Structurally modified indocyanine green dyes. Modification of the polyene linker

Mohammad, Innus; Stanford, Courtney; Morton, Martha D.; Zhu, Quing; Smith, Michael B.

doi:10.1016/j.dyepig.2013.05.001

Cited by 21 publications

(30 citation statements)

References 24 publications

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“…We believe that the reason for the spectrum shift and quantum yield increase of the rigid dye 8 and the dye-conjugate 12 is due to the more rigid structure of the polyene chain, but the specific structural feature that correlates with these changes is unknown at this time. 22 …”

Section: Discussionmentioning

confidence: 99%

“…Fragment 11 was prepared by reaction of commercially available 2-nitroimidazole with ethyl bromoacetate to give 9 , followed by reaction with N-Boc piperazine to give 10 . 22 The coupling agent Pybop, (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate, was used in dimethylformamide (DMF) for the reaction of 8 with 11 , and final purification of the crude product on C18 reversed phase automated flash column chromatography gave 12 in 31% yield.…”

Section: Methodsmentioning

confidence: 99%

“…The reaction mixture was cooled to ambient temperature and anhydrous diethyl ether (5 mL) was added. The resulting precipitate was isolated by vacuum filtration to give a crude solid that was recrystallized (methanol: water) to give 8 as a blue solid (0.09 g, 0.12 mmol, 63%); 22 mp: decomposition at 287 °C; 1 H NMR (400 MHz, CD 3 OD) δ 12.92 (bs, 2H), 8.43 (t, J = 13 Hz, 2H), 8.17 (s, 2H), 8.00 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 6.71 (t, J = 12.4 Hz, 1H), 6.50 (d, J = 13.7 Hz, 2H), 4.15 (bs, 4H), 1.18-1.76 (m, 8H), 1.73 (s, 12H); 13 C NMR (100 MHz, CD 3 OD) δ 175.7, 169.2, 156.8, 147.4, 142.8, 132.3, 128.7, 128.6, 124.6, 112.0, 106.0, 51.7, 50.4, 45.1, 27.9, 27.2, 23.5; 13 C NMR (100 MHz, MeOD) d 175.7, 169.2, 156.8, 147.4, 142.8, 132.3, 128.7, 128.6, 124.6, 112.0, 106.0, 51.7, 50.4, 45.1, 27.9, 27.2, and 23.5 ppm. HRMS (TOF): [M+H]+ Calc'd for C 35 H 43 N 2 O 10 S 2 m/z 715.2359.…”

Section: Methodsmentioning

confidence: 99%

“…20,21 Based on this hypothesis, we examined structural changes in the dye ( 2 ). We found that introduction of a ring into the polyene unit of 2 led to a lower fluorescent yield, 22 but shortening the polyene chain by two carbon atoms (see 8 in Scheme 1) led to significant enhancement in fluorescence (see Table 1). …”

Section: Introductionmentioning

confidence: 99%

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Targeting tumor hypoxia: a third generation 2-nitroimidazole-indocyanine dye-conjugate with improved fluorescent yield

et al. 2015

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Tumor hypoxia is associated with the rapid proliferation and growth of malignant tumors, and the ability to detect tumor hypoxia is important for predicting tumor response to anti-cancer treatments. We have developed a class of dye-conjugates that are related to indocyanine green (ICG, 1) to target tumor hypoxia, based on in vivo infrared fluorescence imaging using nitroimidazole moieties linked to indocyanine fluorescent dyes. We previously reported that linking 2-nitroimidazole to an indocyanine dicarboxylic acid dye derivative (2) using an ethanolamine linker (ethanolamine-2-nitroimidazole-ICG, 3), led to a dye-conjugate that gave promising results for targeting cancer hypoxia in vivo. Structural modification of the dye conjugate replaced the ethanolamine unit with a piperazineacetyl unit and led a second generation dye conjugate, piperzine-2-nitroimidazole-ICG (4). This second generation dye-conjugate showed improved targeting of tumor hypoxia when compared with 3. Based on the hypothesis that molecules with more planar and rigid structures have a higher fluorescence yield, as they could release less absorbed energy through molecular vibration or collision, we have developed a new 2-nitroimidazole ICG conjugate, 12, with two carbon atoms less in the polyene linker. Dye-conjugate 12 was prepared from our new dye (8), and coupled to 2-nitroimidazole using a piperazine linker to produce this third-generation dye-conjugate. Spectral measurements showed that the absorption/emission wavelengths of 657/670 were shifted ∼100 nm from the second-generation hypoxia dye of 755/780 nm. Its fluorescence quantum yield was measured to be 0.467, which is about 5 times higher than that of 4 (0.083). In vivo experiments were conducted with balb/c mice and 12 showed more than twice the average in vivo fluorescence intensity in the tumor beyond two hours post retro-orbital injection as compared with 4. These initial results suggest that 12 may significantly improve in vivo tumor hypoxia targeting.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting tumor hypoxia: a third generation 2-nitroimidazole-indocyanine dye-conjugate with improved fluorescent yield

et al. 2015

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“…Selectively monitoring an exogenous bioreducible and traceable marker is one of the mainstream methods for hypoxia assessment, where 2‐nitroimidazole derivatives are typically used as the hypoxia tracer for indirect measurements . In contrast to 2‐nitroimidazole derivatives as established radiotracers for positron emission tomography (PET) to image tumor hypoxia, indocyanine green (ICG) conjugates of 2‐nitroimidazole are a novel class of near‐infrared (NIR) fluorescent tumor hypoxia tracers demonstrating superb in vivo detectability and biocompatibility . Built on a fluorophore analogous to the commercial ICG as the scaffold structure, this class of compounds has evolved for three generations as ICG conjugates differing in linker and imidazole structures (Scheme S1).…”

Section: Introductionmentioning

confidence: 99%

Treasure hunt for peptides with undefined chemical modifications: Proteomics identification of differential albumin adducts of 2‐nitroimidazole‐indocyanine green in hypoxic tumor

et al. 2019

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2‐Nitroimidazole is a well‐known chemical probe targeting hypoxic environments of solid tumors, and its derivatives are widely used as imaging agents to investigate tissue and tumor hypoxia. However, the underlying chemistry for the hypoxia‐detection capability of 2‐nitroimidazole is still unclear. In this study, we deployed a biotin conjugate of 2‐nitroimidazole‐indocyanine green (2‐nitro‐ICG) for the investigation of in vivo hypoxia‐probing mechanism of 2‐nitro‐ICG compounds. By implementing mass spectrometry‐based proteomics and exhaustive data mining, we report that 2‐nitro‐ICG and its fragments modify mouse serum albumin as the primary protein target but at two structurally distinct sites and possibly via two different mechanisms. The identification of probe‐modified peptides not only contributes to the understanding of the in vivo metabolism of 2‐nitroimidazole compounds but also demonstrates a competent analytical workflow that enables the search for peptides with undefined modifications in complex proteome digests.

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Mitochondria‐Targeting IR‐780 Dye and Its Derivatives: Synthesis, Mechanisms of Action, and Theranostic Applications

Zhang

Long

Chen

2018

Advanced Therapeutics

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Mitochondria are important targets in diverse physiological and pathological conditions associated with cell survival and death. The characterization of mitochondria‐targeting agents is highly useful to the understanding of mitochondrial functions and the development of targeted therapeutic strategies. IR‐780, a prototypical near‐infrared (NIR) heptamethine cyanine dye, has been recently identified as the first mitochondria‐targeting multifunctional NIR dye, it has excellent optical imaging and therapeutic properties and is receiving increasing attention in the field of NIR theranostic applications. Although the targeting mechanisms of IR‐780 dye remain to be fully identified, emerging studies have shown that the targeting process is glycolysis dependent. Therefore, it may represent a new tool to further understand and advance the field of mitochondrial medicine and glycolytic metabolism. Several types of nanostructures also have been developed to encapsulate and deliver IR‐780 dye and its derivatives for therapeutic purposes to improve their bioavailablity and potential toxicity. IR‐780 dye and its derivatives have broadened the concept of targeted imaging and therapy and have shown promise in potential applications. In consideration of the urgent need and rapid development of targeted theranostics, the recent progress on the synthesis, mechanisms of actions, and potential applications of IR‐780‐based heptamethine dyes and nanostructures for multimodal targeted imaging and therapy is reviewed.

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Structurally modified indocyanine green dyes. Modification of the polyene linker

Cited by 21 publications

References 24 publications

Targeting tumor hypoxia: a third generation 2-nitroimidazole-indocyanine dye-conjugate with improved fluorescent yield

Targeting tumor hypoxia: a third generation 2-nitroimidazole-indocyanine dye-conjugate with improved fluorescent yield

Treasure hunt for peptides with undefined chemical modifications: Proteomics identification of differential albumin adducts of 2‐nitroimidazole‐indocyanine green in hypoxic tumor

Mitochondria‐Targeting IR‐780 Dye and Its Derivatives: Synthesis, Mechanisms of Action, and Theranostic Applications

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