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    Home > JACS: Design of probes with excellent PA response based on the conformational limited aza BODIPY platform

    JACS: Design of probes with excellent PA response based on the conformational limited aza BODIPY platform

    • Last Update: 2019-11-22
    • Source: Internet
    • Author: User
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    In recent years, stimulus responsive molecular probes have become an indispensable part of the research process of chemical biologists These molecular probes generate certain response signals by combining with the target analyte, which can be used for the detection of metal ions, signal molecules and enzyme activities Although fluorescence imaging provides a good resolution in cell and tissue samples, the resolution in living animals is significantly reduced, and the use of near-infrared light (NIR) combined with ultrasound to produce high contrast photoacoustic (PA) imaging can solve this problem The PA scan can penetrate about 10 cm of tissue to obtain depth related image resolution Therefore, it is very important to design and develop a reasonable PA stimulus response probe for the study of animal disease models Recently, Professor Jefferson Chan of the University of Illinois at Urbana Champaign designed and synthesized six different modified aza BODIPY dyes, and evaluated their absorption, fluorescence and PA characteristics Finally, the three standards of PA probe (absorption in the near infrared band, strong PA signal and large PA wavelength in response to target stimulation) were used )A good conformational limited aza BODIPY (crab) skeleton was screened out Three kinds of PA probes with different stimulus response were synthesized by using the framework, and the results showed that the PA probe had a better ratio response (2-8 times) in vitro, which further proved the application prospect of crab framework compared with the existing ones Relevant achievements were published on j.am Chem SOC Under the title of "a conformally restrictedaza BODIPY platform for stimulus responsive probes with enhanced photoacoustic properties" (DOI: 10.1021 / JACS 9b06694) In this paper, the author aims to improve the PA strength and δ λ of AZA BODIPY framework The simple modification based on aza BODIPY can restrict the rotation of the side benzene ring and enhance the absorption capacity The author suspects that such modification can generate the corresponding PA signal How the modification affects Δ λ is what the author is interested in A group of conformational limited analogs, hypoxia responsive probe hyp-1 / red-hyp-1, were synthesized and their effects on extinction coefficient, δ λ, quantum yield and PA signal were evaluated (Figure 1) (source: J am Chem SOC.) firstly, the author nitrosates methoxy substituted pyrrole in sodium nitrite and acetic acid, and then adds amine substituted pyrrole in acetic anhydride to obtain asymmetric azadipyrrole methylene intermediate, which then combines with BF 2 to obtain the final product (Figure 2b) In this paper, we use a similar method to obtain the red-hyp-1 analog 1 - 6 (Figure 2a) (source: j.am Chem SOC.) then, the photophysical properties of compounds 1-6 (Table 1) were evaluated The absorption wavelength, emission wavelength, molar absorption coefficient and fluorescence quantum yield of each compound were compared with red-hyp-1 In addition, the PA images of different wavelengths are collected by simulating the process of tissue scattering induced luminescence (Figure 3) Although all the conformations lead to the increase of extinction coefficient, the author found that the PA signal of compound 1 - 3 has the greatest improvement (> 2 times) Next, we studied the related δ λ values of each compound under hypoxia stimulation The author dissolved the compound 1 - 6 in chloroform containing 1% trifluoroacetic acid and determined its maximum absorption wavelength after protonation (Table 2) The experimental results show that the protonation of compounds 1, 2 and 5 results in a narrower Δ λ ratio than red-hyp-1, and the Δ λ ratio of compounds 4 and 6 is similar to red-hyp-1 Only compound 3 has the best Δ λ, which meets the third standard of improving PA signal (source: J am Chem SOC.) because compound 3 (red crab Hyp) satisfies three key factors to improve PA signal, the author synthesized and characterized the corresponding hypoxia responsive probe crab Hyp, and confirmed that the Δ λ (103 nm) obtained from the study of protonation is very similar to the actual Δ λ (98 nm) (Table 3) In order to further determine whether the crab skeleton can optimize the PA signal of AZA BODIPY with various substituents, two other crab analogues, photonod-1 (a NIR activated no donor) and APC analogues (Cu (II) probe) (Figure 4), were synthesized and characterized The experimental results show that the compounds based on crab skeleton have better molar extinction coefficient (1.4-2.5 times), stronger PA signal (maximum 3.2 times) and larger Δ λ (Table 3) than those based on aza BODIPY These properties show that crab skeleton is aza BODIPY The photophysical properties of dyes provide predictable improvements and are essential for the development of stimulus responsive PA probes (source: J am Chem SOC.) interestingly, the authors found that the correlation between PA signal and extinction coefficient of these compounds was weak (Figure 5b), which was inconsistent with the data measured previously for red-hyp-1 analogues 1-6 The author speculates that the absorption coefficient and fluorescence quantum yield both affect the intensity of PA signal, so the author defines a similar PA brightness factor (pabf) to study the linear relationship between extinction coefficient and quantum yield and PA signal (Figure 5C) (source: J am Chem SOC.) later, the author calculated that each crab analog has a good effect on PA signal enhancement (Figure 6a) Based on this, the authors further compared the changes of PA signal of hyp-1, photonod-1, ome APC and their crab analogues after target stimulation (Figure 6b-d) The results showed that the PA signals of hyp-1 and photonod-1 were significantly enhanced compared with their crab analogues However, although the PA signal of crab ome APC responding to Cu (II) and its crab analogues should be increased in theory, they have not been improved in practice, which may be due to the low solubility of crab ome APC in water, which hinders its contact with free Cu (II) (source: J am Chem SOC.) finally, the author evaluated the potential of crab skeleton to improve PA in vivo by studying the PA imaging ability of hyp-1, red-hyp-1, crab-hyp and red crab-hyp in vivo In one hour, the probe and product were imaged with λ blue and λ red respectively (Figure 7a, b), and their PA signal enhancement was analyzed with semi quantitative method (Figure 7C) It was found that crab Hyp had better response to tumor hypoxia than hyp-1 (source: J am Chem SOC.) in a word, based on aza BODIPY dye and certain theoretical basis, the author focused on the influence of structural modification and photophysical parameter contrast ratio PA signal output for the first time, and designed and synthesized a series of functional and responsive PA imaging agents, which could reasonably design more molecules for excellent PA Imaging has taken an important step.
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