Near-infrared fluoroboron dipyrrole compound based on bilinked heterocyclic pyrrole group and its preparation method and use

A technology of fluoroborate dipyrrole and pyrrole group, which is applied in the field of preparing photosensitizers in photodynamic therapy, can solve the problems of low absorption intensity, no test cell photodynamic therapy effect, low efficiency of BODIPY, etc., and achieve triplet efficiency increase Large, attractive application prospects, and the effect of improving efficiency

Inactive Publication Date: 2015-08-26
NANJING UNIV
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  • Abstract
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Problems solved by technology

But there are many deficiencies in this class of photosensitizers: (1) the complex structure is not easy to synthesize and separate; (2) the absorption intensity is very low in the transparent window range (650-900nm) of biological tissues; (3) it is slower to be eliminated from the body, and Long-lasting photosensitivity damage to the skin
However, these compounds still have the following disadvantages: (1) the generation efficiency of singlet oxygen is not very high; (2) the photostability of the compound is extremely poor; (3) the dark toxicity is relatively large
[See: (a) Lavis, L.D.; Raines, R.T. ACS Chem. Biol. 2008, 3, 142. (b) Mishra, A.; Behera, R.K.; Behera, P.K.; Mishra, B.B.; Behera, G.B.; Chem. Rev. 2000, 100, 1973. (c) Wagner, R.W.; Lindsey, J.S. Pure Appl. Chem. 1996, 68, 1373. (d) Malinin, V.S.; Haque, Md.E.; (e) Luedtke, N.W.; Carmichael, P.; Tor, Y.J. Am. Chem. Soc. 2003, 125, 12374. (e) Rurak, K.; .] However, the triplet efficiency of BODIPY dyes is very low, which is not conducive to the generation of singlet oxygen. Therefore, scientists thought of the heavy atom effect and increased its triplet efficiency by introducing heavy atoms such as bromine and iodine into the BODIPY structure , thereby increasing the efficiency of singlet oxygen
At present, these BODIPY dyes are mainly used in PDT for simple BODIPY, styryl-modified BODIPY, and aza-BODIPY. However, these photosensitizers also have many defects: (1) simple BODIPY absorbs light at about 500nm, and light The permeability in the tissue is not good, and the efficiency of singlet oxygen is low; (2) the efficiency of styryl-substituted BODIPY is relatively low; (3) aza-BODIPY is not easy to synthesize and separate, and its water solubility is poor and at a slightly higher Strong dark cytotoxicity at high concentrations
Currently, there are few reports on BODIPY dyes based on this thiophene-fused pyrrole, [see: (a) Awuah, S.G.; Polreis, J.; Biradar, V.; You, Y.Org.Lett.2011, 13, 3884. (b) Umezawa, K.; Nakamura, Y.; Makino, H.; Citterio, D.; Suzuki, K.J.Am.Chem.Soc.2008, 130, 1550. ; Nakamura, Y.; Citterio, D.; Suzuki, K. Chem. Eur. J. 2009, 15, 1096. (d) Landrum, M.; Smertenko, A.; Edwards, R.; Hussey, P.k J. ; Steel, P.G. Plant J. 2010, 62, 529. (e) Matsui, A.; Umezawa, K.; Shindo, Y.; Fujii, T.; Commun., 2011, 47, 10407.] Among them, only the first article is used in singlet oxygen, but the efficiency is not very ideal and the effect of photodynamic therapy in cells is not tested
There is only one patent for this type of BODIPY [see: Suzuki, K.; Umezawa, K. et al. PCT Int. Appl. (2007) 154pp.], and this patent is not used in photodynamic therapy

Method used

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  • Near-infrared fluoroboron dipyrrole compound based on bilinked heterocyclic pyrrole group and its preparation method and use
  • Near-infrared fluoroboron dipyrrole compound based on bilinked heterocyclic pyrrole group and its preparation method and use
  • Near-infrared fluoroboron dipyrrole compound based on bilinked heterocyclic pyrrole group and its preparation method and use

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] The synthesis of embodiment 1.BODIPY-A1:

[0039]

[0040]Add 1mmol (164mg) p-methoxyformylbenzaldehyde, 2mmol (410mg) dithienopyrrole, and 40ml anhydrous dichloromethane into a 100ml round bottom flask, put in a magnet and start stirring, avoid light and protect with argon A drop of trifluoroacetic acid (TFA) was injected into the lower syringe, and reacted at room temperature for 12 hours. After that, add 1mmol DDQ (227mg), react for 1 hour, then add 2ml triethylamine (TEA) and 2ml BF every ten minutes 3 ·Et 2 O, a total of 3 times, then stirred for 1 hour. Water quenching reaction, NaHCO 3 Wash with water, saturated brine successively, anhydrous Na 2 SO 4 Dry, evaporate the solvent under reduced pressure to obtain a black powder, use 100-140 mesh silica gel column, ethyl acetate-petroleum ether as eluent for chromatographic separation, evaporate the solvent to a golden solid, and the yield is 95%, after chloroform and Golden crystals were obtained after recr...

Embodiment 2

[0043] The synthesis of embodiment 2.BODIPY-A2, A3, A4:

[0044]

[0045] Add 0.17mmol (100mg) of BODIPY-A1 prepared in Example 1, 1.02mmol (182mg) of NBS and 30ml of tetrahydrofuran (THF) into a 100ml bottom flask, and stir at room temperature for 6 hours. Sodium thiosulfate solution quenched the reaction, washed with water and saturated brine successively, anhydrous Na 2 SO 4 Dry, evaporate the solvent under reduced pressure to obtain a black powder, use a 100-140 mesh silica gel plate, 20% ethyl acetate / petroleum ether for chromatographic separation, and obtain BODIPY-A2, A3, and A4 with yields of 23% and 57% respectively , 20%. BODIPY-A2 UV 693nm, emission 728nm. MALDI-TOF-MS m / z:calcd 760.842,found:758.402[M-2H] + ,737.428[M-H 3 F] + . BODIPY-A3 UV 698nm, emission 724nm. MALDI-TOF-MS m / z:calcd839.213,found:838.219[M-H] + ,821.072[M-F] + . BODIPY-A4 UV 692nm, emission 727nm. MALDI-TOF-MS m / z:calcd 918.110,found:917.235[M-H] + ,898.676[M-HF] + . See attach...

Embodiment 3

[0048] The synthesis of embodiment 3.BODIPY-A5:

[0049]

[0050] In a 100ml bottom flask add 0.17mmol (100mg) BODIPY-A1, 17.0mmol (2.72g) NBS and 30ml CHCl 3 , stirred at room temperature for 1 hour. Quenched reaction with NaOH solution, washed with water and saturated brine successively, anhydrous Na 2 SO 4 After drying, the solvent was evaporated under reduced pressure to obtain a black powder, which was packed into a 100-140 mesh silica gel column with chloroform as the eluent for chromatographic separation, and evaporated to dryness to obtain a reddish-brown powder. Yield 93%. UV: 633nm, Emission: 723nm. MALDI-TOF-MSm / z:calcd1233.694,found:1212.405[M-H 2 F] + ,1152.502[M-H 2 Br] + . NMR spectrum see attached image 3 .

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Abstract

A near-infrared boron dipyrromethene (BODIPY) compound based on a duplex heterocyclic pyrrole group has the structure as follows (refer to the Specification), wherein the substituent group M, N, P, E, F, M', N', P', E' or F' refers to H or Br. The invention synthesizes a big conjugated BODIPY photosensitizer taking duplex thieno pyrrole as a parent for the first time. Due to introduction of two thiophene groups, the absorption spectrum of the photosensitizer is shifted to 680 to 720 nm in a red shift mode, the emission peak is 716 to 750 nm and is in the range (650 to 900 nm) of a biological window, and the fluorescence quantum efficiency of the dye is high. The molar absorption coefficient of the photosensitizer in solution is up to 200,000 M<-1>cm<-1>. S in the two thiophene groups refers to heavy atoms, so that the triplet efficiency of the photosensitizer is increased, the generation efficiency of singlet oxygen is increased, and attractive application prospect in the aspects of bioimaging and photodynamic therapy is achieved.

Description

technical field [0001] The invention relates to a series of near-infrared BODIPY based on a bilinked heterocyclic pyrrole group, a preparation method thereof and an application in preparing a photosensitizer in photodynamic therapy. Background technique [0002] In recent years, photodynamic therapy (PDT) has attracted more and more attention as a minimally invasive means and method for treating various cancers. This is a photosensitization reaction accompanied by biological effects involving oxygen molecules. The process is that the photosensitizer absorbed by the tissue is excited by the laser irradiation of a specific wavelength, and the photosensitizer in the excited state transitions from the singlet state to the triplet state through the intersystem crossing process (ISC), and then transfers the energy to the surrounding Oxygen molecules generate highly active singlet oxygen, which undergoes oxidation reactions with adjacent biomacromolecules, resulting in cytotoxicit...

Claims

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Application Information

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Patent Type & AuthorityPatents(China)
IPC IPC(8): C07F5/02C09B57/00C09K11/06A61K49/00A61K41/00A61P35/00
Inventor沈珍杨永超
OwnerNANJING UNIV