Synthesis And In Vitro Photodynamic Activities Of Boron Dipyrromethene-based Anticancer Photosensitizers

Photodynamic therapy(PDT)is a highly selective method for the treatment of tumors and non-neoplastic diseases.PDT is mainly composed of three components:light,oxygen and photosensitizers,in which the photosensitizers play the critical role and directly decide the efficiency of PDT.Boron dipyrromethene(BDP)is a new type of fluorescence dyes,BDPs as a new emerging class of photosensitizer is becoming the current hot research topic because of desirable properties such as high molar absorption coefficients,high photostability and synthetic versatility.Considering the deficiencies of photosensitizers,this thesis describes research on modification of BDP structure to improve the functional performance of BDP.Moreover,we report primary studies on photophysical,photochemical and in vitro biological activities of these BDP-based derivatives.Chapter 1 presents a brief review of development of PDT and photosensitizers,discusses the mechanism of PDT and introduces the synthesis of BDP and the current functional photosensitizers.Chapter 2 describes the design,synthesis and characterization of cationized BDP derivatives 8a and 3b substituted with three carboxyl groups.The photophysical,photochemical and in vitro biological properties of the two compounds have been studied.The result shows that:the water-soluble conjugates enhance the water solubility of photosensitizers.They are not aggregated significantly in the cell culture medium.Both of them have high singlet oxygen quantum yield(??),0.42 and 0.38 respectively.The two conjugates 8a and 3b exhibit higher photocytotoxicity in light toward HepG2 cancer cells with IC50 value as low as 0.16 ?M and 0.12 ?M respectively while value within Hela cancer cells are moving up to 0.26 ?M and 0.25?M respectively.Two photosensitizers have no obvious toxicity in dark.They are mainly located in mitochondria and lysosome of HepG2 and Hela cells.Chapter 3 As we know,trifluoromethyl groups is a well medicative groups which can improve the stability of drug metabolism.This chapter presents the synthesis,characterization,photophysical,photochemical and photobiological properties of two types of photosensitizers 3c and 3d conjugated with three or six trifluoromethyl groups.The results show that:the introduction of trifluoromethyl groups not decrease the solubility of photosensitizers.3c and 3d show some degree of aggregation in cell culture mediun,but mainly exist in monomer form.MTT assay shows that these two photosensitizers have high photocytotoxicity against HepG2 and Hela cancer cells.The IC50 value of 3c In HepG2 and Hela cancer cells are 0.49 ?M and 0.42 ?M respectively.The IC50 value are determined to be same 0.45 ?M when photosensitizer 3d towards both HepG2 and Hela cancer cells.Subcellular localization experiments show that the two compounds are most free in the nucle of HepG2 and Hela cells,but strongly distribute in mitochondria and lysosome.1H NMR and HRMS spectra of all the new compounds are given in Appendix.