Proton response type meso-substituted corrorin derivative as well as preparation method and application thereof

Abstract

The invention discloses a proton response type meso-substituted corrorin derivative as well as a preparation method and application thereof, and belongs to the field of organic functional materials. The proton response type meso-substituted corrorin derivative disclosed by the invention is prepared from PhCOr, NPCor, AnCor and PyCor, and the structural formula of the proton response type meso-substituted corrorin derivative is shown in the description, the near-infrared absorption red shift under the acidic condition is realized mainly by regulating and controlling meso-site aryl substituent and protonation state, the absorption range can be expanded to 800-1100nm, and the process is reversible; related materials have wide application prospects in the fields of biological imaging, photo-thermal therapy, near-infrared electronic devices and the like of tumor subacid environment response.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic functional materials, and relates to a proton-responsive meso-substituted corrorin derivative as well as a preparation method and application thereof. BACKGROUND

[0002] Near-infrared (NIR) dyes are widely used in bioimaging, photothermal therapy, photoacoustic imaging and sensor fields due to their excellent tissue penetration and low autofluorescence background. The commonly used NIR dyes include cyanine dyes, BODIPY derivatives and aromatic porphyrinoids. However, in the known porphyrinoid matrix, the protonation-induced NIR response is usually limited to aromatic systems such as porphyrins and corroles, which have a limited spectral response range and weak intramolecular charge transfer (ICT) effect. NIR dyes are often used for the diagnosis and treatment of cancer, and the tumor environment is acidic. However, there are few reports on acid-triggered near-infrared absorption in porphyrinoid compounds.

[0003] Corrorin (structural isomer of corrole) is a double N-inverted non-aromatic porphyrinoid with a unique electronic structure, but its optical regulation characteristics have not been fully developed, especially the pH responsiveness and NIR region absorption regulation are rarely reported. Based on the non-aromaticity and unique electronic structure of corrorin, further introduction of substituents at the meso position (bridging carbon atoms between pyrrole rings) is expected to break through the limitation of traditional porphyrinoid systems mainly relying on aromaticity to enhance the ICT effect, accurately adjust the ICT effect and proton response performance, and realize pH-triggered controllable spectral regulation. SUMMARY

[0004] In view of the problems in the prior art, the present application provides a kind of meso-substituted corrorin derivative and its preparation method and application, which realizes reversible regulation of near-infrared absorption by regulating its 15-position substituent and protonation state.

[0005] To achieve the above technical purpose, the present application provides the following technical scheme:

[0006] The present application first provides a kind of meso-substituted corrorin derivative, the structural formula is as follows:

[0007]

[0008] Among them, R1 includes phenyl, p-nitrophenyl, anthryl and 2,6-dichloropyridyl.

[0009] Further, the meso-substituted corrorin derivative has a protonation site, which includes an internal pyrrole nitrogen and / or a nitrogen atom on R1.

[0010] The application further provides a preparation method of the meso-substituted corrorin derivative, which comprises:

[0011] The N-confused tripyrrane and the aromatic aldehyde are dissolved in anhydrous CH2Cl2, and after stirring and mixing under a nitrogen atmosphere, a reaction solution is obtained, and after pre-cooling, an acid is added for condensation reaction; after the reaction is completed, 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ) is added for oxidation reaction, and after the reaction is completed, the meso-substituted corrorin derivative is obtained.

[0012] The equivalents of the N-confused tripyrrane, the aromatic aldehyde and CH2Cl2 are 0.36 mmol: 0.18 mmol: 50 mL; and the stirring and mixing time is 20 min.

[0013] The aromatic aldehyde includes benzaldehyde, 4-nitrobenzaldehyde, 9-anthracene formaldehyde and 3, 5-dichloropyridine-4-formaldehyde.

[0014] The acid is p-toluenesulfonic acid, and the equivalent is 0.054 mmol; the pre-cooling temperature is 0℃, and the temperature when the acid is added is 0℃.

[0015] The condensation reaction condition is stirring at room temperature for 1 h.

[0016] The equivalent of the DDQ is 1.08 mmol.

[0017] The oxidation reaction condition is stirring at room temperature for 6 h.

[0018] The application of the meso-substituted corrorin derivative in preparing near-infrared dyes.

[0019] The meso-substituted corrorin derivative or the near-infrared dye prepared by the meso-substituted corrorin derivative has any one of the following applications:

[0020] (1) preparing a reagent for biological imaging; or

[0021] (2) preparing a reagent for photothermal therapy; or

[0022] (3) preparing a contrast agent for photoacoustic imaging; or

[0023] (4) preparing an acid-responsive near-infrared optoelectronic device.

[0024] Preferably, the bioimaging reagent comprises a reagent for imaging in response to a tumor acidic microenvironment.

[0025] Compared with the prior art, the present application has the following beneficial effects:

[0026] (1) The present application first introduces meso-substitution regulation on a non-aromatic corrole framework, and four corrole derivatives, PhCor, NPCor, AnCor and PyCor, are prepared; the present application precisely adjusts ICT effect and proton response performance through electronic properties and spatial orientation regulation of the meso-substituent, and exhibits good molecular designability; at the same time, the preparation method provided by the present application is simple, easy to operate, and suitable for industrial production.

[0027] (2) The four corrole derivatives provided by the present application are verified by experiments, and in the process of adding TFA, the Q bands of the four corrole derivatives all appear different degrees of red shift, realizing efficient protonation-induced charge transfer (ICT) process, and breaking through the limitation that traditional porphyrinoid systems mainly rely on aromaticity to enhance ICT; further, the absorption of the four corrole derivatives provided by the present application after protonation can be expanded to more than 1000 nm, covering the NIR-II window, which is obviously superior to the spectral range of traditional porphyrin, corrole and other similar dyes; at the same time, the protonation and deprotonation process is highly reversible, realizing controllable spectral regulation triggered by pH, and having potential for repeated use.

[0028] (3) The four corrole derivatives provided by the present application are highly sensitive to weakly acidic environment, and are particularly suitable for near-infrared imaging, photothermal therapy and development of acidic response near-infrared optoelectronic devices in a tumor micro-acidic environment, and have important medical application prospects. BRIEF DESCRIPTION OF DRAWINGS

[0029] Figure 1 is a Hill plot of the protonation process of PhCor.

[0030] Figure 2 is a Hill plot of the protonation process of NPCor.

[0031] Figure 3 is a Hill plot of the protonation process of AnCor.

[0032] Figure 4 is a Hill plot of the protonation process of PyCor.

[0033] Figure 5Schematic diagram of UV / vis / NIR absorption spectra of corrorin derivatives PhCor (a), NPCor (b), AnCor (c) and PyCor (d) before and after protonation.

[0034] Figure 6 UV / vis / NIR absorption spectra of PyCor in neutral state, protonated state (with TFA) and deprotonated state (with TEA) in dichloromethane, in which the small figures are the real photos of TFA and TEA solutions in dichloromethane.

[0035] Figure 7 Schematic diagram of the application of corrorin derivatives in bioimaging or photothermal therapy. DETAILED DESCRIPTION

[0036] The technical solutions of the present application are further described below through specific examples. It should be understood that the examples are preferred solutions of the present application, which are intended to assist in understanding the technical content of the present application, but not to limit the protection scope of the present application. Without deviating from the basic concept of the present application, those skilled in the art can make various substitutions, equivalent improvements or combined applications, which should be considered to fall within the protection scope of the present application.

[0037] In the following description, many specific details are set forth in order to provide a thorough understanding of the present application. However, the present application can be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the concept of the present application, so the present application is not limited to the specific examples disclosed below.

[0038] 1 HNMR spectra were recorded by Bruker AVANCE II 400 spectrometer (400 MHz) in deuterated chloroform (CDCI3). High resolution mass spectrometry (HRMS) was obtained in two ways: one was on a JEOL LMS-HX-110 spectrometer in fast atom bombardment (FAB) mode using 3-nitrobenzyl alcohol (NBA) as a matrix; the other was on a Thermo Fisher QExactive Focus spectrometer in electrospray ionization (ESI) mode.

[0039] UV / visible / near infrared spectra were recorded on a Shimadzu (Japan) UV-1780 spectrophotometer. Cyclic voltammetry experiments were carried out in a nitrogen-filled electrolytic cell with an electrolyte of dry dichloromethane solution containing 0.1 M tetrabutylammonium perchlorate (TBAP) (dichloromethane was treated by calcium hydride under reduced pressure distillation), and the scanning rate was 100 mV / s. The working electrode was a glassy carbon electrode, the counter electrode was a platinum wire electrode, and the reference electrode was a saturated calomel electrode (SCE).

[0040] The UV-Vis-NIR titration experiment and TEA deprotonation experiment by TFA in this example are all conventional methods in the art.

[0041] Example 1: Synthesis of PhCor

[0042] The derivative synthesized in this example is a meso-substituted corrorin derivative PhCor, in which R1 is phenyl, and its structural formula is as follows:

[0043]

[0044] The synthesis steps are as follows:

[0045] Dissolve N-confused tripyrrane (200 mg, 0.36 mmol) and benzaldehyde (18.4 μL, 0.18 mmol) in anhydrous CH2Cl2(50 mL) and stir at room temperature under nitrogen atmosphere for 20 min; after stirring is complete, pre-cool to 0 °C and add p-TSA (10.3 mg, 0.054 mmol, 0 °C), and stir at room temperature for 1 h; then add DDQ (245.2 mg, 1.08 mmol), and after mixing well, stir the mixture overnight.

[0046] After the reaction is complete, filter the mixture through a short neutral alumina column, and remove the solvent under reduced pressure. Purify the crude product by silica gel column chromatography (eluent: dichloromethane / n-hexane = 1:1, v / v). Collect the first red fraction and evaporate to obtain PhCor as a reddish solid (4.9 mg, yield 2.3%).

[0047] 1 H NMR (400 MHz, CDC13, 298 K) spectral data: δ = 14.58 (s, 1H), 12.61 (s, 2H), 7.41 (d, J = 4.3 Hz, 4H), 7.35 (d, J = 2.8 Hz, 1H), 7.29 (s, 2H), 6.97-6.88 (m, 4H), 6.44 (s, 2H), 6.27 (dd, J = 4.0, 2.3 Hz, 2H), 6.21 (d, J = 3.9 Hz, 2H).

[0048] High resolution mass spectrum (FAB) [M + ](m / z): 1192.1430 (C 59 H 20 F 20 N6calculated 1192.1430).

[0049] 19F NMR (376MHz, CD2Cl2, 298K): δ=–137.29 (dd, J=26.3, 7.5Hz, 4F), –139.02 (dd, J=23.9, 7.8Hz, 4F), –151 .45 (t, J=21.0Hz, 2F), –152.15 (t, J=21.0Hz, 2F), –160.31–160.58 (m, 4F), –160.86 (td, J=18.8Hz, 4F).

[0050] UV / Vis / NearInfrared Spectra (in dichloromethane): λmax(nm)(ε(M) -1 cm -1 ))=545(56500),772(9930).

[0051] By processing the product 1 Analysis using 1H NMR spectroscopy, high-resolution mass spectrometry, and ultraviolet / visible / near-infrared spectroscopy confirmed that the product obtained in this embodiment is the product shown in the structural formula, and it is named PhCor.

[0052] Example 2: Synthesis of NPCor

[0053] The synthesized product in this embodiment is NPCor, a meso-substituted corrorin derivative in which R1 is p-nitrophenyl, and its structural formula is as follows:

[0054]

[0055] The crafting method for NPCor is basically the same as that for PhCor, with the following differences:

[0056] The starting materials were N-confused tripyrrane (200 mg, 0.36 mmol) and 4-nitrobenzaldehyde (27.2 mg, 0.18 mmol). The crude product was purified by silica gel column chromatography (eluent: dichloromethane / n-hexane = 1:1 (v / v)), and the first red fraction was collected. After evaporation, NPCor was obtained as a slightly red solid (2.7 mg, yield 1.2%).

[0057] High-resolution mass spectrometry (ESI) [M+H] + (m / z): 1238.1353 (C 59 H 19 F 20 The calculated value of N7 is 1237.1281.

[0058] 1H NMR (400MHz, CDCl3, 298K): δ=14.56 (s, 1H), 12.75 (s, 2H), 8.28–8.24 (m, 1H), 7.53 (d, J=6.4Hz, 4H), 7.35 (t, J=5.1, 2.2Hz, 3H), 7.31 (s, 1H), 7.13 (dd, J=8.6, 2.5Hz, 3H), 6.90 (d, J=5.1Hz, 1H), 6.46 (s, 1H), 6.29 (dd, J=4.0, 2.3Hz, 1H), 6.23 (d, J=4.0Hz, 1H).

[0059] 19 F NMR (376MHz, CDCl3) δ=–137.29––137.46 (m, 2F), –137.79 (d, J=23.1Hz, 2F), –138.95 (d, J=7.9Hz, 2F), –139.01 (d, J=7 .9Hz, 2F), –151.30 (t, J=21.2Hz, 2F), –151.93 (t, J=21.1Hz, 2F), –160.10––160.33 (m, 4F), –160.39––160.53 (m, 4F).

[0060] UV / Vis / NearInfrared Spectra (in dichloromethane): λmax(nm)(ε(M) -1 cm -1 ))=523(61200),739(11460).

[0061] By processing the product 1 Analysis using 1H NMR spectroscopy, high-resolution mass spectrometry, and ultraviolet / visible / near-infrared spectroscopy confirmed that the product obtained in this embodiment is the product shown in the structural formula, and it is named NPCor.

[0062] Example 3: Synthesis of AnCor

[0063] The synthesized product in this embodiment is AnCor, a meso-substituted corrorin derivative in which R1 is an anthracene group, and its structural formula is as follows:

[0064]

[0065] The synthesis method of AnCor is basically the same as that of PhCor, with the only differences being the following:

[0066] Starting from N-confused tripyrrane (200 mg, 0.36 mmol) and 9-anthraldehyde (37.1 mg, 0.18 mmol). The crude product was purified by column chromatography on silica gel (eluent: dichloromethane / n-hexane = 1 : 1 (v / v)) and the first red fraction was collected and evaporated to yield AnCor as a reddish solid (2.7 mg, 1.2% yield).

[0067] High resolution mass spectrum (ESI) [M+H + ](m / z): 1293.1669 (C 67 H 24 F 20 Calculated for N6 1292.1743).

[0068] 1 H NMR (400 MHz, CDC13, 298 K): δ = 15.37 (s, 1H), 12.74 (s, 1H), 8.53 (s, 1H), 8.04 (d, J = 8.5 Hz, 2H), 7.94 (d, J = 9.0 Hz, 2H), 7.45 (ddd, J = 8.3, 6.5, 1.2 Hz, 2H), 7.36 (ddd, J = 8.1, 6.5, 1.3 Hz, 2H), 7.31 (s, 2H), 6.77-6.72 (m, 2H), 6.50 (s, 2H), 6.30 (dd, J = 4.0, 2.4 Hz, 2H), 6.25 (d, J = 3.9 Hz, 3H), 6.14 (d, J = 5.0 Hz, 2H).

[0069] 19 F NMR (376 MHz, CD2C12, 298 K): δ = -137.29 (dd, J = 22.7, 7.4 Hz, 2F), -137.59 - 137.75 (m, 2F), -139.00 (dd, J = 23.8, 7.8 Hz, 4F), -151.59 (t, J = 20.7 Hz, 2F), -152.76 (t, J = 20.7 Hz, 2F), -160.34 (qd, J = 23.5, 8.4 Hz, 4F), -160.85 (td, J = 22.8, 21.9, 7.5 Hz, 4F).

[0070] UV / Vis / near-IR spectrum (in dichloromethane): λmax(nm) (ε (M -1 cm -1 )) = 530 (59440), 742 (11560).

[0071] The product was identified by performing 1HNMR, high resolution mass spectrometry and UV / visible / near infrared spectroscopy confirmed that the product obtained in this example was the product shown in the structural formula, named AnCor.

[0072] Example 4: Synthesis of PyCor

[0073] Synthesized in this example was a meso-substituted corrorin derivative, PyCor, in which R1was 2,6-dichloropyridyl, and its structural formula was as follows:

[0074]

[0075] The synthesis method of PyCor was basically the same as that of PhCor, with the following differences:

[0076] N-confused tripyrrane (200 mg, 0.36 mmol) and 3,5-dichloropyridine-4- carboxaldehyde (31.7 mg, 0.18 mmol) were used as starting materials. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / n-hexane = 1:1 (v / v)), and the first red fraction was collected and evaporated to obtain PyCor as a reddish solid (14 mg, yield 6.2%).

[0077] High resolution mass spectrometry (ESI) [M+H + ](m / z): 1262.0679 (calcd. for C 59 H 17 Cl2F 20 N7: 1262.0603).

[0078] 1 HNMR (400 MHz, CDC13) δ = 15.28 (s, 1H), 12.62 (s, 2H), 8.60 (s, 2H), 7.31 (s, 1H), 6.90 (dt, J = 5.1, 2.4 Hz, 2H), 6.52 (d, J = 5.1 Hz, 2H), 6.45 (s, 2H), 6.29 (dd, J = 4.0, 2.3 Hz, 2H), 6.24 (d, J = 4.0 Hz, 2H).

[0079] 19F NMR (376MHz, CDCl3, 298K): δ=–137.29––137.45 (m, 2F), –137.54 (ddd, J=23.2, 8.3, 4.1Hz, 2F), –139.02 (dd, J=23.9, 7.8H z, 4F), –151.45 (t, J=21.0Hz, 2F), –152.15 (t, J=21.0Hz, 2F), –160.30 (t, J=22.5Hz, 4F), –160.56 (td, J=22.7, 7.6Hz, 4F).

[0080] UV / Vis / NearInfrared Spectra (in dichloromethane): λmax(nm)(ε(M) -1 cm -1 ))=526(62100),712(11500).

[0081] By processing the product 1 Analysis using 1H NMR spectroscopy, high-resolution mass spectrometry, and ultraviolet / visible / near-infrared spectroscopy confirmed that the product obtained in this embodiment is the product shown in the structural formula, and it is named PyCor.

[0082] Example 5: Protonation behavior of four corrorin derivatives

[0083] The protonation behavior of four corrorin derivatives was studied by UV-Vis-NIR titration experiments using trifluoroacetic acid (TFA) and protonation using TFA equivalents of 0, 2.5, 5, 10, and 100.

[0084] The results are as follows Figures 1-4 As shown in the Hill plots, PhCor, NPCor, AnCor, and PyCor all exhibit significant color shifts in their absorption spectra upon the addition of TFA; among them, Figures 1-3 The slope values ​​of PhCor, NPCor, and AnCor shown are approximately 3, indicating the absorption of three protons: one on the inner pyridine nitrogen atom and two on the outer pyridine nitrogen atom; in contrast, Figure 4 The slope of PyCor shown is 4.2, indicating that the nitrogen of the electron-deficient 2,6-dichloropyridinyl group underwent an additional protonation event; this additional protonation site is the reason for its increased protonation ability.

[0085] like Figure 5The shown ultraviolet-visible-NIR spectrum shows that the Q band of PhCor red shifts from 772 nm to 944 nm; the Q band of NPCor red shifts from 739 nm to 896 nm; the Q band of AnCor red shifts from 742 nm to 865 nm; the Q band of PyCor red shifts from 712 nm to 808 nm; the Q bands of the four corrorin derivatives all appear red shifts to different degrees, wherein PhCor shows the most obvious red shift (Δλ=172 nm) in the Q band; it is shown that the four corrorin derivatives all have adjustable ICT characteristics to respond to the change of PH value; and according to the spectrum shown in Figure 5 , the absorption of the four corrorin derivatives after protonation can be expanded to more than 1000 nm, covering the NIR-II window; it is embodied that the spectral range is superior to that of traditional porphyrin, corrole and other similar dyes.

[0086] Taking PyCor as an example, triethylamine (TEA) deprotonation experiment is carried out, and the result is shown in Figure 6 , from the figure, it can be known that the proton response near-infrared absorption performance of the corrorin derivative (PyCor) has a significant regulation effect, and the protonation process is reversible; and the application of the corrorin derivative in tumor acid microenvironment response imaging, preparation of photothermal treatment reagents, preparation of photoacoustic imaging contrast agents and preparation of acid response near-infrared optoelectronic devices is provided.

[0087] Embodiment 6: Application of the four corrorin derivatives

[0088] Based on the content of the embodiment 5 part of the present application, it can be known that the four corrorin derivatives prepared by the present application all have good acid response near-infrared absorption ability, and can be used as photothermal agents for photothermal treatment and contrast agents for photoacoustic imaging.

[0089] The experimental simulation diagram is shown in Figure 7 , after intravenous injection, the corrorin derivative is enriched in tumor cells, because the intracellular environment of tumor cells is acidic, the corrorin derivative is protonated and red shifted, and the absorption at the emission wavelength of common near-infrared lasers such as 808 nm and 980 nm is enhanced, so the photothermal conversion ability is enhanced. After infrared laser irradiation, the corrorin derivative produces heat to induce tumor cell apoptosis; at the same time, the heating of the surrounding environment produces vibration, which is detected by an ultrasonic probe and used for ultrasonic imaging of tumors, that is, photoacoustic imaging.

Claims

1. A meso-substituted corrorin derivative, characterized in that, The structural formula is as follows: R1 includes phenyl, p-nitrophenyl, anthracene, and 2,6-dichloropyridyl.

2. The meso-substituted corrorin derivative according to claim 1, characterized in that, The meso-substituted corrorin derivative has a protonation site, which includes an inner and outer pyrrole nitrogen and / or a nitrogen atom on R1.

3. The method for preparing the meso-substituted corrorin derivative according to claim 1 or 2, characterized in that, The method includes: N-confused tripyrrane and aromatic aldehydes were dissolved in anhydrous CH2Cl2 and stirred under a nitrogen atmosphere to obtain a reaction solution. After pre-cooling, an acid was added to carry out a condensation reaction. After the reaction was completed, DDQ was added to carry out an oxidation reaction. After the reaction was completed, meso-substituted corrorin derivatives were obtained.

4. The method according to claim 3, characterized in that, The equivalent amounts of N-confused tripyrrane, aromatic aldehyde, and CH2Cl2 were: 0.36 mmol: 0.18 mmol: 50 mL; the mixing time was 20 min.

5. The method according to claim 3, characterized in that, The aromatic aldehydes include benzaldehyde, 4-nitrobenzaldehyde, 9-anthracarbaldehyde, and 3,5-dichloropyridine-4-carbaldehyde.

6. The method according to claim 3, characterized in that, The acid is p-toluenesulfonic acid, with an equivalent of 0.054 mmol; the pre-cooling temperature is 0°C, and the temperature at which the acid is added is 0°C.

7. The method according to claim 3, characterized in that, The conditions for the condensation reaction are: stirring at room temperature for 1 hour.

8. The method according to claim 3, characterized in that, The equivalent of the DDQ is 1.08 mmol; The oxidation reaction was carried out under the condition of stirring at room temperature for 6 hours.

9. The use of the meso-substituted corrorin derivative as described in claim 1 or 2, or the meso-substituted corrorin derivative prepared by the preparation method described in any one of claims 3-8, in the preparation of near-infrared dyes.

10. The meso-substituted corrorin derivative of claim 1 or 2, or the near-infrared dye prepared from the meso-substituted corrorin derivative, includes any of the following applications: (1) Preparation of reagents for biological imaging; or (2) Preparation of reagents for photothermal therapy; or (3) Prepare a contrast agent for photoacoustic imaging; or (4) Prepare an acid-responsive near-infrared optoelectronic device.

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