一种双亲性五甲川吲哚菁染料的合成及体外抗结直肠癌研究  

Synthesis and in vitro anti-colorectal cancer study of an amphipathic pentamethine indocyanine dye

作　　者：史霄 薄佳欣 李晓峰 林祥然 汤昆 SHI Xiao;BO Jia-xin;LI Xiao-feng;LIN Xiang-ran;TANG Kun(Department of Pharmacy,The First Affiliated Hospital of Henan University,Kaifeng 475001,China;College of Pharmacy,Henan University,Kaifeng 475001,China;College of Basic Medicine,Henan University,Kaifeng 475001,China)

机构地区：[1]河南大学第一附属医院药学部,河南开封475001 [2]河南大学药学院,河南开封475001 [3]河南大学基础医学院,河南开封475001

出　　处：《中国药物化学杂志》2023年第12期894-903,共10页Chinese Journal of Medicinal Chemistry

基　　金：河南省科技攻关项目(212102311019)。

摘　　要：目的设计合成键入多条醚链的双亲性五甲川吲哚菁染料Cy5-TEG,并研究其光疗抗结直肠癌活性。方法以对甲苯磺酰氯为起始原料,经取代、还原、Knoevenagel缩合反应等合成目标菁染料;通过紫外光谱、荧光光谱、胞外光热和光动力测试研究其光学性能;通过MTT法、胞内活性氧检测以及亚细胞器定位实验评价其体外抗结直肠癌活性。结果Cy5-TEG的结构经1H-NMR、13C-NMR和HR-ESI-MS确证。Cy5-TEG在水和DMSO两种溶剂中最大荧光发射峰分别为665 nm和673 nm,光稳定性较好,水中荧光量子产率为0.06,油水分配系数为1.2,在胞内外均能产生光热和单线态氧。Cy5-TEG能够蓄积在结直肠癌细胞SW480和HCT116的线粒体中,对两种细胞的暗毒性和光毒性的IC50值分别为6.51μmol·L^(-1)和8.38μmol·L^(-1)、2.01μmol·L^(-1)和1.21μmol·L^(-1),并通过光热和光动力的协同作用抑制肿瘤细胞增殖。结论Cy5-TEG是一种新型的双亲性五甲川吲哚菁染料,兼具近红外成像、线粒体定位、三重毒性等多种功能,是一种潜在的光疗抗结直肠癌光敏剂。The purpose of this study was to design and synthesize an amphiphilic pentamethine indocyanine dye(Cy5-TEG)with multiple ether chains incorporated,and to investigate its phototherapeutic properties against colorectal cancer.The target cyanine dye was synthesized from p-toluenesulfonyl chloride by substitution,reduction,Knoevenagel condensation and other reactions.The optical properties were tested through UV-visible spectroscopy,f luorescence spectroscopy,extracellular photothermal and photodynamic tests.Cy5-TEG exhibited maximum fluorescence emission spectra at 665 nm and 673 nm in water and DMSO,respectively.It demonstrated good photostability,and could generate photothermal and singlet oxygen both in extracellular and intracellular environments.The in vitro anti-colorectal cancer activity was evaluated using MTT assay,intracellular reactive oxygen species detection,and subcellular organelle localization.It could accumulate in the mitochondria of colorectal cancer cells SW480 and HCT116,exhibiting dark toxicity and phototoxicity with IC50 values of 6.51 and 8.38μmol·L^(-1),as well as 2.01 and 1.21μmol·L^(-1),respectively.The inhibition of tumor cell proliferation was mainly achieved through the synergistic effect of photothermal and photodynamic therapy.In general,this novel amphiphilic pentamethine indocyanine dye was a potential photosensitizer for anti-colorectal cancer.

关 键 词：多功能化疗药物 五甲川吲哚菁染料 双亲性 光谱性能 抗肿瘤 

分 类 号：R914[医药卫生—药物化学]