Near-infrared boron dipyrromethene (BODIPY) compound based on duplex heterocyclic pyrrole group, and preparation method and application of BODIPY compound

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...

AI Technical Summary

Problems solved by technology

However, this type of photosensitizer has many shortcomings: (1) complex structure and difficult to synthesize and separate; (2) low absorption intensity in the transparent window range (650-900nm) of biological tissues; (3) slow elimination from the body, and Long-lasting photosensitivity damage to the skin

However, this type of compound still has the following disadvantages: (1) the singlet oxygen generation efficiency is not very high; (2) the photostability of the compound is extremely poor; (3) the dark toxicity is relatively high

[See: (a) Lavis, L.D.; Raines, R.T. ACSChem. Biol. 2008, 3, 142. (b) Mishra, A.; Behera, R.K.; Behera, P.K.; Mishra, B.B.; Behera, G.B.; , 100, 1973. (c) Wagner, R.W.; Lindsey, J.S. Pure Appl. Chem. 1996, 68, 1373. (d) Malinin, V.S.; Haque, Md.E.; Lentz, B.R. Biochemistry 2001, 40, 8292. (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, this kind of BODIPY dyes used in PDT mainly focus on simple BODIPY, styryl-modified BODIPY, and aza-BODIPY. However, these photosensitizers also have many defects: (1) Simple BODIPY absorbs light at around 500nm. 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

At present, 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. (c) Umezawa, K.; Matsui, A. ;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.;Citterio,D.;Oka,K.;Suzuki,K.Chem. 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

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