aza-BODIPY Core Research Articles

Synthesis of D-A-type groups modified aza-BODIPY fluorescent dye encapsulated by amphiphilic polypeptide nanoparticles for NIR-II phototheranostics

An innovative organic small molecule with a D-A structure was synthesized by connecting triphenylamine to BODIPY via a thiophene bridge. Triphenylamine and thiophene units ingeniously modulate the balance between steric hindrance and π-π interactions around the flat aza-BODIPY core. The molecule exhibits near-infrared fluorescence absorption and emits at roughly 1100 nm, featuring a significant Stokes shift. Both the molecule and its nanoparticles demonstrate high stability and achieve a remarkable 35 % photothermal conversion efficiency when conjugated with the P(OEGMA)20-P(Asp)14 copolymer. In vitro assessments show low dark toxicity and outstanding biocompatibility. Moreover, in vivo studies and photothermal therapy in mice indicate substantial tumor shrinkage and reduced recurrence, confirming its potential in cancer treatment. These results highlight the promise of this organic molecule and its nanoparticles for NIR-II imaging-guided photothermal therapy, introducing a novel approach to phototheranostic applications for cancer management.

Aza-BODIPY-based logic gate chemosensors and their applications

Dimethylaniline-substituted aza-BODIPY dyes (DA, DM, DP) were designed and synthesized aiming for ion detection. The Zn2+ recognition ability was found in all compounds and the binding mechanism was possibly via dimethylaniline sites linked to the aza-BODIPY core. Upon Zn2+ addition, the new absorption band and the color change occurred due to the altered charge transfer of the adducts. The custom-made colorimeter was successfully integrated into the dye’s application, demonstrating a good linear relationship between resistance values and Zn2+ concentration. The chromophore test strips were fabricated and exhibited distinct color changes upon aqueous Zn2+ exposure. The compound DA also exhibits logical behavior with DA-Zn2+-Cu2+ system. In terms of environmental hazards, the compounds exhibited no adverse effect on Pseudomonas putida at the concentration level of 0.2 mg/mL. These findings indicated that all synthesized aza-BODIPYs might be suitable for chemosensor probes for Zn2+ detection with possibly low environmental risk.

Aza-BODIPY dye with unexpected bromination and high singlet oxygen quantum yield for photoacoustic imaging-guided synergetic photodynamic/photothermal therapy

Introducing heavy halogen atoms into organic small molecules is a practical strategy for efficient singlet oxygen (1O2) generation. Generally, bromine or iodine atoms are introduced on the aza-boron-dipyrromethene (aza-BODIPY) core, rather than on the periphery aryl rings for efficient 1O2 generation. Herein, an aza-BODIPY dye NBDPBr with unexpected bromination on the periphery aryl rings was synthesized for photoacoustic (PA) imaging-guided synergistic photothermal therapy (PTT) and photodynamic therapy (PDT) in tumor cells. Owing to unexcepted bromination at the periphery aryl rings, NBDPBr demonstrated an outstanding singlet oxygen quantum yield (ΦΔ) of 66% which was superior to similar brominated photosensitizers previously reported. After encapsulation with amphiphilic polymer F-127, hydrophilic NBDPBr nanoparticles (NPs) were fabricated and exhibited an excellent photothermal conversion efficiency (η) of 43.0% under 660 nm photoirradiation. In vivo PA imaging results demonstrated that NBDPBr NPs could specifically accumulate at tumor sites and realized the maximum tumor retention at 7 h post-injection. All the in vitro and in vivo results indicated the significant potence of NBDPBr with unexpected bis-bromination for PA imaging-guided synergetic PDT/PTT.

Tuning the Photophysical Properties of Aza-BODIPYs in the Near-Infrared Region by Introducing Electron-Donating Thiophene Substituents.

This study presents the synthesis, the spectroscopic and electrochemical properties of new bis- and tetra-substituted azaboron-dipyrromethene (aza-BODIPY) dyes substituted by different electron donating groups connected to the aza-BODIPY core through a thiophene unit. In line with theoretical calculations, experimental measurements point out the positive impact of the thiophene group that behave as a secondary donor group leading to an enhancement of the intramolecular charge transfer process in comparison to previously reported aza-BODIPY dyes. This heterocycle has also been found to tune the oxidative potential and to stabilize the electro-generated species.

Novel phenothiazine-based amphiphilic Aza-BODIPYs for high-efficient photothermal therapy

Photothermal therapy (PTT) is one of innovative therapeutics types that have been widely applied in cancer treatment, antibiosis and insecticide. It is of significance to investigate photothermal conversion agents (PCAs) with outstanding photothermal conversion ability, photostability and biocompatibility. Here, we developed three novel phenothiazine-based aza-BODIPYs for high-efficient PTT applications. Phenothiazine, as the electron-donating moiety, was introduced into aza-BODIPY core to achieve red-shifted absorption band (∼20–40 nm) with λmax at 730–745 nm and high molar extinction efficient (105 M−1 cm−1). TEG linker was decorated for further increasing the hydrophilicity and biocompatibility of aza-BODIPYs. After self-assembly, the nanoparticles exhibited the preferable photothermal conversion efficient (53–63%) and high photostability with the appropriate hydrated sizes (60–110 nm) and homogenous morphologies. Finally, the aza-BODIPY nanoparticles can significantly decrease the HeLa cell viability under 808 nm laser irradiation, but have the negligible cytotoxicity in dark environments. The series of phenothiazine-based aza-BODIPY PCAs have much potential for the more applications of clinic photothermal therapy in future.

Multichromophore Integrated Panchromatic AzaBODIPYs: Synthesis, Characterization, and Exploring the Role of AzaBODIPY as an Energy and Electron Relay in Photoinduced Processes.

Panchromatic azaborondipyrromethenes directly connected with N,N-ditolylaniline (TPA) and naphthalene (Naph) at 1,7- and/or 3,5-positions of the azaBODIPY platform, 1, 2, and 3, were synthesized and the role of the individual chromophore constituents in the photo-induced energy and electron transfer processes has been investigated. Optical absorption studies have indicated that, integrating the complementary absorbers, naphthalene and TPA moieties, into the azaBODIPY core yielded broad-band capturing dyes with the absorption ranging from 250-1000 nm. Parallel electrochemical studies revealed that TPA moiety in 1 and 2 is easier to oxidize when compared to azaBODIPY moiety, which are in congruent with the computational studies indicating that TPA moiety would behave as an electron donor and azaBODIPY as an acceptor in PET processes. Steady-state fluorescence studies indicated that the photo-excitation of the TPA moiety in 2 resulted in the occurrence of PET from 1TPA* to azaBODIPY generating (TPA)2+.-(azaBODIPY)-⸱ while that of naphthalene in 3 resulted in PEnT from 1(naphthalene)* to azaBODIPY forming (Naph)2+.-(azaBODIPY)*. Interestingly, in 1, excitation of naphthalene moiety resulted in sequential PEnT from 1(naphthalene)* to azaBODIPY followed by the PET from TPA to 1(azaBODIPY)* generating a charge-separated state, (TPA)2+.-(azaBODIPY)-⸱-(Naph)2. Fluorescence lifetime studies have indicated that the electron and energy transfer process occurred in nanosecond time scales.

Attachment of -tBu groups to aza-BODIPY core at 3,5-sites with ultra-large Stokes shift to enhance photothermal therapy through apoptosis mechanism.

By the introduction of the −tBu groups into aza-BODIPY core, di-tert-butyl-substituted aza-BODIPYs at 3,5-sites (tBuazaBDPs) were prepared for the first time. Based on the X-ray analysis of CN-tBuazaBDP, this molecular structure is twisted. Near-infrared dye SMe-tBuazaBDP has the ultra-large Stokes shift (152 ​nm) in aza-BODIPY system, combining with the twisted intramolecular charge transfer and the free rotation of the −tBu groups at 3,5-sites. Although the barrier-free rotors of the distal −tBu groups in SMe-tBuazaBDP result in low fluorescence quantum yield, the photothermal conversion efficiency is markedly enhanced. SMe-tBuazaBDP nanoparticles with low power laser irradiation were proven to block cancer cell cycle, inhibit cancer cell proliferation, and induce cancer cell apoptosis in photothermal therapy (PTT). The strategy of “direct attachment of −tBu groups to aza-BODIPY core” gives a new design platform for a photothermal therapy agent.

A self-assembled aza-BODIPY linked dicyanostilbenzene with a large Stokes shift, AIE, mechanochromism and singlet oxygen yield

A novel polycatenar liquid crystal containing two α-cyanostilbene (CS) interconnected by an aza-BODIPY core and three alkoxy chains at each end has been prepared via Suzuki coupling and Knoevenagel reactions as key steps. This compound can self-assemble into the enantiotropic columnar phase with p4mm lattice and organogels with different morphologies. Such NIR compound displays a large Stokes shift and AIE effect. It possesses a certain singlet oxygen yield. The CS units also endow such compound mechanochromic luminescence (MCL) responsive property. These properties have been verified by theoretical calculation.

Amplifying the photovoltaic properties of azaBODIPY core based small molecules by terminal acceptors modification for high performance organic solar cells: A DFT approach

Molecular engineering of azaBODIPY based molecule was done to construct four novel small photoactive materials (SM1-SM4) by varying terminal thiophene spaced acceptors for theoretical investigation of photovoltaic properties. In the present study, DFT and TD-DFT methods using B3LYP functionalwith a basis set of 6-31G were employed to systematically evaluate wavelength, determine parameters (absorption values, first excitonic energy, LHE), charge transfer elements (fill factor FF, open circuit voltage Voc), reactivity descriptors (IP and EA) and electronic processes (FMO, DOS, TDM) of modelled molecules (SM1-SM4). All studied molecules showed intense optical absorption in the visible region (710–751 nm), strong light harvesting capability, clearly assigned HOMO-LUMO placement, and lessened exciton binding energies due to highly electron withdrawing acceptor moieties. Greater dipole moment in solution phase than in the gas phase as compared to gaseous medium indicated that these small molecules possessed good solubility in Benzonitrile solvent.The internal reorganization energy values of novel molecules suggested their reliability as efficient hole transport materials. Additionally, results interpreted through analysis of values of Voc (with PTB7-Th), and FF, anticipated an escalation of power conversion efficiency. Among all considered molecules, SM2 and SM3 emerged as promising photovoltaic materials owing to their significant optical properties, reduced band gaps, rapid exciton dissociation, and high estimated PCE. Conclusively, these supportive outcomes favor the structural amendment of small molecules through effective terminal acceptor entities which could enhance the efficiency of photovoltaic materials.

Near-Infrared fluorescent unsymmetrical aza-BODIPYs: Synthesis, photophysics and TD-DFT calculations

In view of the ever-growing demand for efficient NIR fluorophores for biomedical applications, we herein report the synthesis and properties of four unsymmetrical aza-BODIPYs exhibiting NIR fluorescence. Highly desirable photophysical and photochemical properties were induced in these molecules due to the presence of both strongly electron-withdrawing p-nitrophenyl rings (p-NO2Ph-) and mildly electron-donating p-methoxyphenyl rings (p-MeOPh-) within the aza-BODIPY core. In particular, upon excitation with λabs the unsymmetrical aza-BODIPYs studied exhibited NIR emission with λf ranging from 699 nm to 718 nm in toluene. The fluorescence quantum yields (Φf), depending on the substitution pattern, ranged from Φf = 0.49 to Φf = 0.22 and the fluorescence lifetimes ranged from τf = 1.90 ns to τf = 3.59 ns. Aza-BODIPY with electron-donating substituent at 3 position and electron-withdrawing substituent at 5 position was identified as cell permeable, NIR emitting fluorophore suitable for bioimaging.

ANALYSIS OF THE SENSITIVITY OF THE GAS ELECTRON DIFFRACTION METHOD TO THE DETERMINATION OF THE CONFORMATIONAL COMPOSITION OF PHENYL AND THIOPHENYL SUBSTITUTED AZA-BODIPY: THEORETICAL STUDY

Conformational manifold of 1,3,5,7-tetraphenyl-aza-BODIPY and 1,3,5,7-tetra(2-thiophenyl)-aza-BODIPY was studied by B3LYP calculations. The addition of four cyclic groups to the aza-BODIPY core defines the non-planarity of the molecule and movement of the substituents from the heterocycle plane. The rotation angles of the phenyl and thiophenyl groups in the molecules are about 30° and 17°, respectively. For phenyl-substituted aza-BODIPY four conformers were found using quantum chemical calculations (B3LYP/6-31G* and B3LYP/cc-pVTZ), for thiophenyl-substituted aza-BODIPY – 30 conformers. Relative energies of some conformers are quite low, therefore they should be taken into account in the treatment of the gas electron diffraction (GED) experimental data. In current work the sensitivity of the GED method to the structural changes induced by different positions of phenyl and thiophenyl substituents relative to the aza-BODIPY core and each other was examined. Model radial distribution curves f(r) for all conformers were compared. It demonstrates that the bond distances can be reliably determined from experimental data, while the refinement of mutual orientations of neighboring groups relating to each other is at the limit of the possibilities of the GED method. Based on experimental data, it is possible to distinguish 1,3,5,7-tetra(2-thiophenyl)-aza-BODIPY conformers, which differ in the mutual arrangement of sulfur atoms. The use of the results of various quantum chemical calculations leads to the same conclusions about the possibility of the gas electron diffraction method to determine the conformational composition.

An aza-BODIPY-based NIR-II luminogen enables efficient phototheranostics.

The fabrication of a high-performance second near-infrared (NIR-II) biological window fluorophore is in urgent need for precise diagnosis and treatment of cancer. Nevertheless, the construction of phototherapeutic agents in the NIR-II region with excellent imaging performance and minimal side effects remains a big challenge due to the limited availability of core fluorophore candidates. In this study, a new NIR-II fluorescent probe, CB1, which is an aza-BODIPY core conjugated with bulky donors, was designed and synthesized. CB1 was further encapsulated in DSPE-PEG2000 to impart water solubility, which shows brighter NIR-II fluorescence and higher photostability than the clinically used indocyanine green (ICG). CB1 nanoparticles show deep tissue penetration and high imaging contrast in vivo. In addition, molecular conformation enables CB1 nanoparticles to exhibit good photothermal properties. Both in vitro and in vivo assessments confirm that CB1 nanoparticles could be utilized as distinguished theranostic agents for NIR-II fluorescence imaging and tumor growth inhibition with negligible side effects. Collectively, this work provides a promising approach for constructing a new platform for cancer diagnosis and therapy.

Aza-BODIPY based probe for photoacoustic imaging of ONOO−in vivo

The effective detecting ONOO− variations in vivo is of great importance to well understand the complex pathophysiological processes. We reported here a photoacoustic (PA) probe AZB-1 for imaging ONOO−in vivo. AZB-1 showed an originally strong photoacoustic signal at 660 nm. And its PA signal can be turned off by shutting the ICT effect caused by the conjugated electron withdrawing group at 2-position of the aza-BODIPY core. Moreover, the probe was successfully employed to imaging ONOO− variations in inflammatory mice models. Wisely utilized this strategy may serve as powerful platforms for the preparation of novel PA chemosensors.

Synthesis and optical properties of 1-ethyl-indol-3-yl-substituted aza-BODIPY dyes at the 1,7-positions

New aza-BODIPYs with significant bathochromic shifts in their UV–vis absorption spectrum were synthesized by the installation of 1-ethyl-indol-3-yl moieties at the 1,7-positions of the aza-BODIPY core bearing 4-substituted phenyl or thien-2-yl groups at the 3,5-positions. The compounds described herein show strong NIR absorptions up to 779 nm, and emissions up to 805 nm in chloroform solution, and present large molar extinction coefficients. The absorption and emission bands of aza–BODIPYs were significantly red-shifted, by ca 100 nm, relative to the 3,5-dianisyl-1,7-diphenyl aza-BODIPY. TD-DFT calculations indicate an effective electronic conjugation between the aza-BODIPY core and the substituents. Absorption of the studied aza-BODIPY derivatives corresponds to a charge transfer from donor substituents toward the boron-centered core. Moreover, computational results show that all the compounds present HOMO–LUMO band gap values that are in the organic semiconductor range. • A series of new aza-BODIPYs with 1-ethyl-indol-3-yl substituents were synthesized. • These dyes show strong NIR absorptions up to 779 nm, and emissions up to 805 nm in chloroform solution. • DFT-calculated and optical band gap values are found to lie in the organic semiconductor range.

Benzothiadiazole-Substituted Aza-BODIPY Dyes: Two-Photon Absorption Enhancement for Improved Optical Limiting Performances in the Short-Wave IR Range.

Aza-boron dipyrromethenes (aza-BODIPYs) presenting a benzothiadiazole substitution on upper positions are described. The strong electron-withdrawing effect of the benzothiadiazole moiety permits enhancement of the accepting strength and improves the delocalization of the aza-BODIPY core to attain a significant degree of electronic communication between the lower donating groups and the upper accepting groups. The nature of the intramolecular charge transfer is studied both experimentally and theoretically. Linear spectroscopy highlighted the strongly redshifted absorption and emission of the synthesized molecules with recorded fluorescence spectra over 1000 nm. Nonlinear optical properties were also investigated. Strong enhancement of the two-photon absorption of the substituted dyes compared with the unsubstituted one (up to 4520 GM at 1300 nm) results in an approximately 15-20 % improvement of the optical power limiting performances. These dyes are therefore a good starting point for further improvement of optical power limiting in the short-wave IR range.

A general strategy to optimize the performance of aza-BODIPY-based probes for enhanced photoacoustic properties.

In this chapter, we describe a generalizable strategy to obtain a high PA output platform that is optimized for ratiometric imaging. Our approach entails conformationally restricting pendant aryl rings on the aza-BODIPY core to enhance orbital overlap which consequently increases the extinction coefficient. This strategy can potentially be applied to other dye platforms to enhance their signal intensity. We provide detailed protocols for the synthesis, in vitro characterization, and in vivo application.

3, 3,5 and 2,6 Expanded Aza-BODIPYs Via Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling Reactions: Synthesis and Photophysical Properties.

Novel symmetrical aza-borondipyrromethene (aza-BODIPY) compounds bearing 4-methoxyphenyl, 4-methoxybiphenyl, 2,4-dimethoxybipheny, 4-bromophenyl and N,N-diphenyl-4-biphenylamine groups on the 3, 3,5 and 2,6 positions of aza-BODIPY core were synthesized via Suzuki-Miyaura coupling reactions while unsymmetrical analogues were obtained from the starting mono Br-substituted aza-BODIPY material which was obtained from nitrosolated pyrrole derivative. The characterizations were performed by means of 1H-NMR, 13C-NMR, FTIR and HRMS-TOF-ESI techniques. The spectral properties of the aza-BODIPY derivatives were investigated using absorption and fluorescence spectroscopy. The novel compounds with extended conjugation have broadband absorption in near infrared region and show significant shifts on their absorption and fluorescence spectra compared to unsubstituted analogues. The highest bathochromic shifts were observed π-extended and strong electron donating groups at 3,5 positions of the aza-BODIPY scaffold. Depend on substitution positions of attached groups to the indacene core, the fluorescence quantum yields of chromophores were determined to be drastic changes. The singlet oxygen generation capability of the compounds were evaluated and 2,6-bromine substituted compounds AA1 and CC1 showed high singlet oxygen quantum yields (71% and 74%, respectively). Enhanced photophysical properties such as intense absorption, extended conjugation and singlet oxygen production make the investigated aza-BODIPYs promising candidates for photodynamic therapy applications and organic photovoltaic cells in NIR region.

NIR Absorbing AzaBODIPY Dyes for pH Sensing.

Two near-infrared (NIR) absorbing di(thien-2-nyl)-di(dimethylanilino)azaBODIPY dyes 2a and 2b were synthesized and characterized that differ depending on whether the dimethylaniline substituents are introduced at the 3,5- or 1,7-positions of the azaBODIPY core. The main spectral bands lie at 824 and 790 nm, respectively, in CH2Cl2. The effect of substituent position on the photophysical and pH sensing properties was analyzed through a comparison of the optical properties with the results of time-dependent density functional theory (TD-DFT) calculations. Protonation of the dimethylamino nitrogen atoms eliminates the intramolecular charge transfer properties of these compounds, and this results in a marked blue-shift of the main absorption bands to 696 and 730 nm, respectively, in CH2Cl2, and a fluorescence “turn-on” effect in the NIR region. The pH dependence studies reveal that the pKa values of the non-protonated 2a and 2b molecules are ca. 6.9 (±0.05) and 7.3 (±0.05), respectively, while that of the monoprotonated species for both dyes is ca. 1.4 (±0.05) making them potentially suitable for use as colorimetric pH indicators under highly acidic conditions.

Near-IR aza-BODIPY-based probe for the selective simultaneous detection of Cu2+ in aqueous buffer solutions and its application in biological samples

On the basis of an aza-BODIPY core, a near-IR BDT probe was designed for Cu2+ detection. The Cu2+ sensing ability of the BDT probe demonstrated absorbance and fluorescence signals in near-IR regions. The probe capably detected Cu2+ with high sensitivity and selectivity in aqueous buffer solutions with a low detection limit of 3.75 ppb which is lower than the acceptable drinking water concentration specified by the U.S. Environmental Protection Agency and World Health Organization. The sensing ability of the probe also increased selectivity to Cu2+ over Hg2+ by adding cysteine as an auxiliary reagent. The binding of BDT-Cu2+ was proven to be 2:1 via molecular modeling and Job’s plot analysis. Interestingly, the BDT probe exhibited outstanding chromogenic and luminescent change in the presence of only Cu2+ and could detect Cu2+ in HepG2 cells as a biological sample.

Rational Design of Ratiometric Near-Infrared Aza-BODIPY-Based Fluorescent Probe for in Vivo Imaging of Endogenous Hydrogen Peroxide.

Precise in vivo tracking of hydrogen peroxide is still challenging due to its dynamic complexity and intrinsic background interference. Herein, we describe a rational design strategy to construct asymmetric aza-boron-dipyrromethane derivative (BODIPY)-based ratiometric probes for in vivo tracking H2O2, which are composed of a near-infrared aza-BODIPY core, active targeting group, and H2O2-specific recognition unit. We take advantage of two terminal functionalized conjunctions in the bis-condensed aza-BODIPY by rationally introducing carbonyl group as an electron-deficiency linker for regulating intramolecular charge transfer-induced wavelength shift and by attaching hydrophilic polyethylene glycol-biotin segment as the active targeting moiety. The probe BP5-NB-OB features several striking characteristics: (i) ratiometric near infrared response in both absorption and emission spectra; (ii) active targeting ability (biotin receptor-mediated endocytosis) with excellent biocompatibility; and (iii) in vivo tracking of endogenous H2O2. It was demonstrated that the probe BP5-NB-OB was successfully utilized for tracking endogenous H2O2 in living cells and tumor-bearing mice, providing opportunities to insight into H2O2 related diseases for clinical application.