Design and Synthesis of BODIPY-Hetero[5]helicenes as Heavy-Atom-Free Triplet Photosensitizers for Photodynamic Therapy of Cancer.

Designing heavy-atom-free triplet photosensitizers (PSs) is a challenge for the efficient photodynamic therapy (PDT) of cancer. Helicenes are twisted polycyclic aromatic hydrocarbons (PAHs) with an efficient intersystem crossing (ISC) that is proportional to their twisting angle. But their difficult syntheses and weak absorption profile in the visible spectral region restrict their use as heavy-atom-free triplet PSs for PDT. On the other hand, boron-containing PAHs, BODIPYs are highly recognized for their outstanding optical properties. However, planar BODIPY dyes has low ISC and thus they are not very effective as PDT agents. We have designed and synthesized fused compounds containing both BODIPY and hetero[5]helicene structures to develop red-shifted chromophores with efficient ISC. One of the pyrrole units of the BODIPY core was also replaced by a thiazole unit to further enhance the triplet conversion. All the fused compounds have helical structure, and their twisting angles are also increased by substitutions at the boron centre. The helical structures of the BODIPY-hetero[5]helicenes were confirmed by X-ray crystallography and DFT structure optimization. The designed BODIPY-hetero[5]helicenes showed superior optical properties and high ISC with respect to [5]helicene. Interestingly their ISC efficiencies increase proportionally with their twisting angles. This is the first report on the relationship between the twisting angle and the ISC efficiency in twisted BODIPY-based compounds. Theoretical calculations showed that energy gap of the S1 and T1 states decreases in BODIPY-hetero[5]helicene as compared to planar BODIPY. This enhances the ISC rate in BODIPY-hetero[5]helicene, which is responsible for their high generation of singlet oxygen. Finally, their potential applications as PDT agents were investigated, and one BODIPY-hetero[5]helicene showed efficient cancer cell killing upon photo-exposure. This new design strategy will be very useful for the future development of heavy-atom-free PDT agents.

A BODIPY-O-glycoside based near-infrared fluorescent sensor for serum albumin.

Highly sensitive and selective near-infrared fluorescent bioprobes for serum albumin detection and quantification are in high demand for biomedical applications. Herein, we report a near-infrared emitting BODIPY-O-glycoside dye as a turn-on emission sensor for serum albumin. To the best of our knowledge, this is the first report of NIR-emitting BODIPY dyes for serum albumin sensing. Despite the various outstanding photophysical properties of the BODIPY dyes, their insolubility in water/biological media restricts their real biomedical applications. To overcome this issue, highly stable unadulterated BODIPY-O-glycoside nanoparticles (BDP-Glu-NPs) were prepared in aqueous solution by self-assembly of amphiphilic BODIPY-O-glycoside dyes. The BDP-Glu-NPs were characterized by spectroscopic, NMR, DLS and TEM studies. The ability of the BDP-Glu-NPs for the detection and quantification of serum albumin was demonstrated. It showed a 150-fold fluorescence enhancement in the presence of serum albumin, with excellent selectivity over other amino acids, porphyrin, proteins and various inorganic salts. Detection of human serum albumin (HSA) in urine samples showed that the bioprobe is applicable to a clinically significant range of the analytes with very low detection limit. These results suggested that the BDP-Glu-NPs can act as potential bioprobe to quantify albumin in biochemical and clinical samples.

Tuning of electron tunneling: a case study using BODIPY molecular layers.

Redox active π-conjugated organic molecules have shown the potential to be used as electronic components such as diode and memory elements. Here, we demonstrate that using simple surface chemistry, rectification characteristics can be tuned to reproducible negative differential resistance (NDR) with a very high peak-to-valley ratio (PVR) up to 1000 in 2,6-diethyl-4,4-difluoro-1,3,5,7,8-pentamethyl-4-bora-3a,4a-diaza-s-indecene (BODIPY) grafted on Si. The change in properties is related to oxidation and reduction of BODIPY, which results in the change in resonant to non-resonant tunneling of electrons under bias. This has been explained by the ab initio molecular-orbital theoretical calculations.

Hydrogen Bonding as a Supramolecular Tool for Robust OFET Devices.

In the present study, we demonstrated the effect of hydrogen bonding in the semiconducting behaviour of a small molecule used in organic field-effect transistors (OFETs). For this study, the highly soluble dumbbell-shaped molecule, Boc-TATDPP based on a Boc-protected thiophene-diketopyrrolopyrrole (DPP) and triazatruxene (TAT) moieties was used. The two Boc groups of the molecule were removed by annealing at 200 °C, which created a strong hydrogen-bonded network of NH-TATDPP supported by additional π-π stacking. These were characterised by thermogravimetric analysis (TGA), UV/Vis and IR spectroscopy, XRD and high-resolution (HR)-TEM measurements. FETs were fabricated with the semiconducting channel made of Boc-TATDPP and NH-TATDPP separately. It is worth mentioning that the Boc-TATDPP film can be cast from solution and then annealed to get the other systems with NH-TATDPP. More importantly, NH-TATDPP showed significantly higher hole mobilities compared to Boc-TATDPP. Interestingly, the high hole mobility in the case of NH-TATDPP was unaffected upon blending with [6,6]-phenyl-C71-butyric acid methyl ester (PC71 BM). Thus, this robust hydrogen-bonded supramolecular network is likely to be useful in designing efficient and stable organic optoelectronic devices.

Synthesis of Indolo[3,2- b]carbazole-Based Boron Complexes with Tunable Photophysical and Electrochemical Properties.

New synthetic strategies were developed for the synthesis of indolo-pyridine boron difluoride (IPBD) dyes and antiladder-type π-conjugated dyes based on the pyridine/pyrazine-indolocarbazole (ICZ) structures. The photophysical and electrochemical properties of the dyes were measured in solution, solid state, and thin films and rationalized by theoretical calculations. Interestingly, these properties of the dyes can be tuned in a wide range using the developed chemical route. For example, the absorption range and fluorescence color of the dyes in solution and solid state and the HOMO-LUMO energy gaps were tuned by structure modulations. The absorption properties of those new boron complexes cover most of the UV-visible-NIR spectrum. Therefore, this appealing tunability feature makes these new types of dyes very promising candidates for their further use in functional material development.

Modulation of the Photophysical Properties of ß-substituted BODIPY Dyes.

Photophysical properties of BODIPY dyes containing acetyl acetone and benzoyl acetone BF2 unit as an electron accepting substituent at beta position linked via double bond have been investigated using a wide range of solvents of different polarities. The substitution effect at beta position of the BODIPY dyes on their absorption, emission and quantum yield of fluorescence have been the aim of present study. For the synthesized BODIPY dyes fluorescence quantum yields and lifetimes show very sharp decrease with an increase in the solvent polarity, suggesting the involvement of highly polar ICT state de-excitation mechanism along with the local excitation process. The polarity dependent changes in average fluorescence life time and quantum yield values rationalize the formation of ICT states.

Enhanced fluorescence of aqueous BODIPY by interaction with cavitand cucurbit[7]uril.

One cationic BODIPY chromophore was synthesized and its complexation behaviour with the macrocyclic host cucurbit[7]uril (CB[7]) was studied using different spectroscopy techniques such as UV-vis absorption, steady-state and time-resolved fluorescence, 1H NMR as well as DFT based quantum calculations. The dye showed formation of a 1 : 1 dye-CB[7] complex with improvement in the fluorescence intensity. These new results of the formation of moderate association of aqueous BODIPYs with the nontoxic host CB[7] may lead to promising applications of the dye molecule as a sensitive and efficient off-on mode fluorescent probe in chemical and biological studies.

Proton Induced Modulation of ICT and PET Processes in an Imidazo-phenanthroline Based BODIPY Fluorophores.

BODIPY fluorophores linked with an imidazo-phenanthroline donor at α and ß positions have been synthesized. Intriguing intramolecular charge transfer phenomenon is observed in both the dyes which has been extensively investigated using UV-vis absorption, steady-state and time-resolved fluorescence measurements. H-bonding and intrinsic polarity of the solvents has modulated the absorption and emission bands of these fluorophores strongly causing significant increase in the Stokes shifts. In spite of having difference only in terms of the position of donor subunit, the photophysics of these dyes are not only significantly different from each other, but contradictory too. Interestingly, acidochromic studies revealed the shuttling mechanism between ICT and PET processes for BDP 2. Quantum chemical calculations have been employed further to support experimental findings. DFT and TD-DFT method of analysis have been used to optimize ground and excited state geometries of the synthesized dyes.

Solvent-Driven Conformational Exchange for Amide-Linked Bichromophoric BODIPY Derivatives.

The fluorescence lifetime and quantum yield are seen to depend in an unexpected manner on the nature of the solvent for a pair of tripartite molecules composed of two identical boron dipyrromethene (BODIPY) residues attached to a 1,10-phenanthroline core. A key feature of these molecular architectures concerns the presence of an amide linkage that connects the BODIPY dye to the heterocyclic platform. The secondary amide derivative is more sensitive to environmental change than is the corresponding tertiary amide. In general, increasing solvent polarity, as measured by the static dielectric constant, above a critical threshold tends to reduce fluorescence but certain hydrogen bond accepting solvents exhibit anomolous behaviour. Fluorescence quenching is believed to arise from light-induced charge transfer between the two BODIPY dyes, but thermodynamic arguments alone do not explain the experimental findings. Molecular modelling is used to argue that the conformation changes in strongly polar media in such a way as to facilitate improved rates of light-induced charge transfer. These solvent-induced changes, however, differ remarkably for the two types of amide.

Quinone-Bodipy H-bonding interaction over π-stacking in toluene.

Quinone type compounds (o-chloranil, p-chloranil and DDQ) demonstrate excellent H-bonding interactions with a meso-phenol Bodipy dye (1) in both ground and excited state in a non-polar toluene medium. The spectroscopic detection of isosbestic absorption occurs with both quinones and fullerenes, but only quinones form isoemissive complexes with dye 1. (1)H NMR study and Monte Carlo global minima searching justified the above mentioned results with efficiency.

Masking and demasking strategies for the BF2-BODIPYs as a tool for BODIPY fluorophores.

An efficient and chemoselective route for transforming BF2-BODIPYs to Et2B-BODIPYs (masking) was developed using Et2AlCl. The Et groups can be easily replaced with F atoms using BF3·Et2O in moist CH2Cl2 to regenerate the BF2-BODIPYs (demasking). The masking-demasking strategy is very useful for synthesizing functionalized BODIPYs via nucleophilic and reductive reactions. The masking strategy was used to synthesize a BODIPY dimer by McMurry coupling of a formyl Et2B-BODIPY, while a new BODIPY with an asymmetrically substituted B-center was synthesized using the demasking strategy.

Helical BODIPY Dyes as Heavy-Atom-Free Triplet Photosensitizers for Photodynamic Therapy of Cancer.

Despite of having many advantages over the popular cancer therapies, photodynamic therapy still is not widely acceptable for clinical applications. Scarcity of efficient triplet photosensitizers (PSs) is one of the main bottlenecks for this. Although numerous heavy atom attached PSs are developed as PDT agents, but these are not suitable for clinical applications due to several reasons. Thus, development of heavy-atom-free organic PSs is urgently required. In this context, development of new type of helical BODIPYs as PSs for PDT is discussed. BODIPYs have rich photophysical properties and structural helicity further enhances their triplet conversion rates. This new concept of structural helicity to enhance the triplet conversion of BODIPYs is discussed with reported helical BODIPYs. Helical geometries of these dyes are checked by X-ray crystallography studies and their high triplet conversions as compared to planar BODIPYs are also confirmed. Importantly, these dyes have high triplet lifetimes and are capable of generating high singlet oxygens even in hypoxia condition as compared to conventional heavy atom attached BODIPYs. All these make the helical BODIPYs excellent candidates as PDT agents. Finally, their successful applications as PDT agents in killing of various types of cancer cells are also discussed. The results are encouraging which indicate that helical BODIPYs could be next generation heavy-atom-free PSs for PDT applications.

meso-Methyl Amination of BODIPYs by Regiospecific Cross Dehydrogenative Coupling via Direct C(sp3)-N(sp3) Bond Formation.

Herein, we report a direct meso-methyl amination of BODIPY dyes by C(sp3)-N(sp3) bond formation using PIDA as an oxidant with a wide range of aliphatic secondary amines. This metal free cross dehydrogenative coupling reaction is regiospecific at the meso-methyl position of BODIPY in the presence of C1, C3, C5, and C7 methyl groups. Detailed nuclear magnetic resonance spectroscopy, high-resolution mass spectrometry, and X-ray crystallographic studies were performed to establish the reaction mechanism and the regiospecificity of the reaction. Finally, the photophysical and electrochemical properties of the newly synthesized dyes were evaluated and rationalized.

Rational design of boradiazaindacene (BODIPY)-based functional molecules.

Three boradiazaindacene (BODIPY) dyes with different-coloured (greenish-yellow, orange and red) fluorescence and good Stokes shifts were synthesised starting from the greenish-yellow BODIPY dye PM546. The high Stokes shifts of the dyes are due to the release of the steric strain in their excited states relative to that in the highly twisted ground states. One of these compounds might be a useful water-soluble fluorophore, whereas the other two are promising H(+) sensors.

Change of boron substitution improves the lasing performance of Bodipy dyes: a mechanistic rationalisation.

Bodipy laser dyes are highly efficient but degrade rapidly in solution by reacting with in situ generated singlet oxygen ((1)O(2)). To increase the lasing lifetimes of these dyes, we have designed and synthesised two different congeners of the widely studied Pyrromethene 567 (PM567) by substitution at the boron centre and/or at both the boron centre and the meso position. The two new dyes showed high lasing efficiencies with increased photostability. The results of theoretical and pulse radiolysis studies revealed that the substitution at the boron centre reduced the (1)O(2) generation capacity of these dyes as well as their rate of reaction with (1)O(2), thereby enhancing their lifetimes even under lasing conditions.

In house synthesized novel distyryl-BODIPY dye and polymer assembly as deep-red emitting probe for protamine detection.

In this contribution, we designed and synthesized a deep-red emitting distyryl-BODIPY dye (dye 3) which is non-fluorescent in aqueous solution due to the formation of non-emissive aggregates. However, in presence of an amphiphilic polymer (polystyrene sulfonate, PSS), the aggregated dye molecules de-aggregate and form dye 3-PSS complex, which significantly modulates the optical features of the bound dye. Interestingly, the dye 3-PSS complex shows turn-on fluorescence response in deep-red region in presence of protamine (Pr) due to the formation of dye 3-PSS-Pr ternary complex. Such enhancement follows a linear trend in the dynamic range of 0-8.75 µM of Pr which has been utilized to determine Pr with limit of detection (LOD) of 15.04(±0.5) nM in phosphate buffer. Furthermore, excellent selectivity of the dye 3-PSS system towards Pr allows us to determine Pr even in complex biological matrix like 1% human serum. Thus, dye 3-PSS system can be applied as a very effective tool for the detection and quantification of Pr in deep-red region, overcoming several limitations encountered with the probes in the shorter wavelength region. This is the first report on BODIPY dye based supramolecular assembly for sensing and quantification of protamine.

Sensing lysozyme fibrils by salicylaldimine substituted BODIPY dyes - A correlation with molecular structure.

Quick and efficient detection of protein fibrils has enormous impact on the diagnosis and treatment of amyloid related neurological diseases. Among several methods, fluorescence based techniques have garnered most importance in the detection of amyloid fibrils due to its high sensitivity and extreme simplicity. Among other classes of molecular probes, BODIPY derivatives have been employed extensively for the detection of amyloid fibrils. However, there are very few studies on the relationship between the molecular structure of BODIPY dyes and their amyloid sensing activity. Here in a BODIPY based salicylaldimine Schiff base and its corresponding boron complex have been evaluated for their ability to sense amyloid fibrils from hen-egg white lysozyme using steady state and time-resolved spectroscopic techniques. Both dyes show fluorescence enhancement as well as increase in their excited state lifetime upon their binding with lysozyme fibrils. However, the BODIPY derivative which shows more emission enhancement in fibrillar solution has much lower affinity towards amyloid fibrils as compared to other derivative. This contrasting behaviour in the emission enhancement and binding affinity has been explained on the basis of differences in their photophysical properties in water and amyloid fibril originating from the difference in their molecular structure. Such correlation between the amyloid sensitivity and the molecular structure of the probe can open up a new strategy for designing new efficient amyloid probes.

Synthesis of Dihydrobenzofuro[3,2-b]chromenes as Potential 3CLpro Inhibitors of SARS-CoV-2: A Molecular Docking and Molecular Dynamics Study.

The recent emergence of pandemic of coronavirus (COVID-19) caused by SARS-CoV-2 has raised significant global health concerns. More importantly, there is no specific therapeutics currently available to combat against this deadly infection. The enzyme 3-chymotrypsin-like cysteine protease (3CLpro) is known to be essential for viral life cycle as it controls the coronavirus replication. 3CLpro could be a potential drug target as established before in the case of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). In the current study, we wanted to explore the potential of fused flavonoids as 3CLpro inhibitors. Fused flavonoids (5a,10a-dihydro-11H-benzofuro[3,2-b]chromene) are unexplored for their potential bioactivities due to their low natural occurrences. Their synthetic congeners are also rare due to unavailability of general synthetic methodology. Here we designed a simple strategy to synthesize 5a,10a-dihydro-11H-benzofuro[3,2-b]chromene skeleton and it's four novel derivatives. Our structural bioinformatics study clearly shows excellent potential of the synthesized compounds in comparison to experimentally validated inhibitor N3. Moreover, in-silico ADMET study displays excellent druggability and extremely low level of toxicity of the synthesized molecules. Further, for better understanding, the molecular dynamic approach was implemented to study the change in dynamicity after the compounds bind to the protein. A detailed investigation through clustering analysis and distance calculation gave us sound comprehensive data about their molecular interaction. In summary, we anticipate that the currently synthesized molecules could not only be a potential set of inhibitors against 3CLpro but also the insights acquired from the current study would be instrumental in further developing novel natural flavonoid based anti-COVID therapeutic spectrums.

Stimuli Responsive Confinement of a Molecular Rotor Based BODIPY Dye inside a Cucurbit[7]uril Nanocavity.

Present study reports the interaction of a molecular rotor based BODIPY dye, 8-anilino-BODIPY (ABP), with a versatile macrocyclic molecule, cucurbit[7]uril (CB7), investigated through various techniques such as ground-state absorption, steady-state fluorescence, time-resolve emission, proton NMR, and quantum chemical studies. Although BODIPY dyes have widespread applications due to their intriguing photochemical properties, studies on their noncovalent interactions with different macrocyclic hosts, especially regarding their supramolecularly induced modulations in photophysical properties are very limited. The investigated BODIPY dye, especially its protonated ABPH+ form (pH ∼ 1), shows a large fluorescence enhancement on its interaction with the CB7 host, due to large reduction in the structural flexibility for the bound dye, causing a suppression in its nonradiative de-excitation process in the excited state. Unlike ABPH+, the neutral ABP form (pH ∼ 7) shows considerably weaker interaction with CB7. For ABPH+-CB7 system, observed photophysical results indicate formation of both 1:1 and 1:2 dye-to-host complexes. Plausible geometries of these complexes are obtained from quantum chemical studies which are substantiated nicely from 1H NMR results. The response of the ABPH+-CB7 system toward changing temperature of the solution have also been investigated elaborately to understand the potential of the system in different stimuli-responsive sensor applications.

Monitoring the formation of insulin oligomers using a NIR emitting glucose-conjugated BODIPY dye.

Protein oligomers, which are formed due to the aggregation of protein molecules under physiological stress, are neurotoxic and responsible for several neurological diseases. Early detection of protein oligomers is essential for the timely intervention in the associated diseases. Although several probes have been developed for the detection of insoluble matured protein fibrils, fluorescent probes with emission in the near infrared (NIR) region for probing protein oligomers are very rare. In the present study we have designed and synthesized a glucose-conjugated BODIPY dye with emission in the NIR spectral range. Our detailed studies show that the new probe is not only capable of detecting matured fibrils but can also probe the formation of oligomers from the native protein. The new probe shows a large increase in its emission intensity upon association with oligomers and matured fibrils. Hence, the present probe has a great potential for the in vivo imaging of protein oligomers and matured fibrils. Detailed spectroscopic properties of the new probes in molecular solvents have been performed to understand its oligomers- and fibril- sensing mechanism.