Polymethine Cyanine Dyes Research Articles

No more gap-shifting: Stochastic many-body-theory based TDHF for accurate theory of polymethine cyanine dyes.

We introduce an individually fitted screened-exchange interaction for the time-dependent Hartree-Fock (TDHF) method and show that it resolves the missing binding energies in polymethine organic dye molecules compared to time-dependent density functional theory (TDDFT). The interaction kernel, which can be thought of as a dielectric function, is generated by stochastic fitting to the screened-Coulomb interaction of many-body perturbation theory (MBPT), specific to each system. We test our method on the flavylium and indocyanine green dye families with a modifiable length of the polymethine bridge, leading to excitations ranging from visible to short-wave infrared. Our approach validates earlier observations on the importance of inclusion of medium range exchange for the exciton binding energy. Our resulting method, TDHF@vW, also achieves a mean absolute error on a par with MBPT at a computational cost on a par with local-functional TDDFT.

Polymethine cyanine dyes: Synthesis, cytotoxic activity, and molecular docking study

Virtually, an efficient synthetic procedure was adapted to synthesize new methine cyanine dyes 3–22 from N-arenium salt 2 which was synthesized from the reaction of 1,6-dibromohexane, and 2-benzylpyridine in the presence of dry toluene. Cytotoxicity effects of the synthesized methine cyanine dyes were estimated against two cancer cell lines, HepG2 (liver), MCF-7 (breast), and two normal cells, WI‐38 (human lung fibroblasts), and Vero cells (kidney epithelial cells) as well. All compounds showed cytotoxic activity surpassing the reference 5‐fluorouracil. Of them, compounds 3, 12, 13, 14, and 17 revealed a slight cytotoxic effect on the two normal cells. Moreover, by means of molecular docking, the effectiveness of our compounds towards AKT1 has been studied as it exerts a pivotal role in cell growth, proliferation, survival, and metabolism. All the studied compounds showed good binding mode as well as good binding energy into the pocket of Akt. Thus, highlighting their usefulness as up-and-coming candidates for further preclinical studies.

Photostability investigation of a near-infrared-II heptamethine cyanine dye

The development of small-molecule organic fluorophores in the second near-infrared region (NIR-II, 1000–1700 nm) has recently received immense attention due to deep tissue light penetration and reduced autofluorescence. Polymethine cyanine dyes as important building blocks are frequently used to design NIR-II light-activated fluorophores. However, applications of these fluorophores were restricted by their poor photostability. Herein, we synthesized a NIR-II heptamethine cyanine dye 4 as the model compound to investigate its photostability and identify its photoproducts. Compound 4 shows improved photostability compared to ICG, and remains relatively stable even under sunlight irradiation. The cyanine scaffold’s good photostability promoted its stable photothermal properties. The effective photothermal activity of cyanine dye 4 and the low toxicity of its one major photoproduct demonstrated its potential for further photo-therapeutic applications. This work would pave the way for the development of NIR-II cyanines with photostability through delicate structure design.

Supramolecular Mitigation of the Cyanine Limit Problem.

Currently, there is a substantial research effort to develop near-infrared fluorescent polymethine cyanine dyes for biological imaging and sensing. In water, cyanine dyes with extended conjugation are known to cross over the "cyanine limit" and undergo a symmetry breaking Peierls transition that favors an unsymmetric distribution of π-electron density and produces a broad absorption profile and low fluorescence brightness. This study shows how supramolecular encapsulation of a newly designed series of cationic, cyanine dyes by cucurbit[7]uril (CB7) can be used to alter the π-electron distribution within the cyanine chromophore. For two sets of dyes, supramolecular location of the surrounding CB7 over the center of the dye favors a nonpolar ground state, with a symmetric π-electron distribution that produces a sharpened absorption band with enhanced fluorescence brightness. The opposite supramolecular effect (i.e., broadened absorption and partially quenched fluorescence) is observed with a third set of dyes because the surrounding CB7 is located at one end of the encapsulated cyanine chromophore. From the perspective of enhanced near-infrared bioimaging and sensing in water, the results show how that the principles of host/guest chemistry can be employed to mitigate the "cyanine limit" problem.

Encapsulation of Trimethine Cyanine in Cucurbit[8]uril: Solution versus Solid-State Inclusion Behavior.

Inclusion of polymethine cyanine dyes in the cavity of macrocyclic receptors is an effective strategy to alter their absorption and emission behavior in aqueous solution. In this paper, the effect of the host‐guest interaction between cucurbit[8]uril (CB[8]) and a model trimethine indocyanine (Cy3) on dye spectral properties and aggregation in water is investigated. Solution studies, performed by a combination of spectroscopic and calorimetric techniques, indicate that the addition of CB[8] disrupts Cy3 aggregates, leading to the formation of a 1 : 1 host‐guest complex with an association constant of 1.5×106 M−1. At concentrations suitable for NMR experiments, the slow formation of a supramolecular polymer was observed, followed by precipitation. Single crystals X‐ray structure elucidation confirmed the formation of a polymer with 1 : 1 stoichiometry in the solid state.

A Peierls Transition in Long Polymethine Molecular Wires: Evolution of Molecular Geometry and Single-Molecule Conductance

Molecules capable of mediating charge transport over several nanometers with minimal decay in conductance have fundamental and technological implications. Polymethine cyanine dyes are fascinating molecular wires because up to a critical length, they have no bond-length alternation (BLA) and their electronic structure resembles a one-dimensional free-electron gas. Beyond this threshold, they undergo a symmetry-breaking Peierls transition, which increases the HOMO-LUMO gap. We have investigated cationic cyanines with central polymethine chains of 5-13 carbon atoms (Cy3+-Cy11+). The absorption spectra and crystal structures show that symmetry breaking is sensitive to the polarity of the medium and the size of the counterion. X-ray crystallography reveals that Cy9·PF6 and Cy11·B(C6F5)4 are Peierls distorted, with high BLA at one end of the π-system, away from the partially delocalized positive charge. This pattern of BLA distribution resembles that of solitons in polyacetylene. The single-molecule conductance is essentially independent of molecular length for the polymethine salts of Cy3+-Cy11+ with the large B(C6F5)4- counterion, but with the PF6- counterion, the conductance decreases for the longer molecules, Cy7+-Cy11+, because this smaller anion polarizes the π-system, inducing a symmetry-breaking transition. At higher bias (0.9 V), the conductance of the shorter chains, Cy3+-Cy7+, increases with length (negative attenuation factor, β = -1.6 nm-1), but the conductance still drops in Cy9+ and Cy11+ with the small polarizing PF6- counteranion.

DNA Minor Groove-Induced cis-trans Isomerization of a Near-Infrared Fluorescent Probe.

The discovery of small molecules that exhibit turn-on far-red or near-infrared (NIR) fluorescence upon DNA binding and understanding how they bind DNA are important for imaging and bioanalytical applications. Here we report the DNA-bound structure and the DNA binding mechanism of quinone cyanine dithiazole (QCy-DT), a recently reported AT-specific turn-on NIR fluorescent probe for double-stranded DNA. The nuclear magnetic resonance (NMR)-derived structure showed minor groove binding but no specific ligand-DNA interactions, consistent with an endothermic and entropy-driven binding mechanism deduced from isothermal titration calorimetry. Minor groove binding is typically fast because it minimally perturbs the DNA structure. However, QCy-DT exhibited unusually slow DNA binding. The cyanine-based probe is capable of cis-trans isomerization due to overlapping methine bridges, with 16 possible slowly interconverting cis/trans isomers. Using NMR, density functional theory, and free energy calculations, we show that the DNA-free and DNA-bound environments of QCy-DT prefer distinctly different isomers, indicating that the origin of the slow kinetics is a cis-trans isomerization and that the minor groove preferentially selects an otherwise unstable cis/trans isomer of QCy-DT. Flux analysis showed the conformational selection pathway to be the dominating DNA binding mechanism at low DNA concentrations, which switches to the induced fit pathway at high DNA concentrations. This report of cis/trans isomerization of a ligand, upon binding the DNA minor groove, expands the prevailing understanding of unique discriminatory powers of the minor groove and has an important bearing on using polymethine cyanine dyes to probe the kinetics of molecular interactions.

Explorations into the Effect of meso-Substituents in Tricarbocyanine Dyes: A Path to Diverse Biomolecular Probes and Materials.

Polymethine cyanine dyes have been widely recognized as promising chemical tools for a range of life science and biomedical applications, such as fluorescent staining of DNA and proteins in gel electrophoresis, fluorescence guided surgery, or as ratiometric probes for probing biochemical pathways. The photophysical properties of such dyes can be tuned through the synthetic modification of the conjugated backbone, for example, by altering aromatic cores or by varying the length of the conjugated polymethine chain. Alternative routes to shaping the absorption, emission, and photostability of dyes of this family are centered around the chemical modifications on the polymethine chain. This Minireview aims to discuss strategies for the introduction of substituents in the meso‐position, their effect on the photophysical properties of these dyes and some structure–activity correlations which could help overcome common limitations in the state of the art in the synthesis.

Heptamethine and nonamethine cyanine dyes: novel synthetic strategy, electronic transitions, solvatochromic and halochromic evaluation

New polymethine cyanine dyes covering heptamethine cyanine dyes (tricarbocyanine dyes) and nonamethine cyanine dyes (tetracarbocyanine dyes) derived from the nucleus benzo[(2,3-b)benzoxazine; (2',3'-b')furo (3,2- d)pyrazole] were designed and prepared using novel synthetic strategy. Electronic transitions for all the synthesized cyanine dyes was determined and evaluated through investigating their electronic visible absorption spectra in 95% ethanol solution. The dyes were thought to be better electronic transitions when they absorb light at higher wavelength bands (bathochromic shifted and/or red shifted dyes). Consequently, the electronic transitions of the dyes decreases when they absorb light at lower wavelength bands (hypsochromic shifted and/or blue shifted dyes). Solvatochromic and/or halochromic evaluation for some selected dyes was carried out and determined through examining their electronic visible absorption spectra in 6 (six) pure solvents having different polarities [water (78.54), dimethylformamide (36.70), ethanol (24.3), chloroform (4.806), carbontetrachloride (2.238) and dioxane (2.209)] and/or in 8 (eight) aqueous universal buffer solutions owing varied pH values (1.99, 2.99, 4.30, 6.87, 7.96, 8.91, 10.55 and 12.04 units), respectively. Structural characterization and determination was carried out via elemental analysis, visible, mass, IR and 1HNMR spectroscopic data.

Excited state absorption and relaxation dynamics in a series of heptamethine dyes under femtosecond and nanosecond excitations

We show that the near-infrared-absorbing polymethine cyanine dyes exhibit nonlinear absorption (NLA) in the visible region, where they have negligible or very low linear absorption. In chloroform solvent, the studied cyanines were found to be photo-unstable and exhibited photo-degradation under prolonged exposures as compared to methanol and dimethyl sulphoxide solvents, where they were stable. Excitation with femtosecond (fs) pulses in the visible region (400–750 nm) exhibits excited state absorption (ESA) as characterized by positive differential absorption (ΔOD) in transient absorption signal. Non-resonant excitations in the visible region are governed by reverse saturable absorption (RSA) mechanism leading to ESA. Excitation with nanosecond pulses also shows NLA owing to ESA from triplet states as compared to that from singlet states under fs excitations. Single beam Z-scan studies were performed with nanosecond (ns) pulses to evaluate ground (σgr) and excited state (σex) absorption cross-sections, which confirms the mechanism of RSA as σex were found to be greater than σgr. The population relaxation from higher excited singlet states shows ultrafast behavior with multi-exponential decay components. The fast time component decay varies from a few hundreds of fs (τ1) to some hundreds of picoseconds (τ2), and the long-time decay is in the ns domain (τ3).

Isomerization and Properties of Isomers of Carbocyanine Dyes

One of the important features of polymethine (cyanine) dyes is isomerization around one of C–C bonds of the polymethine chain. In this review, spectral properties of the isomers, photoisomerization and thermal back isomerization of carbocyanine dyes, mostly meso-substituted carbocyanine dyes, are considered. meso-Alkyl-substituted thiacarbocyanine dyes are present in polar solvents mainly as cis isomers and, hence, exhibit no photoisomerization, whereas in nonpolar solvents, in which the dyes are in the trans form, photoisomerization takes place. In contrast, the meso-substituted dyes 3,3′-dimethyl-9-phenylthiacarbocyanine and 3,3′-diethyl-9-(2-hydroxy-4-methoxyphenyl)thiacarbocyanine occur as trans isomers and exhibit photoisomerization in both polar and nonpolar solvents. The behavior of these dyes may be explained by the fact that the phenyl ring of the substituent in their molecules can be twisted at some angle, removing the substituent from the plane of the molecule and reducing its steric effect on the conformation of the trans isomer. In some cases, photoisomerization of cis isomers of meso-substituted carbocyanine dyes is also observed (for some meso-alkyl-substituted dyes complexed with DNA and chondroitin-4-sulfate; for 3,3′-diethyl-9-methoxythiacarbocyanine in moderate polarity solvents). The cycle photoisomerization–thermal back isomerization of cyanine dyes can be used in various systems of information storage and deserves further investigation using modern research methods.

Theoretical and experimental spectroscopic investigation of new polymethine donor-π-acceptor cyanine dyes: Synthesis, photophysical, and TDDFT studies

New series of polymethine cyanine dyes with different length of π-chain have been synthesized and characterized. These new dyes are based on D-π-A architecture with long π-electron systems. The UV–vis/emission spectral studies showed that the dyes are absorbed in the region of λmax (485–570) nm and emitted at (540–600) nm. This makes these dyes favorable for the detection of biological and chemical analytes. Their electron cloud delocalization in HOMO/LUMO levels were studied by DFT using Gaussian 09 software. DFT results reveal that the dyes showed effective charge separation in its molecular orbitals levels, which reflected in its ICT behavior. Time-dependent density functional theory (TD-DFT) were applied to theoretically explored the first excitation energy (E0-0) of these dyes which in high compatibility with experimental results with an accuracy of 0.1–0.3 eV. This approach has been successfully applied to describe the great effect of π-conjugation length and substituents of chromophore on the variations of maximum absorption and excitation energy of the dyes.

Near‑infrared fluorescence imaging of prostate cancer using heptamethine carbocyanine dyes.

Near-infrared fluorescence (NIRF) imaging is an attractive novel modality for the detection of cancer. A previous study defined two organic polymethine cyanine dyes as ideal NIRF probes, IR-783 and its derivative MHI-148, which have excellent optical characteristics, superior biocompatibility and cancer targeting abilities. To investigate the feasibility of NIRF dye-mediated prostate cancer imaging, dye uptake and subcellular co-localization were investigated in PC-3, DU-145 and LNCaP human prostate cancer cells and RWPE-1 normal prostate epithelial cells. Different organic anion transporting peptide (OATP) inhibitors were utilized to explore the potential role of the OATP subtype, including the nonspecific OATP inhibitor bromosulfophthalein, the OATP1 inhibitor 17β-estradiol, the selective OATP1B1 inhibitor rifampicin and the selective OATP1B3 inhibitor cholecystokinin octapeptide. NIRF dyes were also used for the simulated detection of circulating tumor cells and the rapid detection of prostate cancer in human prostate cancer tissues and prostate cancer xenografts in mouse models. The results revealed that the cancer-specific uptake of these organic dyes in prostate cancer cells occurred primarily via OATP1B3. A strong NIRF signal was detected in prostate cancer tissues, but not in normal tissues that were stained with IR-783. Prostate cancer cells were recognized with particular NIR fluorescence in isolated mononuclear cell mixtures. The results of the present study demonstrated that NIRF dye-mediated imaging is a feasible and practicable method for prostate cancer detection, although further investigative studies are required before clinical translation.

Size-dependent spectral linewidth narrowing of H-bands in organic nanoparticles of pentamethine cyanine dye

Abstract Considering that cationic polymethine cyanine dyes such as 3,3′-diethylthiadicarbocyanine (DTDC) are used for near-IR (NIR) probes of biological tissues such as mitochondria, we synthesize DTDC organic nanoparticles based on ion association between the dye cation and hydrophobic tetrakis(4-fluorophenyl)borate (TFPB) anion in the presence of neutral stabilizing polymer. Size tuning of the dye nanoparticles is successful by varying the molar ratio of the loaded anion to the dye cation. Binding of DTDC with TFPB results in the prominent appearance of a broad electronic absorption band at 580–590 nm, which we assign to an H-aggregate of DTDC chromophore. The dye nanoparticles show an interesting size-dependent spectroscopic property; linewidth narrowing of H-bands. Spectral deconvolution analysis in terms of a linear combination of Gaussian bands reveals the existence of three types of H-aggregates possessing different transition energies, and the linewidth narrowing of all H-bands is detected as a function of particle size. Meanwhile, monomer bandwidths are almost unchanged. The results suggest that H-aggregates of DTDC dye are readily subject to inhomogeneous broadening that is associated with size-dependent stochastic fluctuations or conformational heterogeneity in the nanoparticles.

Comparative Tumor Imaging and PDT Efficacy of HPPH Conjugated in the Mono- and Di-Forms to Various Polymethine Cyanine Dyes: Part - 2

Previous reports from our laboratory have shown that a bifunctional agent obtained by conjugating a photosensitizer (HPPH) to a cyanine dye (CD) can be used for fluorescence image-guided treatment of tumor by photodynamic therapy (PDT). However, the resulting HPPH-CD conjugate showed a significant difference between the tumor-imaging and therapeutic doses. It was demonstrated that the singlet oxygen (1O2*, a key cytotoxic agent in PDT) produced by the conjugate upon excitation of the HPPH moiety was partially quenched by the CD-moiety; this resulted in a reduced PDT response when compared to HPPH-PDT under similar treatment parameters. To improve the therapeutic potential of the conjugate, we synthesized a series of dual functional agents in which one or two HPPH moieties were separately conjugated to three different dyes (Cypate, modified IR820 or modified IR783). The newly synthesized conjugates were compared with our lead compound HPPH-CD in terms of photophysical properties, in vitro and in vivo PDT efficacy, tumor uptake and imaging potential. Among the analogs investigated, the conjugate, in which two HPPH moieties were linked to the modified IR820 produced enhanced tumor uptake and tumor contrast in both Colon 26 (a murine Colon carcinoma) and U87 (a human glioblastoma) cell lines. The long-term PDT efficacy (cure) of this conjugate in BALB/c mice, bearing Colon 26 tumors was also enhanced; however, its efficacy in Nude mice bearing U87 tumors was slightly reduced. It was also found that in all the conjugates the singlet oxygen generation and, consequently, PDT efficacy were compromised by a competing pathway, whereby an electronic excitation of HPPH, the energy donor, is deactivated through an electronic excitation energy transfer (Forster Resonance Energy Transfer, FRET) to the CD fluorophore, the energy acceptor, resulting in overall reduction of the singlet oxygen production. Conjugates with increased FRET showed reduced singlet oxygen production and PDT efficacy. Among the conjugates investigated, the bifunctional agent in which two HPPH moieties were linked to the benzoindole-based cyanine dye 11 showed superiority over the lead candidate 9 (mono HPPH-cyanine dye).

Synthesis and physicochemical studies of some new quinolinoxazine pentamethine cyanine dyes

Polymethine cyanine dyes belong to a well-known class of organic compounds, which have been used in photography and as information storage in laser technology. A series of novel cyanine dyes were synthesized through the formylation of quinolinium[b,c]1,4-oxazine-chloride salt 1. Reaction of compound 2-chloro-3-formyl-quinolinium[b,c]1,4-oxazine-chloride salt 2 with different molar ratios of 2(4)-methyl substituted heterocyclic in basic catalysis afforded the corresponding 2-chloroquinolinium[b,c]1,4-oxazine-chloride salt-3[2(4)]-dimethine (3a–c), quinolinium[b,c]-1,4-oxazinechloride salt-2,3[2(4)]-pentamethine (4a–c) and quinolino[b,c]1,4-oxazine-6yl[2(4)]-monomethine-/2,3[2(4)]-pentamethine cyanine dyes (5a–c) respectively. The structure of the dyes was characterized by elemental analysis, visible absorption, fluorescence emission, IR, 1H-NMR and mass spectroscopy. The correlations between the structure and properties of these dyes have been studied. A comparison of the visible absorption maxima between compounds 3b, 4b and 5b showed that asymmetrical mono-pentamethine cyanine dye 5b reveals a bathochromic shift than both dimethine 3b and pentamethine cyanine dyes 4b. This could be attributed to the more extensive π-conjugation and increasing number of methine groups in asymmetric pentamethine. All the observations and analytical spectra in this paper support the syntheses of new di-, penta- and mono-/pentamethine cyanine dyes. The absorption spectra of dyes were investigated in organic solvents. The results indicated that the excitation for their colour is a simple charge-transfer from oxygen atom of oxazine nucleus and/or nitrogen atom of pyridine (quinoline) nucleus to N-quaternary salts in di-, penta- and mono-/pentamethine cyanine dyes respectively. These dyes showed positive solvatochromism with increased solvent polarity, which depends on the structure and the type of dye.

Structures and conformations of acridinium mono- and polymethine cyanine dyes and their UV–Vis absorption spectra in protic solvents: A PCM/TD-DFT study

► Conformers of novel mono- and polymethine cyanine dyes were theoretically studied. ► Conformers in either methanol or water were more preferable than in gas phase. ► Absorption maxima were due to the HOMO–LUMO transitions for all dye conformers. ► The longer polymethine chain of the dyes caused the larger red-shift. Structures of the acridinium mono- and polymethine cyanine dyes with different lengths of polymethine chain of four compounds were obtained using DFT calculations. The differences of the energies and free energies of their corresponding conformers in methanol and in water were determined using the DFT/B3LYP and PCM(UAKS)-DFT/B3LYP approaches. The absorption maxima computed using the PCM(UAKS)-TDDFT/B3LYP/6-311+G(d,p) calculations for the four acridine-containing cyanine dyes and their conformers are in agreement with the experiments. It was found that the absorption maxima of all the acridinium cyanine dyes are mainly caused by the electronic transition from HOMO to LUMO.

Interaction between gold nanoparticle plasmons and aggregates of polymethine dyes: “Invisible” nanoparticles

Composite nanoparticles consisting of rodlike gold particles coated by an organic layer and polymethine (cyanine) dyes of J-aggregates of different structures absorbing light in red and infrared spectrum ranges have been synthesized. It has been demonstrated that, for dyes with J-band absorption maxima in the gold plasmon-band range, one observes an absorption dip as a result of the interference of the photoexcited states of nanoparticles and J-aggregates. The latter results in the decoloration of the gold colloid solution. The effect of the emergence of new intensive absorption bands of dye aggregates, which is assumed to be related to the perturbance of dye aggregate electron levels by gold plasmons and, consequently, lifting the ban on electron transitions to perturbed levels of aggregates, has been found.

Polymethine cyanine dyes in β‐cyclodextrin solution: multiple equilibria and chemical oxidation

AbstractAbsorption and fluorescence spectroscopy, electrochemical techniques, and semiempirical calculations were employed to characterize the multiple complexation equilibria between two polymethine cyanine dyes (IR‐786 and Indocyanine green‐ICG, S) and β‐cyclodextrin (β‐CD, L), as well as the chemical reactivity of the complexed and uncomplexed species against the oxidizing agents hypochlorite (HC) and hydrogen peroxide (HP). IR‐786 dimerization is favored with the increase in β‐CD concentration in the form of (SL)2 complexes. In the case of ICG, free dimers (D) and SL complexes are favored. Both IR‐786 and ICG react and discolor in the presence of HC and HP. For IR‐786, the reaction with HP and HC proceeds with observed rate constants of 10−3 and 0.28 s−1 and second‐order rate constants (k2) of ∼10−3 and 104 M−1s−1, respectively. The intermediate species observed in the bleaching reactions of IR‐786 and ICG were shown, by cyclic voltammetry and VIS absorption, to result from one electron oxidation. IR‐786 complexed with β‐CD is protected against bleaching in the presence of HP and HC by factors of 20 and 4, respectively. This protection was not observed in ICG complexes. Superdelocalizability profile of both dyes and frontier orbital analysis indicates that β‐CD does not protect ICG from oxidation by HP or HC, whereas the 2:2 IR‐786/β‐Cd complex is able to avoid the oxidation of IR‐786. We concluded that the decrease in the chemical reactivity of the dyes against oxidant agents in the presence of β‐CD is due to the formation of (SL)2 complexes. Copyright © 2010 John Wiley & Sons, Ltd.

Synthesis and Spectroscopic and DNA-Binding Properties of Fluorogenic Acridine-Containing Cyanine Dyes

The synthesis of a new subclass of mono- and polymethine cyanine dyes that incorporate an acridinium moiety and that absorb in the orange to near-infrared region of the spectrum is reported. The mono-, tri-, and pentamethine dyes in particular exhibit promising fluorogenic properties. Their ability to aggregate in solution and to interact with B-DNA is also discussed.