron-dipyrromethene (BODIPY) have attracted increased attention because of their excellent optoelectronic properties in addition to the robust skeletons required for the construction of efficient organic electronics. Herein, novel π-extended polycyclic chromenopyridines 3a-d, 5, and 7 were synthesized via base-catalyzed cascade reaction of 3-cyano-7,8-benzochromone 1 with acetonitrile derivatives 2a-d, ethyl chloroacetate 4, and phenylpyrazolone 6 in very good to excellent yields. Density functional theory (DFT) calculation and electrochemical evaluation of compounds 3a-d, 5, and 7 revealed a decreased energy gap (Eg) compared to the precursor 3-cyanochromone 1 indicating their superior semiconducting and light-harvesting abilities. In addition, the observed thermal stability of chromenopyridines 3a-d, 5, and 7 with maximum weight loss at temperatures between 301.72 and 557.28 °C qualified them for wide organic electronic applications.

Boron Dipyrromethene-Based Phototheranostics for Near Infrared Fluorescent and Photoacoustic Imaging-Guided Synchronous Photodynamic and Photothermal Therapy of Cancer

The regulation of photochemical properties of phototheranostics, especially the absorption, fluorescence, singlet oxygen (1O2) generation, and photothermal conversion efficiency, is a hot research topic. Here, we designed and synthesized four boron dipyrromethene (BODIPY) derivatives with high absorption coefficients and intense fluorescence in the near-infrared (NIR) region. The substituted electron-donating group significantly improved 1O2 generation and fluorescence of BODIPYs, whereas the electron-withdrawing group boosts photothermal conversion. These hydrophobic BODIPYs were further coated with DSPE-PEG-2000 to form water dispersible nanoparticles (NPs). Among these BODIPY NPs, the B-OMe-NPs with methoxyl substituted at the meso-position showed the highest 1O2 generation, a photothermal conversion efficiency of 66.5%, and an NIR fluorescence peak at 809 nm. In vitro and in vivo experiments demonstrated that B-OMe-NPs might be used for NIR fluorescent and photoacoustic imaging-guided photodynamic and photothermal therapy of cancer.

Synthesis of a new tripod BODIPY dye bearing N-tert-Butoxycarbonyl amine and its acetylation

A new tripod boron dipyrromethene (BODIPY) dye bearing N-tert-butoxycarbonyl (N-Boc) amine side chain was synthesized and the functionality was confirmed by means of its acetylation reaction with acetic anhydride. Deprotection of the N-Boc protective group had been successfully performed using boron trifluoride etherate (BF3·OEt2) solution alone or the combination of BF3·OEt2 and molecular sieves to solve the susceptibility of the BODIPY fluorophore under the protonic acid conditions. All the new structures had been characterized by NMR, HRMS and IR spectra. A conformational isomeric phenomenon was observed originating from partly restricted rotation of the RNH group attached to the 1,3,5-triazine ring. This work made the chemical transformation via amine functionality around meso position in the tripod BODIPY available.

Detection of gamma radiation processed onion during storage using propidium iodide based fluorescence microscopy

The determination of absorbed dose in gamma radiation processed onion (treated with 20–100 Gy for sprout inhibition) during storage is an important regulatory requirement to control unfair practices. To address this problem, a microscopy based method was developed using propidium iodide (PI) staining of onion adaxial epidermis. A proportional radiation dose dependent increase in nuclei count was observed during ambient (26 ± 2 °C) and low (2 ± 1 °C) temperature storage. The method was validated and dose of radiation could be determined accurately in stored onions using blind tests. During mechanism studies, boron-dipyrromethene (BODIPY) dye staining and malondialdehyde (MDA) estimation showed dose dependent increase in peroxidation of membrane lipids. The fluorescein diacetate (FDA) stained onion adaxial epidermis showed decrease in fluorescence indicating lowering of physiological activity. Enzyme peroxidase (POD), phenylalanine ammonia lyase (PAL) activities and phytochemicals (phenolics, flavonoids, ascorbic acid and pyruvic acid) did not change significantly with increasing dose of gamma radiation.

Activatable iodinated BODIPYs for selective imaging and photodynamic disruption of amyloid structures in pathogenic bacterial biofilms

We report the application of two iodinated boron dipyrromethene (BODIPY) photocatalysts as theranostic compounds against pathogenic bacterial biofilms. These derivatives, which are activated through a polarity effect upon binding, have exquisite selectivity towards amyloids in the biofilm extracellular matrix (ECM). This property can be exploited in fluorescence microscopy to stain the ECM of uropathogenic bacterial biofilms, displaying a superior selectivity compared to Thioflavin T, the gold standard for amyloid detection. Moreover, we show that the ability of these compounds to photosensitize reactive oxygen species upon binding can be used to weaken the mechanical barrier of the ECM and restore the activity of conventional antimicrobial agents, whose effect is strongly limited in intact biofilms. The combination of activatable near-infrared fluorescence and photo-oxygenation properties of these compounds upon binding to amyloid structures provides a powerful theranostic tool for simultaneous detection and treatment of pathogenic biofilm infections.

BODIPY-Based Nanomaterials—Sensing and Biomedical Applications

Cancerous diseases are rightfully considered among the most lethal, which have a consistently negative effect when considering official statistics in regular health reports around the globe. Nowadays, metallic nanoparticles can be potentially applied in medicine as active pharmaceuticals, adjustable carriers, or distinctive enhancers of physicochemical properties if combined with other drugs. Boron dipyrromethene (BODIPY) molecules have been considered for future applications in theranostics in the oncology field, thus expanding the potential of conceivable applicability. Hence, taking into account positive practical features of both metal-based nanostructures and BODIPY derivatives, the present study aims to gather recent results connected to BODIPY-conjugated metallic nanoparticles. This is with respect to their expediency in the diagnosis and treatment of tumor ailments as well as in sensing of heavy metals. To fulfill the designated objectives, multiple research documents were analyzed concerning the latest discoveries within the scope of BODIPY-based nanomaterials with particular emphasis on their utilization for diagnostical sensing as well as cancer diagnostics and therapy. In addition, collected examples of mentioned conjugates were presented in order to draw the attention of the scientific community to their practical applications, elucidate the topic in a consistent manner, and inspire fellow researchers for new findings.

Phenylthiol-BODIPY-based supramolecular metallacycles for synergistic tumor chemo-photodynamic therapy

The development of more effective tumor therapy remains challenging and has received widespread attention. In the past decade, there has been growing interest in synergistic tumor therapy based on supramolecular coordination complexes. Herein, we describe two triangular metallacycles (1 and 2) constructed by the formation of pyridyl boron dipyrromethene (BODIPY)-platinum coordination. Metallacycle 2 had considerable tumor penetration, as evidenced by the phenylthiol-BODIPY ligand imparting red fluorescent emission at ∼660 nm, enabling bioimaging, and transport visualization within the tumor. Based on the therapeutic efficacy of the platinum(II) acceptor and high singlet oxygen (1O2) generation ability of BODIPY, 2 was successfully incorporated into nanoparticles and applied in chemo-photodynamic tumor therapy against malignant human glioma U87 cells, showing excellent synergistic therapeutic efficacy. A half-maximal inhibitory concentration of 0.35 μM was measured for 2 against U87 cancer cells invitro. In vivo experiments indicated that 2 displayed precise tumor targeting ability and good biocompatibility, along with strong antitumor effects. This work provides a promising approach for treating solid tumors by synergistic chemo-photodynamic therapy of supramolecular coordination complexes.

“Domain Directional Optimization” strategy for the development of UGT1A1-activated fluorescent probe and the application in living systems

Activity-based fluorescent probes have emerged as the powerful tool for directly monitoring enzyme activity in living systems. Whereas, constructing high isoform-specific fluorescent probes for a target isoenzyme with multiple subtypes is still facing challenge. UGT1A1, as an isoform of UGTs, is a clear target for neonatal jaundice, irinotecan-induced toxicity, and fatal Crigler-Najjar syndrome type I. Herein, a “Domain Directional Optimization” strategy was proposed based on the systematic computational chemistry and synchronously experimental verification. Finally, an isoform-specific “switch-on” fluorescent probe (BUHE) was developed for UGT1A1 based on the boron-dipyrromethene (BODIPY) skeleton. BUHE exhibited the high selectivity and sensitivity toward UGT1A1 and the catalytic progress followed typical Michaelis-Menten kinetic. Moreover, BUHE had a good biocompatibility and chemical stability which was successfully applied to the activity evaluation and in situ imaging of UGT1A1 in complicated bio-systems including living cells, tissue slices and whole organs. In summary, the “Domain Directional Optimization” strategy could serve as a powerful method for developing the isoform-specific fluorescent probe.

A Comparison of the Photophysical, Electrochemical and Cytotoxic Properties of meso-(2-, 3- and 4-Pyridyl)-BODIPYs and Their Derivatives.

Boron dipyrromethene (BODIPY) dyes bearing a pyridyl moiety have been used as metal ion sensors, pH sensors, fluorescence probes, and as sensitizers for phototherapy. A comparative study of the properties of the three structural isomers of meso-pyridyl-BODIPYs, their 2,6-dichloro derivatives, and their corresponding methylated cationic pyridinium-BODIPYs was conducted using spectroscopic and electrochemical methods, X-ray analyses, and TD-DFT calculations. Among the neutral derivatives, the 3Py and 4Py isomers showed the highest relative fluorescence quantum yields in organic solvents, which were further enhanced 2-4-fold via the introduction of two chlorines at the 2,6-positions. Among the cationic derivatives, the 2catPy showed the highest relative fluorescence quantum yield in organic solvents, which was further enhanced by the use of a bulky counter anion (PF6−). In water, the quantum yields were greatly reduced for all three isomers but were shown to be enhanced upon introduction of 2,6-dichloro groups. Our results indicate that 2,6-dichloro-meso-(2- and 3-pyridinium)-BODIPYs are the most promising for sensing applications. Furthermore, all pyridinium BODIPYs are highly water-soluble and display low cytotoxicity towards human HEp2 cells.

Phototoxicity of BODIPY in long-term imaging can be reduced by intramolecular motion

For long-term live-cell fluorescence imaging and biosensing, it is crucial to work with a dye that has high fluorescence quantum yield and photostability without being detrimental to the cells. In this paper, we demonstrate that neutral boron-dipyrromethene (BODIPY)-based molecular rotors have great properties for high-light-dosage demanding live-cell fluorescence imaging applications that require repetitive illuminations. In molecular rotors, an intramolecular rotation (IMR) allows an alternative route for the decay of the singlet excited state (S1) via the formation of an intramolecular charge transfer state (CT). The occurrence of IMR reduces the probability of the formation of a triplet state (T1) which could further react with molecular oxygen (3O2) to form cytotoxic reactive oxygen species, e.g., singlet oxygen (1O2). We demonstrate that the oxygen-related nature of the phototoxicity for BODIPY derivatives can be significantly reduced if a neutral molecular rotor is used as a probe. The studied neutral molecular rotor probe shows remarkably lower phototoxicity when compared with both the non-rotating BODIPY derivative and the cationic BODIPY-based molecular rotor in different light dosages and dye concentrations. It is also evident that the charge and localization of the fluorescent probe are as significant as the IMR in terms of the phototoxicity in a long-term live-cell imaging.Graphical abstract

A near-infrared photoacoustic probe for specific detection of fluoride ion in vivo

Fluoride is an essential trace element in the human body and plays an essential role in various physiological processes. However, fluoride ion detection in vivo remains challenging due to the lack of probes that can enter the organism and emit at the near infrared region (NIR). Herein, we developed a boron-dipyrromethene (BODIPY)-based NIR probe that takes advantage of the high resolution and deep penetration of photoacoustic imaging, which can produce high NIR absorption at 803 nm in the presence of fluoride ions, resulting in a strong photoacoustic signal in the NIR region. In addition, the probe exhibits high selectivity for fluoride ions. In view of these outstanding features, the probe was then successfully applied to fluoride ion imaging in living mice, proving that a probe is a promising tool for fluoride ion detection in vitro and in vivo.

Near‐Infrared Circularly Polarised Luminescence from Helically Extended Chiral N,N,O,O‐Boron Chelated Dipyrromethenes

AbstractSynthetically straightforward π‐extension of helically chiral N,N,O,O‐boron chelated borondipyrromethenes (BODIPYs) has been achieved by incorporation of naphthyl rings into the BODIPY 3‐ and 5‐positions. The effect of this extension on the photophysical and chiroptical properties is strongly dependent on the regiochemistry of the naphthyl substituents (4 exo, 4 lin, 4 endo). The most helicene‐like regioisomer 4 endo is a near infra‐red (NIR) emitter (λemmax=751 nm) with an emission band between 675–875 nm, displaying circularly polarised luminescence (CPL) with a luminescence dissymmetry factor, |glum|=5.7×10−3 and CPL brightness, BCPL=27, rivalling the best NIR CPL‐emitting small organic molecules reported to date.

Intravital Subcellular Microscopy of the Mammary Gland.

The mammary gland constitutes a model par excellence for investigating epithelial functions, including tissue remodeling, cell polarity, and secretory mechanisms. During pregnancy, the gland expands from a primitive ductal tree embedded in a fat pad to a highly branched alveolar network primed for the formation and secretion of colostrum and milk. Post-partum, the gland supplies all the nutrients required for neonatal survival, including membrane-coated lipid droplets (LDs), proteins, carbohydrates, ions, and water. Various milk components, including lactose, casein micelles, and skim-milk proteins, are synthesized within the alveolar cells and secreted from vesicles by exocytosis at the apical surface. LDs are transported from sites of synthesis in the rough endoplasmic reticulum to the cell apex, coated with cellular membranes, and secreted by a unique apocrine mechanism. Other preformed constituents, including antibodies and hormones, are transported from the serosal side of the epithelium into milk by transcytosis. These processes are amenable to intravital microscopy because the mammary gland is a skin gland and, therefore, directly accessible to experimental manipulation. In this paper, a facile procedure is described to investigate the kinetics of LD secretion in situ, in real-time, in live anesthetized mice. Boron-dipyrromethene (BODIPY)665/676or monodansylpentane are used to label the neutral lipid fraction of transgenic mice, which either express soluble EGFP (enhanced green fluorescent protein) in the cytoplasm, or a membrane-targeted peptide fused to either EGFP or tdTomato. The membrane-tagged fusion proteins serve as markers of cell surfaces, and the lipid dyes resolve LDs ≥ 0.7 µm. Time-lapse images can be recorded by standard laser scanning confocal microscopy down to a depth of 15-25 µm or by multiphoton microscopy for imaging deeper in the tissue. The mammary gland may be bathed with pharmacological agents or fluorescent dyes throughout the surgery, providing a platform for acute experimental manipulations as required.

Direct Utilization of Near-Infrared Light for Photooxidation with a Metal-Free Photocatalyst.

Near-infrared (NIR) light-triggered photoredox catalysis is highly desirable because NIR light occupies almost 50% of solar energy and possesses excellent penetrating power in various media. Herein we utilize a metal-free boron dipyrromethene (BODIPY) derivative as the photocatalyst to achieve NIR light (720 nm LED)–driven oxidation of benzylamine derivatives, sulfides, and aryl boronic acids. Compared to blue light–driven photooxidation using Ru(bpy)3Cl2 as a photocatalyst, NIR light–driven photooxidation exhibited solvent independence and superior performance in large-volume (20 mL) reaction, presumably thanks to the neutral structure of a BODIPY photocatalyst and the deeper penetration depth of NIR light. We further demonstrate the application of this metal-free NIR photooxidation to prodrug activation and combination with Cu-catalysis for cross coupling reaction, exhibiting the potential of metal-free NIR photooxidation as a toolbox for organic synthesis and drug development.

An advanced multifunctional prodrug combining photodynamic therapy with chemotherapy for highly efficient and precise tumor ablation

It is urgently required to develop the molecular agents with high therapeutic efficacy and low side effects for precise cancer therapy. Herein, an advanced multifunctional prodrug B-BDP-CL-CPT, consisting of a glutathione (GSH)-responsive boron dipyrromethene (BDP)-based photosensitizer, a chemo drug camptothecin (CPT), a reactive oxygen species (ROS)-sensitive chain linking BDP with CPT, and a biotin fragment with specific affinity to biotin-receptor, was designed and synthesized. Owing to the introduction of 2,4-dinitrobenzenesulfonate (DNBS) as the quencher into BDP core and chemical modification of CPT at the active site, B-BDP-CL-CPT is non-cytotoxic. Having biotin as the targeting ligand, the prodrug can be efficiently internalized by biotin-acceptor positive cancer cells, and then activated to generate substantial light-induced ROS through removal of the stopper DNBS by intracellular GSH which is abundant in cancer cells. The resulting ROS can not only serve for photodynamic therapy (PDT) but also further cleave thioketal linkage causing the release of CPT, to achieve dual PDT and chemotherapy. And the combination of preferential accumulation with specific activation in tumor tissues for this prodrug is conducive to improving the dual therapeutic outcome meanwhile greatly reducing the photo-damage and the release of CPT in adjacent healthy tissues. In addition, the activated B-BDP-CL-CPT can give bright fluorescence signals which are favor for imaging-guided PDT and real-time tracking the release of therapeutic agent. The in vitro and in vivo investigations have been performed to demonstrate the targeted and combined anticancer activities of this prodrug against HepG2 and HeLa cancer cells, and the mice with H22 tumors. This study proposes a new tactics for highly efficient and precise cancer treatment.

A Near-Infrared BODIPY-Based Rhomboidal Metallacycle for Imaging-Guided Photothermal Therapy

Although boron dipyrromethene (BODIPY)-based metallacycles are expected to be promising candidates for imaging probes and therapeutic agents, their biomedical applications are restricted by their short absorption/emission wavelengths. In this work, we report a rhombic metallacycle M with broad absorption in the near-infrared (NIR) range and emissions at wavelengths >800 nm, which exhibits an efficient photothermal conversion capacity. Metallacycle M was encapsulated via Pluronic F127 to fit the biotic environment, resulting in the generation of F127/M nanoparticles (NPs) with high hydrophilicity and biocompatibility. In vitro studies demonstrated that the F127/M NPs underwent efficient cellular uptake and exhibited satisfactory photothermal therapeutic activity. Furthermore, in vivo experiments revealed that tumor growth was effectively inhibited, and the degree of undesirable biological damage was minimal in treatment with F127/M NPs and laser irradiation. Finally, the F127/M NPs could be visualized through NIR fluorescence imaging in living mice, thereby allowing their distribution to be monitored in order to enhance treatment accuracy during photothermal therapy. We envision that such BODIPY-based metallacycles will provide emerging opportunities for the development of novel therapeutic agents for biomedical applications.

Synthesis, Optical Properties, Preliminary Antimycobacterial Evaluation and Docking Studies of Trifluoroacetylated 3‐Pyrrolyl Boron‐Dipyrromethene

AbstractThe article provides the route to trifluoroacetylated fluorescent boron dipyrromethene dye (2). The compound performs intensive absorption and emission bands in near‐red wavelength region. Photophysical properties of 2 are investigated in different solvents. A notable increase of fluorescence quantum yield after trifluoroacetyl group insertion connected with a change in intramolecular interactions parameters. The role of molecular geometry aspects in observed photophysical properties and molecular fragments rotation energy barriers are explained by quantum‐mechanical calculations. 2 performs considerable antimycobacterial activity. According to molecular docking simulations, 2 is capable of affinity binding in the active sites of mycobacterial MycP1 and MycP3 serine proteases. The geometries of final ligand‐protein complexes show the possibility of protein active site covalent modification at the serine residue of the catalytic triad. At lower concentrations, 2 can act as a fluorescent dye for microscopy analysis and corresponding staining patterns are shown for Mycobacterium smegmatis and Staphylococcus aureus cells.

Rotor-Tuning Boron Dipyrromethenes for Dual-Functional Imaging of Aβ Oligomers and Viscosity.

Alzheimer's disease (AD), known as a common incurable and elderly neurodegenerative disease, has been widely explored for accurate detection of its biomarker (Aβ oligomers) for early diagnosis. Although great efforts have been made, it is still of great importance to develop fluorescence probes for Aβ oligomers with good selectivity and low background. Herein, starting from BODIPY493/503 (a commercial dye for neutral lipid droplets), which exhibited a small Stokes shift and no response toward Aβ peptides, two fluorescence probes 5MB-SZ and B-SZ with a benzothiazole rotor at the 2-position of the BODIPY core and a methyl or benzyl group at the meso position have been designed and synthesized, which exhibited excellent optical properties/stability and could successfully image β-amyloid fibrils and viscosity. Upon exposure to Aβ oligomers, the fluorescence intensity of 5MB-SZ was enhanced by 43.64-fold with the corresponding fluorescence quantum yields changing from 0.85% to 27.43%. Meanwhile, probe 5MB-SZ showed a highly sensitive viscosity response in both solutions and living cells. In vitro and in vivo experiments confirmed that probe 5MB-SZ exhibited an excellent capacity for imaging β-amyloid fibrils. Therefore, 5MB-SZ, as a rotor-tuning BODIPY analogue, could possibly serve as a highly potential and powerful fluorescence probe for early diagnosis of AD.

Optimization of Peptide Linker-Based Fluorescent Ligands for the Histamine H1 Receptor.

The histamine H1 receptor (H1R) has recently been implicated in mediating cell proliferation and cancer progression; therefore, high-affinity H1R-selective fluorescent ligands are desirable tools for further investigation of this behavior in vitro and in vivo. We previously reported a H1R fluorescent ligand, bearing a peptide-linker, based on antagonist VUF13816 and sought to further explore structure–activity relationships (SARs) around the linker, orthostere, and fluorescent moieties. Here, we report a series of high-affinity H1R fluorescent ligands varying in peptide linker composition, orthosteric targeting moiety, and fluorophore. Incorporation of a boron-dipyrromethene (BODIPY) 630/650-based fluorophore conferred high binding affinity to our H1R fluorescent ligands, remarkably overriding the linker SAR observed in corresponding unlabeled congeners. Compound 31a, both potent and subtype-selective, enabled H1R visualization using confocal microscopy at a concentration of 10 nM. Molecular docking of 31a with the human H1R predicts that the optimized peptide linker makes interactions with key residues in the receptor.

Exploring BODIPY derivatives as photosensitizers for antibacterial photodynamic therapy

There is an urgent need to develop efficient and safe antimicrobials to augment traditional antibiotics for fighting drug-resistant bacteria. Antimicrobial photodynamic therapy (aPDT), is a promising antimicrobial stize antibiotic resistance and may reduce systemic side effects. Boron-dipyrromethene (BODIPY) is a type of photosensitizer (PSs) for aPDT with tunable structures and rational photophysical features. Herein, six kinds of BODIPY derivatives (BDP1-BDP6) modified with different atoms or groups such as iodine atoms, thiophene, cyano, phenyl, aldehyde and nitro groups were synthesized and their photophysical behaviors were characterized. The results indicated that BDP3, which had 2, 6-diiodo and 8-phenyl substitution, was the best PS candidate with the highest reactive oxygen species (ROS) generation efficacy. BDP3 and BDP5 could rapidly kill Staphylococcus aureus (S. aureus) with the minimum inhibitory concentration (MIC) of 10 nM upon illumination. They also possessed excellent biofilm inhibition ability against S. aureus and could efficaciously restrain the formation of bacterial biofilm. The results of Live/Dead staining assay and scanning electron microscopy (SEM) demonstrated that BDP3 destroyed the cell membrane structure of bacteria by generating ROS, which ultimately led to bacterial lysis and death. Finally, the biosafety evaluation toward the mouse fibroblasts (L929 cells) suggested BDP3 had good cytocompatibility. This work exhibits the great potential of rational designs of PS for aPDT applications.